WO1995017890A1 - Method of treatment of traumatic brain injury - Google Patents
Method of treatment of traumatic brain injury Download PDFInfo
- Publication number
- WO1995017890A1 WO1995017890A1 PCT/US1994/014401 US9414401W WO9517890A1 WO 1995017890 A1 WO1995017890 A1 WO 1995017890A1 US 9414401 W US9414401 W US 9414401W WO 9517890 A1 WO9517890 A1 WO 9517890A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- lower alkyl
- injury
- compound
- hydrogen
- Prior art date
Links
- 0 CC**(CCC(C*1*)[C@](C(C2O3)(O)OCC2O)(C3=O)O)CCC1=O Chemical compound CC**(CCC(C*1*)[C@](C(C2O3)(O)OCC2O)(C3=O)O)CCC1=O 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Definitions
- the present invention is directed to a method of
- TBI TBI injuries
- Intracranial hypertension (IH) following traumatic brain injury is associated with direct effects on cerebral perfusion which may be responsible for secondary ischemia.
- abnormalities in vascular permeability is characteristic of acute inflammation.
- the present invention now provides a method of treatment of traumatic brain injuries in mammals, including humans, by administering to a mammal suffering from traumatic brain injury a therapeutically effective amount of a butyrolactone derivative of the formula
- R is selected from the group consisting of hydrogen and lower alkyl
- R 2 is selected from the group consisting of hydrogen, lower alkyl and CH 3 YCH 2 -;
- R 5 and R 6 are selected from the group consisting of hydrogen and lower alkyl and may be the same or different;
- R 8 is selected from the group consisting of hydrogen and lower alkyl
- R 7 may be R 8 or
- R 9 is selected from the group consisting of and ;
- R 10 and R 11 are selected from the group consisting of hydrogen, lower alkyl, phenyl and hydroxyl substituted lower alkyl and may be the same or different;
- R 7 when R 7 contains a hydroxyl group in the ⁇ , ⁇ or position, R 7 may form the hemiketal ring closure at carbon 3 of the
- R 12 is selected from the group consisting of hydrogen, lower alkyl and lower haloalkyl
- R 13 is lower alkyl
- n 2, 3 or 4;
- n 1, 2 or 3;
- x is O, S or NH
- Y is O or S.
- butyrolactone derivatives for treatment of inflammation in mammals, such as acute inflammation.
- none of the prior art has proposed the use of compounds (I) to (V) for the treatment of traumatic brain injury.
- the compounds (I) to (V) for the treatment of traumatic brain injury.
- nonsteroidal anti-inflammatory drugs is not likely to be successful due to a number of factors, including the inability of conventional anti-inflammatory agents to cross the blood-brain barrier. It was therefor unexpected that the
- butyrolactone derivatives used in the present invention would be useful in the treatment of traumatic brain injury.
- R 12 is lower alkyl
- m is 2, 3 or 4
- R 13 is hydrogen, lower alkyl or lower haloalkyl and Y is O or S.
- Methoxatone which has the formula
- a suitable daily dosage for obtaining attenuation of the effects of traumatic brain injury is from about 10 to about 1000 mg/kg body weight, although the optimum dosage of the compound (I) to (V) will be determined by the physician taking into account the age, weight and general health of the subject.
- the daily dosage may also be administered in one or several treatments over a period of time, such as by way of single or multiple doses per day or from sustained release compositions.
- the compounds (I) to (V) may be administered alone or, more usually, in the form of a pharmaceutical composition comprising a therapeutically effective amount of the active agent in combination with an inert pharmaceutically acceptable diluent or carrier therefor.
- a pharmaceutical composition comprising a therapeutically effective amount of the active agent in combination with an inert pharmaceutically acceptable diluent or carrier therefor.
- the choice of the diluent or carrier will be determined by the route of administration, the solubility of the compound and standard pharmaceutical
- Oral and parenteral dosage units will be prepared in accordance with standard procedures and may contain the selected active compound (I) - (V) as the only or principal active ingredient in the composition.
- Any of a wide variety of known inert excipients may be employed to prepare useful compositions. These include, for example, dextrose, starch, talc, various types of clay, mineral oil, cottonseed or sesame oil, as well as water or various miscible and immiscible aqueous compositions in which the therapeutic agent is soluble or may be suspended with the aid of known surfactants.
- the active ingredient can be formulated in tablet form with water-soluble binding agents, such as lactose or other palatable
- suppositories or inserts containing the active ingredient dispersed in such reagents as cocoa butter, petrolatum, or other natural lubricants or in a synthetic emollient such as polyethylene glycol 1000 or polyethylene glycol 4000 may be used.
