CA2108794C - Use of torasemide for the treatment of brain oedemas - Google Patents
Use of torasemide for the treatment of brain oedemas Download PDFInfo
- Publication number
- CA2108794C CA2108794C CA002108794A CA2108794A CA2108794C CA 2108794 C CA2108794 C CA 2108794C CA 002108794 A CA002108794 A CA 002108794A CA 2108794 A CA2108794 A CA 2108794A CA 2108794 C CA2108794 C CA 2108794C
- Authority
- CA
- Canada
- Prior art keywords
- brain
- oedemas
- treatment
- torasemide
- toluideno
- 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.)
- Expired - Lifetime
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
- A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Biomedical Technology (AREA)
- Pharmacology & Pharmacy (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Enzymes And Modification Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Summary Use of torasemide for the treatment of brain oedemas and orally and parenterally administerable torasemide.
Description
Use of Torasemide for the Treatment of Brain Oedemas The invention relates to the use of torasemide for the treatment of the swellings of nerve and glia cells in the case of brain oedemas which arise as a result of e.g. skull-brain traumas and metastases and orally and parenterally administrable torasemide.
In accordance with the invention there is provided use of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl] urea or oI its pharmacologically acceptable salts for the manufacture of medicaments for the treatment of brain oedemas.
In accordance with another aspect of the invention there is provided of a pharmaceutical composition for the treatment of~ brain oedemas comprising a physiologically acceptable amount of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
In accordance with still another aspect of~ the invention there is provided 1-isopropyl-3-[(4-rn-Toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof for use in the treatment of brain oedemas.
In particular embodiments of the afore-mentioned aspects of the invention the brain oedemas are those resulting from severe skull-brain traumas, cerebral ischaemia, strokes, metastases, epileptic fits, or initiated by hypoosmolar hyperhydration.
Torasemide, chemical designation 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl]urea is known as a loop diuretic in the case of the systemic administration of which urine volumes and electrolyte excretion increase linearly with the logarithm of the torasemide dose.
In in vitro investigations, it could be shown that torasemide clearly reduces the acidosis-induced swelling of C'.6 glioma cells. Furthermore, in the case of in vivo investigations on rats, it was ascertained that torasemide as able to lower the intracranial pressure (ICP) in cytotoxic brain oedema initiated by hypoosmolar hyperhydration.
An acidosis occurs in the brain in the case of cerebral ischaemia, in the case of skull-brain traumas, in the case of epileptic attacks, as well as under other pathophysiological conditions. In the case. of cerebral ischaemia, the pH
value can decrease to 6.5 to 6.0, under hyperglycaemic conditions the acidosis can be even more marked.
210~'~04 _3_ As~a result of the. acidosis and of the reduced energy metabolism involved therewith, a net inflow of N~+ and CI-dons into the cells taken place, whereby' the intracellular increase of the osmolarity leads to a corresponding warter movement and .thus to a cell swelTLi.ng,.
For diuretics such as e,.g~ bumetanide and furosemide which act in the kidney like torasemide via- the NaG1 KCl. co-transport, it. was shown tha°t.
theyr were not able. to influence an experimentally increased intracrani.al pressure (s.ee the article "Effe.ct of furosemide~, bumetanide and mannitol on intracranial pre~s~ure in expermmental brain edema of the ran" by C., Plangger arid H,. Volkl in Zent b1 Neurochir 50: 142-144,; 1.989):" In this regardr it was' surprising that,. o~ith torasemide,., a lowering of the. increased intracranial pressure could be observed"
The effectivanes~s o.f torasemide in the reduction of the swelling ccf glia cells or in the. _lowering of 20. the' TCP is~ .shown by the.. investigations described in more; detail in the following and illustrated by Fi:gure~.~~
The Fig" 1 and 2. show the chronological caurae of an in vitro acidasia-induced sell swelling of C,6 glioma ceTls~ after incubat~:an with torasemide or in the~case:of control experiments without verum administration,. The chronological change of the vitality of the C6 glioma cells iii the Case of these experiments is illustrated in Fig" 3,. The figP ~, to, 6 SNOW the chronological changes of the ICP, of the average systemic arterial blood pressure and of the cerebral perfusion pressure in rats after ind~zction of a brain oedema in two experimental Series'" whereby in one experimental series torasemide was' ~,tlmi:nister.ed intravenously and in the other (control) experimental series iso.to.ni.c common salt TO solution,.