- compositions suitable for such preparations are known and can be usefully employed.
- the selected therapeutic agent may be in a time disintegrating tablet or pellet coated with various thicknesses of known materials such as carnauba wax, cellulose esters and ethers, fats, keratin, gluten or various natural or synthetic esters. Tablets in which the selected agent is contained in a slowly dissolving core such as dehydrogenated castor oil or fatty acids can also be employed.
- the active agent may be in a time disintegrating tablet or pellet coated with various thicknesses of known materials such as carnauba wax, cellulose esters and ethers, fats, keratin, gluten or various natural or synthetic esters. Tablets in which the selected agent is contained in a slowly dissolving core such as dehydrogenated castor oil or fatty acids can also be employed.
- the active agent may be in a time disintegrating tablet or pellet coated with various thicknesses of known materials such as carnauba wax, cellulose esters and ethers, fats, keratin
- ion exchange resin such as a sulfuric acid type cation exchange resin.
- transdermal formulations are possible for use in the practice of this invention. They are discrete dosage forms in construction systems which, when applied to the skin, deliver the therapeutic agent through the skin at a controlled rate for systemic circulation.
- a transdermal device typically comprises an outer covering barrier, a drug reservoir which may have a rate of release controlling membrane, a contact adhesive applied to some or parts of the device at the
- the drug reservoir is normally some type of polymer matrix such as a polyvinylpyrrolidone or a silicone polymer from which the drug is slowly released.
- a microporous membrane such as a polypropylene film may serve as a membrane to control the rate of release.
- the compounds (I) - (V) may also be used in association with other therapeutic agents including, for example,
- Example 1-5 of the following Example illustrates the present invention through the use of an accepted animal model for traumatic brain injury. This Example refers to Figs. 1-5 of the
- ketamine and xylazine premedicated with ketamine and xylazine, weighed, and brought to the surgical laboratory where anesthesia was induced with isoflurane by mask. They were then intubated, placed supine, and ventilated with an anesthetic gas mixture (oxygen 23%, nitrogen 75%, isoflurane 2%) to maintain normal arterial blood gases.
- the left femoral artery and vein were cannulated for continuous arterial blood pressure monitoring and placement of a flow-directed pulmonary artery catheter for central venous pressure (CVP), pulmonary artery (PA) and pulmonary capillary wedge pressure (PCWP) monitoring. A cystotomy was performed and a 14 French Foley catheter was placed for urine output monitoring.
- CVP central venous pressure
- PA pulmonary artery
- PCWP pulmonary capillary wedge pressure
- the right subclavian vein was cannulated for venous access.
- a rectal thermistor was placed for core temperature monitoring.
- the animals were then repositioned prone and the heads were immobilized in a frame.
- the skull was exposed though a sagittal scalp incision and both cerebral ventricles were cannulated using the right-angle technique.
- Intracranial pressure was continuously monitored with a fiberoptic pressure transducer (Camino Labs, San Diego,
- An 18-gauge teflon catheter placed in the contralateral ventricle confirmed ICP by manometry.
- the sagittal sinus was catheterized with a PE-10 polyethylene cannula for sagittal sinus pressure (SSP) monitoring.
- SSP sagittal sinus pressure
- a 14-mm burr hole was made through the right frontal bone, with care taken to avoid injury to the underlying dura.
- the injury screw was cemented in place to form a water-tight seal with methylmethacrylate, and attached to a fluid percussion device by a 3-cm length of nondistensible Tygon ® tubing.
- the system was filled with normal saline at 37°C and purged of air.
- Compliance 0.4343 PVI / P where P is the ICP at the point when the compliance measurement was determined and 0.4343 is a constant. A minimum of three determinations were made during the baseline period in all animals.
- a 14 mm burr hole was made in the frontal region, contralateral to the injury screw, in all animals for epidural placement of a flexible reflectance photoplethysmography probe.
- the probe consisted of miniature red and infrared light-emitting diodes (LED's) and a silicon photodetecting diode mounted on a flexible circuit board. Output from the photodetector was selectively tuned to provide data on
- the probe was connected to a photodemodulation circuit and an analog-to- digital converter connected to a microcomputer (Macintosh II, Apple Computer, Cupertino, California). Reflected red and infrared photoplethysmograms were employed to evaluate
- Hemoglobin within cerebral cortex illuminated by the LED's on the surface of the probe, reflects red and infrared light which is detected by the photodiode.