Tn the:case: of the in vitro investigations concerning the influewce of torasemide on acidosis;, induced cell swelling,. C6 glioma cells with glia-sEpecsfic propertaes~ were. used, The glia cells grew I5 as monolayer in Petr~dishes under conventional culture conditions with 95~ ambient air" 5g~ C02 and at a temperature of.3~oC., Culture medium was DuTbecco's minimal essential medium (DM~"I) with 25 mM bicarbonate as' buffer, Furthermore, the medium 20 contained 10~ foetal calf serum (FCS), as well as 100 TU/ml of penicillin G and 50 ~,~,g/ml strepto-m~cin, Far the carrying out of an experiment" the culls were~harvested from 6 culture dishes wibh trgps~in, washed Mice with FCS-fp~ee medium and 25 s~ubsequentl~r introduced into an experimental chamber,.
The chamber ensured a homogeneous stability of the individual suspension for several hours, as' well as 2~~8'~~~
the: monitOrlrig Of the medium by continuous recording Of the pH value, of the oxygen partial,pressure and of the temperatures The determination of the cell volume took place quantitative~.y with the help: of a flowthrough eytomete~r according to the Coulter process. In addition, the apgaretus employed. hydro-dynamic focussing of the: particles for the improvement of the measurement exa.ctitude,. In this way,. cha~nge~
of the cell volume of [ 1~ can be detected with certaint~r" The: vitadli.ty of the cells was determined flowthro.ugh-c~rtometrically bg determina.tion by -propidium iadide~
C&~rr~ing out of experiment: The cell volume" as well as the cell vitahity,,were first examined in a control T5 phase (45 min) for their constant course,. Furthermore"
the osmolarity of the medium was determined In addition, it was:ascertained in parallel experiments tha-t,, in the case of exclusive addition of t.orasemide, no significant change of the cell volume and no influencing of the?
vitality of the: C.6 glinma cells took place".The cell sFwelling was~produced.after the control phase by lowering of the pH valu~ to 6,.6 or 5,.0, ~espectivaZy, with the help~of isotonic lactic acid" The,pCa2 of the chamber w.aa simultaneously increased to 80 to 2'S TOO mm H~, The eRperimental period amounted to 60 minutely Tn each case,,2 parallel experiments were carri$d out at pH 6"2.and. 5,0,. In the case of in _6_ each case one.experiment, torasemide was~added to the medium in an end concentration of l~mM 15 minutes before the acidification. The other experiment served as control,.
S The results axe set out in Fig, l and 2,, in which the: cell volume (in ~ of the starting value) is plotted against the experimental period,. Furthermore,; in each ca.s~e the time span is given during which the pH value had sunk to 6, 2= or.~ 5,,0;" respectivel~r,. The time: spans T.0 between the: two experiments, w~,thin which the experimental data: obtained under torasemide were sign3ficantTy different (,p < 0,.01) from the control, are also ma~cked;. The cell volume values plotted in the curves are. arithmetic averages ($).+ w;EM~ The:
15 results clearly show the inhibition ~of the cell swelling by' toravsemide, As Fig,. 3 shaves,; .torasemide furthermore has peruse no influence on the vitality of C6 glioma. cells,. In Fi:g,. 3 is shaven the change of the vitality of the C6 ghioma~ cslls~ over the experi-20 mental period, Fur.~thermo.re, the time span is marked during which the pf3 value had sunk to 5,.0, One sees from the curves~~ that admittedly the pH sink3:ng but not the torasemido add~.t~.on hae~ an influence on the vita.Tity~",. The. results of. the described. experiments ~5 ~wexe. ana~lysed.~for significance with the help of the. variance analysis and the Kruskal-Wallis test for the intergro.up comparison,.
21a8"~9~
_7_.