- the intensity of the red and infrared signals varies with the cardiac cycle and is dependent upon the SaO 2 .
- the oximetry technique analyzes the pulsatile (referred to as the a.c. component), rather than absolute, non-pulsatile (referred to as the d.c. component), reflected light intensity of red and infrared
- photoplethysmograms measured at 660 and 910 nm, respectively.
- the wavelengths chosen represent portions of the spectral region where the absorption coefficients of reduced and oxygenated hemoglobin in tissue are markedly different (660 nm), and where they are relatively similar (910 nm).
- CBV Cerebral blood volume
- the collimator employed a 20 percent window over the 140-keV photopeak of 99m Tc.
- Arterial blood samples (2.0 mL), obtained at the time of gamma emission data collection, were divided into three equal aliquots. One aliquot was used for the determination of total hemoglobin by co-oximetry (blood gas analyzer Model 288, Ciba Corning, Medfield, MA); the
- hematocrit was determined by microcentrifugation. The two remaining aliquots were placed in a well counter and total blood sample counts were decay corrected to the time they were drawn by the equation:
- C o Ce ⁇ t
- C o decay-corrected counts
- Ce decayed counts
- ⁇ 0.693/6.02 hr physical half life of 99m Tc
- t the time between when the sample was drawn and when it was counted.
- the supratentorial brain was removed intact and representative sections from the right frontal lobe directly under the injury screw, the left frontal lobe, the left occipital lobe and left parietal lobe were sharply dissected free and placed in neutral buffered
- kerosene/bromobenzene density gradient column and allowed to equilibrate.
- the column was calibrated against beads of known density. Measurements were taken after 2, 3, 5 and 10 minutes on the column to factor out non-specific evaporation of surface water in different specimens.
- Physiological data are expressed as mean ⁇ standard error of the mean. Differences between groups at each time point were compared using the Wilcoxon nonparametric analysis. A two-way analysis of variance (ANOVA) was employed to examine differences in individual variables within groups with respect to time. Correlation of individual physiological variables between multiple groups was evaluated using the Spearman ranked correlation coefficient. Histological data was
- CBV decreased from this peak at the time of injury, it remained significantly elevated above baseline levels throughout the experimental period in Group I. CBV returned to near baseline values in Group II by 60 minutes and remained at this level throughout the experimental period.
- CVII cerebrovascular injury and inflammatory cell infiltration according to the grading scale described above.
- CVII cerebrovascular injury index
- the injured right and left frontal lobes in untreated animals showed significantly greater evidence of injury and inflammation than in the control group (Group III) (Table 2, Fig. 5 A-I).
- Methoxatone significantly attenuated the intracranial hypertension seen in untreated animals following TBI.
- Methoxatone appeared to exert its effect within 60 minutes of administration. As seen in Fig. 3, ICP remained significantly lower in the Methoxatone treated group compared to untreated controls, from 150 minutes following administration to the end of the experimental period. Although ICP was still
- Methoxatone appears to protect the injured brain from the uncoupling of metabolic demand and cerebral blood flow as evidenced by the preservation of near-baseline oxygen extraction, compared to significantly elevated oxygen
- Methoxatone treated animals developed less tissue edemas as measured by tissue specific gravity, approaching
- Methoxatone reduces the post-traumatic defect in cerebrovascular permeability which promotes the movement of water into the tissue
- Methoxatone had a significant effect on post-traumatic inflammation, as evidenced by the lower CVII Histopathology scores in treated animals compared to untreated controls.
- A-(63 x) Right frontal lobe section, sub-meningeal cortex, taken 6 hours following intracerebroventricular infusion of 20uM LTC4.
- An intense meningovasculitis characterized by margination and diapedesis of neutrophils, infiltration of neutrophils into the parenchyma, and meningitis with a dense neutrophil-rich exudate in the subarachnoid space.
- Intraparenchymal neutrophils are shown phagocytizing an astrocyte. Multiple neutrophils are seen throughout the neuropil.
- Intraparenchymal arteriole without evidence of neutrophil margination Numerous pyknotic cells without intraparenchymal neutrophil infiltration.
- Intraparenchymal vessel ( ⁇ ) with small contraction artifact halo. Pyknotic neuron ( ) and only isolated intraparenchymal neutrophil (- ->).