The action of torase.mide in the case of brain Oedema wag investigated in vivo in the pharmacolog-ical model of the cytotoxic brain oedema of the rat"
In the case of 150 to 240: g weighted male rats, for the continuous detection of the s~:stemic arterial blood pressurev, a catheter was inserted into the right a~rteria femoralis~ a.nd measured bar means of a Could Fl0 E2 blood. pressure transformer, of a S~iemens m~rnitor and o.f a:2-canal recorder (Zinseis L~650~
and recorded,,- For the continuous detection of the=
TCg, a Wick catheter. was~introduced. through a " trepa.naaion of the; left front side of the:skullP
The: IOP waw,measured and recorded bg means- of an eTect.romagnetic Statham transformer P'23 Db~. which was' connected with a He~:Tige el.ectromanome~er, and of a 2-canal. recorder- (Zins.eis~ I~ 650).. Iri order to exclude a possible diuretic effect" the rats wexee functionally nephrectomis~ed.,, Carrying out the: experiment z For. the inducing cr:f the brain oedema, T00 ml bidistilled~;wate~~;~kg ..b~5dy .
weight was. infused at.0"5 ml/,min into the right vane ~ugularis~~,. ~I~,rea.fter ~warer ink~cted l00 mg toraeemide/kg body weight 3.n l0 ml liqua,d/kg bod~r weight and in a parallel exp7eriment 10 ml of isn.tonic 2.5. ~~mmo~n salt sohutiQ.n (;pl.acebo)/kg body weight, LCP
and blood prevaure. w.e.re: continuously recorded for.
In accordance with the invention there is provided use of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl] urea or oI its pharmacologically acceptable salts for the manufacture of medicaments for the treatment of brain oedemas.
In accordance with another aspect of the invention there is provided of a pharmaceutical composition for the treatment of~ brain oedemas comprising a physiologically acceptable amount of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
In accordance with still another aspect of~ the invention there is provided 1-isopropyl-3-[(4-rn-Toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof for use in the treatment of brain oedemas.
In particular embodiments of the afore-mentioned aspects of the invention the brain oedemas are those resulting from severe skull-brain traumas, cerebral ischaemia, strokes, metastases, epileptic fits, or initiated by hypoosmolar hyperhydration.
Torasemide, chemical designation 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl]urea is known as a loop diuretic in the case of the systemic administration of which urine volumes and electrolyte excretion increase linearly with the logarithm of the torasemide dose.
In in vitro investigations, it could be shown that torasemide clearly reduces the acidosis-induced swelling of C'.6 glioma cells. Furthermore, in the case of in vivo investigations on rats, it was ascertained that torasemide as able to lower the intracranial pressure (ICP) in cytotoxic brain oedema initiated by hypoosmolar hyperhydration.
An acidosis occurs in the brain in the case of cerebral ischaemia, in the case of skull-brain traumas, in the case of epileptic attacks, as well as under other pathophysiological conditions. In the case. of cerebral ischaemia, the pH
value can decrease to 6.5 to 6.0, under hyperglycaemic conditions the acidosis can be even more marked.
210~'~04 _3_ As~a result of the. acidosis and of the reduced energy metabolism involved therewith, a net inflow of N~+ and CI-dons into the cells taken place, whereby' the intracellular increase of the osmolarity leads to a corresponding warter movement and .thus to a cell swelTLi.ng,.
For diuretics such as e,.g~ bumetanide and furosemide which act in the kidney like torasemide via- the NaG1 KCl. co-transport, it. was shown tha°t.
theyr were not able. to influence an experimentally increased intracrani.al pressure (s.ee the article "Effe.ct of furosemide~, bumetanide and mannitol on intracranial pre~s~ure in expermmental brain edema of the ran" by C., Plangger arid H,. Volkl in Zent b1 Neurochir 50: 142-144,; 1.989):" In this regardr it was' surprising that,. o~ith torasemide,., a lowering of the. increased intracranial pressure could be observed"
The effectivanes~s o.f torasemide in the reduction of the swelling ccf glia cells or in the. _lowering of 20. the' TCP is~ .shown by the.. investigations described in more; detail in the following and illustrated by Fi:gure~.~~
The Fig" 1 and 2. show the chronological caurae of an in vitro acidasia-induced sell swelling of C,6 glioma ceTls~ after incubat~:an with torasemide or in the~case:of control experiments without verum administration,. The chronological change of the vitality of the C6 glioma cells iii the Case of these experiments is illustrated in Fig" 3,. The figP ~, to, 6 SNOW the chronological changes of the ICP, of the average systemic arterial blood pressure and of the cerebral perfusion pressure in rats after ind~zction of a brain oedema in two experimental Series'" whereby in one experimental series torasemide was' ~,tlmi:nister.ed intravenously and in the other (control) experimental series iso.to.ni.c common salt TO solution,.
Tn the:case: of the in vitro investigations concerning the influewce of torasemide on acidosis;, induced cell swelling,. C6 glioma cells with glia-sEpecsfic propertaes~ were. used, The glia cells grew I5 as monolayer in Petr~dishes under conventional culture conditions with 95~ ambient air" 5g~ C02 and at a temperature of.3~oC., Culture medium was DuTbecco's minimal essential medium (DM~"I) with 25 mM bicarbonate as' buffer, Furthermore, the medium 20 contained 10~ foetal calf serum (FCS), as well as 100 TU/ml of penicillin G and 50 ~,~,g/ml strepto-m~cin, Far the carrying out of an experiment" the culls were~harvested from 6 culture dishes wibh trgps~in, washed Mice with FCS-fp~ee medium and 25 s~ubsequentl~r introduced into an experimental chamber,.
The chamber ensured a homogeneous stability of the individual suspension for several hours, as' well as 2~~8'~~~
the: monitOrlrig Of the medium by continuous recording Of the pH value, of the oxygen partial,pressure and of the temperatures The determination of the cell volume took place quantitative~.y with the help: of a flowthrough eytomete~r according to the Coulter process. In addition, the apgaretus employed. hydro-dynamic focussing of the: particles for the improvement of the measurement exa.ctitude,. In this way,. cha~nge~
of the cell volume of [ 1~ can be detected with certaint~r" The: vitadli.ty of the cells was determined flowthro.ugh-c~rtometrically bg determina.tion by -propidium iadide~
C&~rr~ing out of experiment: The cell volume" as well as the cell vitahity,,were first examined in a control T5 phase (45 min) for their constant course,. Furthermore"
the osmolarity of the medium was determined In addition, it was:ascertained in parallel experiments tha-t,, in the case of exclusive addition of t.orasemide, no significant change of the cell volume and no influencing of the?
vitality of the: C.6 glinma cells took place".The cell sFwelling was~produced.after the control phase by lowering of the pH valu~ to 6,.6 or 5,.0, ~espectivaZy, with the help~of isotonic lactic acid" The,pCa2 of the chamber w.aa simultaneously increased to 80 to 2'S TOO mm H~, The eRperimental period amounted to 60 minutely Tn each case,,2 parallel experiments were carri$d out at pH 6"2.and. 5,0,. In the case of in _6_ each case one.experiment, torasemide was~added to the medium in an end concentration of l~mM 15 minutes before the acidification. The other experiment served as control,.
S The results axe set out in Fig, l and 2,, in which the: cell volume (in ~ of the starting value) is plotted against the experimental period,. Furthermore,; in each ca.s~e the time span is given during which the pH value had sunk to 6, 2= or.~ 5,,0;" respectivel~r,. The time: spans T.0 between the: two experiments, w~,thin which the experimental data: obtained under torasemide were sign3ficantTy different (,p < 0,.01) from the control, are also ma~cked;. The cell volume values plotted in the curves are. arithmetic averages ($).+ w;EM~ The:
15 results clearly show the inhibition ~of the cell swelling by' toravsemide, As Fig,. 3 shaves,; .torasemide furthermore has peruse no influence on the vitality of C6 glioma. cells,. In Fi:g,. 3 is shaven the change of the vitality of the C6 ghioma~ cslls~ over the experi-20 mental period, Fur.~thermo.re, the time span is marked during which the pf3 value had sunk to 5,.0, One sees from the curves~~ that admittedly the pH sink3:ng but not the torasemido add~.t~.on hae~ an influence on the vita.Tity~",. The. results of. the described. experiments ~5 ~wexe. ana~lysed.~for significance with the help of the. variance analysis and the Kruskal-Wallis test for the intergro.up comparison,.
21a8"~9~
_7_.