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP95905942A EP0810859A1 (en) | 1993-12-29 | 1994-12-15 | Method of treatment of traumatic brain injury |
AU14365/95A AU1436595A (en) | 1993-12-29 | 1994-12-15 | Method of treatment of traumatic brain injury |
JP7518072A JPH09510187A (en) | 1993-12-29 | 1994-12-15 | Treatment for traumatic brain injury |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/174,829 US5527822A (en) | 1993-12-29 | 1993-12-29 | Method of treatment of traumatic brain injury |
US08/174,829 | 1993-12-29 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1995017890A1 true WO1995017890A1 (en) | 1995-07-06 |
Family
ID=22637699
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1994/014401 WO1995017890A1 (en) | 1993-12-29 | 1994-12-15 | Method of treatment of traumatic brain injury |
Country Status (6)
Country | Link |
---|---|
US (1) | US5527822A (en) |
EP (1) | EP0810859A1 (en) |
JP (1) | JPH09510187A (en) |
AU (1) | AU1436595A (en) |
CA (1) | CA2179824A1 (en) |
WO (1) | WO1995017890A1 (en) |
Families Citing this family (45)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2296056A1 (en) * | 1997-07-10 | 1999-01-21 | Keith Baker | Methods for universally distributing therapeutic agents to the brain |
US8512718B2 (en) | 2000-07-03 | 2013-08-20 | Foamix Ltd. | Pharmaceutical composition for topical application |
US20030040660A1 (en) * | 2001-08-27 | 2003-02-27 | George Jackowski | Method for diagnosing and distinguishing traumatic brain injury and diagnostic devices for use therein |
IL152486A0 (en) | 2002-10-25 | 2003-05-29 | Meir Eini | Alcohol-free cosmetic and pharmaceutical foam carrier |
US20080138296A1 (en) | 2002-10-25 | 2008-06-12 | Foamix Ltd. | Foam prepared from nanoemulsions and uses |
US9668972B2 (en) | 2002-10-25 | 2017-06-06 | Foamix Pharmaceuticals Ltd. | Nonsteroidal immunomodulating kit and composition and uses thereof |
US9265725B2 (en) | 2002-10-25 | 2016-02-23 | Foamix Pharmaceuticals Ltd. | Dicarboxylic acid foamable vehicle and pharmaceutical compositions thereof |
US8119150B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Non-flammable insecticide composition and uses thereof |
US9211259B2 (en) | 2002-11-29 | 2015-12-15 | Foamix Pharmaceuticals Ltd. | Antibiotic kit and composition and uses thereof |
US7820145B2 (en) | 2003-08-04 | 2010-10-26 | Foamix Ltd. | Oleaginous pharmaceutical and cosmetic foam |
US10117812B2 (en) | 2002-10-25 | 2018-11-06 | Foamix Pharmaceuticals Ltd. | Foamable composition combining a polar solvent and a hydrophobic carrier |
KR101108439B1 (en) | 2002-10-25 | 2012-01-31 | 포믹스 리미티드 | Cosmetic and pharmaceutical foam |
US7700076B2 (en) | 2002-10-25 | 2010-04-20 | Foamix, Ltd. | Penetrating pharmaceutical foam |
US7704518B2 (en) | 2003-08-04 | 2010-04-27 | Foamix, Ltd. | Foamable vehicle and pharmaceutical compositions thereof |
US8900554B2 (en) | 2002-10-25 | 2014-12-02 | Foamix Pharmaceuticals Ltd. | Foamable composition and uses thereof |
US8119109B2 (en) | 2002-10-25 | 2012-02-21 | Foamix Ltd. | Foamable compositions, kits and methods for hyperhidrosis |
US8486376B2 (en) | 2002-10-25 | 2013-07-16 | Foamix Ltd. | Moisturizing foam containing lanolin |
WO2005037286A1 (en) * | 2003-03-25 | 2005-04-28 | Vasopharm Biotech Gmbh | Use of pteridine derivatives for the treatment of increased intracranial pressure and secondary ischemia |
DE10315574A1 (en) * | 2003-04-05 | 2004-10-28 | ETH Zürich | Device for determining blood flow in an organ |
US7575739B2 (en) | 2003-04-28 | 2009-08-18 | Foamix Ltd. | Foamable iodine composition |
US8486374B2 (en) | 2003-08-04 | 2013-07-16 | Foamix Ltd. | Hydrophilic, non-aqueous pharmaceutical carriers and compositions and uses |
US8795693B2 (en) | 2003-08-04 | 2014-08-05 | Foamix Ltd. | Compositions with modulating agents |
WO2007022292A2 (en) * | 2005-08-15 | 2007-02-22 | Brigham Young University | Methods and system for determining brain compliance |
US7833165B2 (en) * | 2005-08-15 | 2010-11-16 | Kim Manwaring | System for monitoring neural shunt function and associated methods |