The action of torase.mide in the case of brain Oedema wag investigated in vivo in the pharmacolog-ical model of the cytotoxic brain oedema of the rat"
In the case of 150 to 240: g weighted male rats, for the continuous detection of the s~:stemic arterial blood pressurev, a catheter was inserted into the right a~rteria femoralis~ a.nd measured bar means of a Could Fl0 E2 blood. pressure transformer, of a S~iemens m~rnitor and o.f a:2-canal recorder (Zinseis L~650~
and recorded,,- For the continuous detection of the=
TCg, a Wick catheter. was~introduced. through a " trepa.naaion of the; left front side of the:skullP
The: IOP waw,measured and recorded bg means- of an eTect.romagnetic Statham transformer P'23 Db~. which was' connected with a He~:Tige el.ectromanome~er, and of a 2-canal. recorder- (Zins.eis~ I~ 650).. Iri order to exclude a possible diuretic effect" the rats wexee functionally nephrectomis~ed.,, Carrying out the: experiment z For. the inducing cr:f the brain oedema, T00 ml bidistilled~;wate~~;~kg ..b~5dy .
weight was. infused at.0"5 ml/,min into the right vane ~ugularis~~,. ~I~,rea.fter ~warer ink~cted l00 mg toraeemide/kg body weight 3.n l0 ml liqua,d/kg bod~r weight and in a parallel exp7eriment 10 ml of isn.tonic 2.5. ~~mmo~n salt sohutiQ.n (;pl.acebo)/kg body weight, LCP
and blood prevaure. w.e.re: continuously recorded for.
3 hours after admin~~.tr~a.ticrn of torasemide o.r 210~'~~~
_8_ placebo, 6 rats received a torasemide injections 7 rats received placebo, The evaluated results of the TCP and blood pressure measurements are set out in Fig, 4 a:nd 5, respect~:valy, Fig,. 4 shows that the TCP in the case of the xats~
treated with toras.emide was, as every point o:f time, lower than in the case of animals treated with placebo in the para:;llel experiment,. However" the differences' were. not statistically significant, Therefore, for the ve~xification of the finding, the cerebral perfusion pressure was also determined (the cerebral.perfusian pressure iw equal to the difference between the systemic average. arterial blood pre.ssure~ and the: ICP), It way thereby found. (see Fig, 6) that the values thereof 90 and T00.minutes; ofter the~administration of tora~s~mide were. significantly higher' than in the control graup, This was mainly to be attributed to the much Lower TCP values.~in the rats~treated with tara~semide" 'In Fig, 4 t:o 6 are. plot~tad arithmetic average values (~c)~ -~ Wit. against the: time, The testing far significant differences between the exp~.riinente~.
groups treated with taras~emaLde. arid placebo took place by means a~f a one-sided Student t-test for unpaired data,.
25. ~ummarising",it can be raids Not only the. in vitro.
experiments with C6 glioma cells but also the i~a vivcov experiments on rats show that torasemide acts ~1087~~
swelling-inhibitingly or pressure lowering in tl~e Case of induced swelling of the glia cells and increased ZCl'~. Torasemide is,, therefore, also favourable because - as has been:escertained in experiments with C6 glioma cells (see above) --torasemide does. no.t inpair the. vitality of the- gT.ia cells; this is reduced in the. same experimental procedure e.,g" by amiloride. Possible causes for~the pharmacological action observed with torasemide but 1~~ not with e,.g, furosemide and bumetanide is the high lipophilia of torasemide (octanol/H20 coefficient:
/ 0.71., a The preparation of torasemide takes place according to the proces<:s described in the Patent specification DE 25 l6 025 C2,.
On the basis of its high bioavailability~; tora-semide.can be used in equivalent dose not only orall~r but also parenterall~ for the therapy of brain oedemas of various genesis..
~20 Eorr the. preparation of medicaments to be adminis-tered orally, torasemide is mired in per se, l~nown manner. with suitable pharmaceutical carrie r substances, aroma, flavouring and colouring rnater3als~and formed, f.or example, as tablets or d~agees or, with the addition of appropriate adjuvants,, suspended or dissolved in water or oil." such as e,,g" olive oil, _10_.