US7643858B2 (en) | 2006-09-28 | 2010-01-05 | Nellcor Puritan Bennett Llc | System and method for detection of brain edema using spectrophotometry |
US20080260655A1 (en) | 2006-11-14 | 2008-10-23 | Dov Tamarkin | Substantially non-aqueous foamable petrolatum based pharmaceutical and cosmetic compositions and their uses |
US8636982B2 (en) | 2007-08-07 | 2014-01-28 | Foamix Ltd. | Wax foamable vehicle and pharmaceutical compositions thereof |
US9439857B2 (en) | 2007-11-30 | 2016-09-13 | Foamix Pharmaceuticals Ltd. | Foam containing benzoyl peroxide |
WO2010041141A2 (en) | 2008-10-07 | 2010-04-15 | Foamix Ltd. | Oil-based foamable carriers and formulations |
WO2009072007A2 (en) | 2007-12-07 | 2009-06-11 | Foamix Ltd. | Carriers, formulations, methods for formulating unstable active agents for external application and uses thereof |
CA2712120A1 (en) | 2008-01-14 | 2009-07-23 | Foamix Ltd. | Poloxamer foamable pharmaceutical compositions with active agents and/or therapeutic cells and uses |
US9285459B2 (en) * | 2008-05-09 | 2016-03-15 | Analog Devices, Inc. | Method of locating an object in 3D |
US20090279107A1 (en) * | 2008-05-09 | 2009-11-12 | Analog Devices, Inc. | Optical distance measurement by triangulation of an active transponder |
US9746544B2 (en) * | 2008-12-03 | 2017-08-29 | Analog Devices, Inc. | Position measurement systems using position sensitive detectors |
WO2010125470A2 (en) | 2009-04-28 | 2010-11-04 | Foamix Ltd. | Foamable vehicle and pharmaceutical compositions comprising aprotic polar solvents and uses thereof |
EP2434945B1 (en) * | 2009-05-27 | 2018-12-19 | Analog Devices, Inc. | Multiuse optical sensor |
WO2011013008A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surface active agent non polymeric agent hydro-alcoholic foamable compositions, breakable foams and their uses |
WO2011013009A2 (en) | 2009-07-29 | 2011-02-03 | Foamix Ltd. | Non surfactant hydro-alcoholic foamable compositions, breakable foams and their uses |
US9849142B2 (en) | 2009-10-02 | 2017-12-26 | Foamix Pharmaceuticals Ltd. | Methods for accelerated return of skin integrity and for the treatment of impetigo |
WO2011064631A1 (en) | 2009-10-02 | 2011-06-03 | Foamix Ltd. | Surfactant-free, water-free, foamable compositions and breakable foams and their uses |
US9702690B2 (en) | 2011-12-19 | 2017-07-11 | Analog Devices, Inc. | Lens-less optical position measuring sensor |
US9826913B2 (en) | 2013-07-11 | 2017-11-28 | Vivonics, Inc. | Non-invasive intracranial pressure monitoring system and method thereof |
MX2020012139A (en) | 2016-09-08 | 2021-01-29 | Vyne Pharmaceuticals Inc | Compositions and methods for treating rosacea and acne. |
CA3087927C (en) | 2018-01-08 | 2023-05-23 | Vivonics, Inc. | System and method for cooling the brain of a human subject |
US11674797B2 (en) | 2020-03-22 | 2023-06-13 | Analog Devices, Inc. | Self-aligned light angle sensor using thin metal silicide anodes |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5102909A (en) * | 1988-07-28 | 1992-04-07 | Theracel Corporation | Pharmaceutically useful furyl substituted dihydroxyethylbutyrolactones |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4620014A (en) * | 1978-06-20 | 1986-10-28 | National Foundation For Cancer Research | 2-furylbutyrolactones and methods for using same |
US4518611A (en) * | 1983-04-04 | 1985-05-21 | National Foundation For Cancer Research, Inc. | 2-Furylbutyrolactone modulation of the immune system in mammals |
US5098933A (en) * | 1986-04-29 | 1992-03-24 | Theracel Corporation | Pharmaceutically useful Michael addition products of unsaturated aldehydes and ketones and ascorbic acid |
US4883808A (en) * | 1987-08-27 | 1989-11-28 | American Biotechnology Company | Condensation products of cyclic diketones and ascorbic acid as immunomodulatory agents |
US4883813A (en) * | 1988-08-24 | 1989-11-28 | American Biotechnology Company | Method of treating inflammation in mammals utilizing ketobutyrolactones and furylbutyrolactones |
-
1993
- 1993-12-29 US US08/174,829 patent/US5527822A/en not_active Expired - Fee Related
-
1994
- 1994-12-15 WO PCT/US1994/014401 patent/WO1995017890A1/en not_active Application Discontinuation
- 1994-12-15 EP EP95905942A patent/EP0810859A1/en not_active Withdrawn
- 1994-12-15 JP JP7518072A patent/JPH09510187A/en active Pending
- 1994-12-15 CA CA002179824A patent/CA2179824A1/en not_active Abandoned
- 1994-12-15 AU AU14365/95A patent/AU1436595A/en not_active Abandoned
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5102909A (en) * | 1988-07-28 | 1992-04-07 | Theracel Corporation | Pharmaceutically useful furyl substituted dihydroxyethylbutyrolactones |
Also Published As
Publication number | Publication date |
---|---|
AU1436595A (en) | 1995-07-17 |
US5527822A (en) | 1996-06-18 |
CA2179824A1 (en) | 1995-07-06 |
JPH09510187A (en) | 1997-10-14 |
EP0810859A1 (en) | 1997-12-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US5527822A (en) | Method of treatment of traumatic brain injury | |
Parks et al. | Contributions of ischemia and reperfusion to mucosal lesion formation | |
Drummond et al. | The influence of dextrose administration on neurologic outcome after temporary spinal cord ischemia in the rabbit | |
Raimbach et al. | Prevention of glucose-induced hypotension by the somatostatin analogue octreotide (SMS 201-995) in chronic autonomic failure: haemodynamic and hormonal changes | |
Wiegmann et al. | Effect of angiotensin-converting enzyme inhibition on renal function and albuminuria in normotensive type I diabetic patients | |
US20140079729A1 (en) | Method for improving endothelial function and decreasing cardiovascular morbidity using shilajit | |
CA2810732C (en) | Compositions and method for improving endothelial function and cardiovascular health | |
Stein et al. | Effect of beta-adrenergic blockade on coronary blood flow | |
Edvinsson et al. | Calcium antagonists: Effects on cerebral blood flow and blood‐brain barrier permeability in the rat | |
Josephson et al. | Hemodynamic effects of intravenous flecainide relative to the level of ventricular function in patients with coronary artery disease | |
Mrowietz et al. | Anthralin (dithranol) in vitro inhibits human monocytes to secrete IL‐6, IL‐8 and TNF‐α, but not IL‐1 | |
Schubert et al. | Skin microcirculatory and thermal changes in elderly subjects with early stage of pressure sores | |
Abou-Elenin et al. | The effect of aspirin and various iontophoresis solution vehicles on skin microvascular reactivity | |
Lianos et al. | Angiotensin-induced sodium excretion patterns in cirrhosis: role of renal prostaglandins | |
Jern | Effects of acute carbohydrate administration on central and peripheral hemodynamic responses to mental stress. | |
STEINHORN et al. | Pharmacodynamic response to ionized calcium during acute sepsis | |
CLARK et al. | Effects of slow infusion of a low dosage of endotoxin on systemic haemodynamics in conscious horses | |
Long et al. | Treatment of canine aspiration pneumonitis: fluid volume reduction vs. fluid volume expansion | |
Daneshmend et al. | Effects of chronic oral cimetidine on apparent liver blood flow and hepatic microsomal enzyme activity in man. | |
Pitts et al. | Chronic cocaine reduces α2-adrenoceptor elicited mydriasis and inhibition of locus coeruleus neurons | |
Millen et al. | Low levels of concussive brain trauma and pulmonary edema | |
AU624370B2 (en) | Method of preventing or reducing adverse reactions to protamine using a thromboxane a2 receptor antagonist | |
Milligan et al. | Effect of venesection on calf blood flow in polycythaemia. | |
Jern | Effects of insulin on vascular responses to mental stress and norepinephrine in human forearm. | |
Rimpiläinen et al. | Lamotrigine plus leukocyte filtration as a neuroprotective strategy in experimental hypothermic circulatory arrest |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU BR CA JP KR NZ |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2179824 Country of ref document: CA Ref document number: 1995905942 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1995905942 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1995905942 Country of ref document: EP |