For the production of a pharmaceutical preparation to be administered parenterally~ torasemide~, possibly in the form of its pharmacologically acceptable salts, is suspended or dissolved in water in per se known way' with addition of appropriate adjuvants~ srch as' e-..g.. emul~ifiera-, morasemide is administered in amounts between 5 and 40 mg per. dayv An exemplary formulation for a tablet with lCl mg of active material is composed as followa~:
~torasemide 10,0 mg ' hactose .. 1 H20 116"0 mg maize ~ta.rch 32,.0 mg colloidal silicon dioxide 1,2 mg 1.5 magnesium stearate: 0,4 - 1,0 mg weight of a. ta~blea. 159.6 - 160,2 mg An exemplary formulation for a pharmaceutical preparation to be administered parenterallg with 10 mg of active material. is composed as~follows:
sodium tora~semide= 10,631 mg e~odium. hydrox~.de:: 0,05 mg tromeatamoT (,2-amino-2-hydraacymethy~l-.~ 025 m f."3-propanediol) ~ g macrogol (polye.thylena glycols) 225,00 mg 2'S wa?ter 1804"069 mg ni trrogen q's,~
_8_ placebo, 6 rats received a torasemide injections 7 rats received placebo, The evaluated results of the TCP and blood pressure measurements are set out in Fig, 4 a:nd 5, respect~:valy, Fig,. 4 shows that the TCP in the case of the xats~
treated with toras.emide was, as every point o:f time, lower than in the case of animals treated with placebo in the para:;llel experiment,. However" the differences' were. not statistically significant, Therefore, for the ve~xification of the finding, the cerebral perfusion pressure was also determined (the cerebral.perfusian pressure iw equal to the difference between the systemic average. arterial blood pre.ssure~ and the: ICP), It way thereby found. (see Fig, 6) that the values thereof 90 and T00.minutes; ofter the~administration of tora~s~mide were. significantly higher' than in the control graup, This was mainly to be attributed to the much Lower TCP values.~in the rats~treated with tara~semide" 'In Fig, 4 t:o 6 are. plot~tad arithmetic average values (~c)~ -~ Wit. against the: time, The testing far significant differences between the exp~.riinente~.
groups treated with taras~emaLde. arid placebo took place by means a~f a one-sided Student t-test for unpaired data,.
25. ~ummarising",it can be raids Not only the. in vitro.
experiments with C6 glioma cells but also the i~a vivcov experiments on rats show that torasemide acts ~1087~~
swelling-inhibitingly or pressure lowering in tl~e Case of induced swelling of the glia cells and increased ZCl'~. Torasemide is,, therefore, also favourable because - as has been:escertained in experiments with C6 glioma cells (see above) --torasemide does. no.t inpair the. vitality of the- gT.ia cells; this is reduced in the. same experimental procedure e.,g" by amiloride. Possible causes for~the pharmacological action observed with torasemide but 1~~ not with e,.g, furosemide and bumetanide is the high lipophilia of torasemide (octanol/H20 coefficient:
/ 0.71., a The preparation of torasemide takes place according to the proces<:s described in the Patent specification DE 25 l6 025 C2,.
On the basis of its high bioavailability~; tora-semide.can be used in equivalent dose not only orall~r but also parenterall~ for the therapy of brain oedemas of various genesis..
~20 Eorr the. preparation of medicaments to be adminis-tered orally, torasemide is mired in per se, l~nown manner. with suitable pharmaceutical carrie r substances, aroma, flavouring and colouring rnater3als~and formed, f.or example, as tablets or d~agees or, with the addition of appropriate adjuvants,, suspended or dissolved in water or oil." such as e,,g" olive oil, _10_.
For the production of a pharmaceutical preparation to be administered parenterally~ torasemide~, possibly in the form of its pharmacologically acceptable salts, is suspended or dissolved in water in per se known way' with addition of appropriate adjuvants~ srch as' e-..g.. emul~ifiera-, morasemide is administered in amounts between 5 and 40 mg per. dayv An exemplary formulation for a tablet with lCl mg of active material is composed as followa~:
~torasemide 10,0 mg ' hactose .. 1 H20 116"0 mg maize ~ta.rch 32,.0 mg colloidal silicon dioxide 1,2 mg 1.5 magnesium stearate: 0,4 - 1,0 mg weight of a. ta~blea. 159.6 - 160,2 mg An exemplary formulation for a pharmaceutical preparation to be administered parenterallg with 10 mg of active material. is composed as~follows:
sodium tora~semide= 10,631 mg e~odium. hydrox~.de:: 0,05 mg tromeatamoT (,2-amino-2-hydraacymethy~l-.~ 025 m f."3-propanediol) ~ g macrogol (polye.thylena glycols) 225,00 mg 2'S wa?ter 1804"069 mg ni trrogen q's,~
Claims (9)
- Use of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl] urea or of its pharmacologically acceptable salts for the manufacture of medicaments for the treatment of brain oedemas.
- 2. Use according to claim 1 for the manufacture of medicaments for the treatment of brain oedemas, which occur as a result of severe skull-brain traumas, cerebral ischaemia, strokes, metastases or epileptic fits.
- 3. Use according to claim 1 for the manufacture of medicaments for the treatment of cytotoxic brain oedemas initiated by hypoosmolar hyperhydration.
- 4. A pharmaceutical composition for the treatment of brain oedemas comprising a physiologically acceptable amount of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.
- 5. A pharmaceutical composition for the treatment of brain oedemas, which occur as a result of severe skull-brain traumas, cerebral ischaemia, strokes, metastases or epileptic fits, comprising a physiologically acceptable amount of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl]
urea or a pharmacologically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. - 6. A pharmaceutical composition for the treatment of brain oedemas initiated by hypoosmolar hyperhydration, comprising a physiologically acceptable amount of 1-isopropyl-3-[(4-m-toluideno-3-pyridyl)-sulfonyl]
urea or a pharmacologically acceptable salt thereof, in association with a pharmaceutically acceptable carrier. - 7. 1-isopropyl-3-[(4-m-Toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof for use in the treatment of brain oedemas.
- 8. 1-isopropyl-3-[(4-m-Toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof for use in the treatment of brain oedemas, which occur as a result of severe skull-brain traumas, cerebral ischaemia, strokes, metastases or epileptic fits.
- 9. 1-isopropyl-3-[(4-m-Toluideno-3-pyridyl)-sulfonyl] urea or a pharmacologically acceptable salt thereof for use in the treatment of brain oedemas initiated by hypoosmolar hyperhydration.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4113820.1 | 1991-04-27 | ||
| DE4113820A DE4113820A1 (en) | 1991-04-27 | 1991-04-27 | USE OF TORASEMIDE FOR THE TREATMENT OF HIRNOEDEMES |
| PCT/EP1992/000884 WO1992019245A1 (en) | 1991-04-27 | 1992-04-22 | Use of torasemide for the treatment of cerebral oedema |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2108794A1 CA2108794A1 (en) | 1992-10-28 |
| CA2108794C true CA2108794C (en) | 2003-06-24 |
Family
ID=6430498
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002108794A Expired - Lifetime CA2108794C (en) | 1991-04-27 | 1992-04-22 | Use of torasemide for the treatment of brain oedemas |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0583280B1 (en) |
| JP (1) | JP3429507B2 (en) |
| AT (1) | ATE141053T1 (en) |
| AU (1) | AU1669092A (en) |
| CA (1) | CA2108794C (en) |
| DE (2) | DE4113820A1 (en) |
| ES (1) | ES2093257T3 (en) |
| WO (1) | WO1992019245A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10894055B2 (en) | 2013-11-06 | 2021-01-19 | Aeromics, Inc. | Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate |
| US11084778B2 (en) | 2012-05-08 | 2021-08-10 | Aeromics, Inc. | Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE102008000737A1 (en) | 2008-03-18 | 2009-09-24 | Robert Bosch Gmbh | Hand tool, in particular hand-guided grinding machine |
| US9867837B2 (en) | 2011-03-01 | 2018-01-16 | Pharnext | Compositions for treating neurological disorders |
| US10010515B2 (en) | 2011-03-01 | 2018-07-03 | Pharnext | Therapeutic approaches for treating Parkinson's disease |
| US9241933B2 (en) | 2011-03-01 | 2016-01-26 | Pharnext | Compositions for treating amyotrophic lateral sclerosis |
| US9248111B2 (en) | 2011-03-01 | 2016-02-02 | Pharnext | Therapeutic approaches for treating parkinson's disease |
| UA113165C2 (en) * | 2011-03-01 | 2016-12-26 | APPLICATION OF A COMBINATION OF Baclofen AND ACOMPROSAT FOR THE TREATMENT OF NEUROLOGICAL DISEASES AND A COMPOSITION CONTAINING Baclofen AND ACAMPROSAT | |
| US9931326B2 (en) | 2011-03-29 | 2018-04-03 | Pharnext | Composition comprising torasemide and baclofen for treating neurological disorders |
| CN110054647B (en) * | 2019-05-23 | 2021-06-15 | 上海勋和医药科技有限公司 | Torsemide phosphate prodrug, preparation method and composition thereof |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB8809205D0 (en) * | 1988-04-19 | 1988-05-25 | Nye P C G | Treatment of oedema |
-
1991
- 1991-04-27 DE DE4113820A patent/DE4113820A1/en not_active Withdrawn
-
1992
- 1992-04-22 DE DE59206872T patent/DE59206872D1/en not_active Expired - Lifetime
- 1992-04-22 ES ES92909055T patent/ES2093257T3/en not_active Expired - Lifetime
- 1992-04-22 EP EP92909055A patent/EP0583280B1/en not_active Expired - Lifetime
- 1992-04-22 AU AU16690/92A patent/AU1669092A/en not_active Abandoned
- 1992-04-22 CA CA002108794A patent/CA2108794C/en not_active Expired - Lifetime
- 1992-04-22 WO PCT/EP1992/000884 patent/WO1992019245A1/en not_active Ceased
- 1992-04-22 JP JP50848692A patent/JP3429507B2/en not_active Expired - Lifetime
- 1992-04-22 AT AT92909055T patent/ATE141053T1/en active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11084778B2 (en) | 2012-05-08 | 2021-08-10 | Aeromics, Inc. | Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia |
| US11873266B2 (en) | 2012-05-08 | 2024-01-16 | Aeromics, Inc. | Methods of treating or controlling cytotoxic cerebral edema consequent to an ischemic stroke |
| US12503425B2 (en) | 2012-05-08 | 2025-12-23 | Aeromics, Inc. | Methods of treating or controlling cytotoxic cerebral edema |
| US10894055B2 (en) | 2013-11-06 | 2021-01-19 | Aeromics, Inc. | Pharmaceutical compositions, methods of making pharmaceutical compositions, and kits comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}4-chlorophenyl dihydrogen phosphate |
| US11071744B2 (en) | 2013-11-06 | 2021-07-27 | Aeromics, Inc. | Prodrug salts |
| US11801254B2 (en) | 2013-11-06 | 2023-10-31 | Aeromics, Inc. | Pharmaceutical compositions and methods of making pharmaceutical compositions comprising 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate |
| US12213987B2 (en) | 2013-11-06 | 2025-02-04 | Aeromics, Inc. | Prodrug salts |
| US12496308B2 (en) | 2013-11-06 | 2025-12-16 | Aeromics, Inc. | Methods of administering a pharmaceutically acceptable salt of 2-{[3,5-bis(trifluoromethyl)phenyl]carbamoyl}-4-chlorophenyl dihydrogen phosphate |
Also Published As
| Publication number | Publication date |
|---|---|
| CA2108794A1 (en) | 1992-10-28 |
| WO1992019245A1 (en) | 1992-11-12 |
| ES2093257T3 (en) | 1996-12-16 |
| DE4113820A1 (en) | 1992-10-29 |
| EP0583280B1 (en) | 1996-08-07 |
| DE59206872D1 (en) | 1996-09-12 |
| JP3429507B2 (en) | 2003-07-22 |
| ATE141053T1 (en) | 1996-08-15 |
| JPH06506677A (en) | 1994-07-28 |
| EP0583280A1 (en) | 1994-02-23 |
| AU1669092A (en) | 1992-12-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Szczeklik et al. | Circulatory and anti-platelet effects of intravenous prostacyclin in healthy men | |
| CA2108794C (en) | Use of torasemide for the treatment of brain oedemas | |
| Brezis et al. | Determinants of intrarenal oxygenation. I. Effects of diuretics | |
| Rosa et al. | A study of induced hyponatremia in the prevention and treatment of sickle-cell crisis | |
| KR850000072B1 (en) | 5- (2-formyl-3-hydroxyphenoxy) pentanoic acid | |
| US20160038474A1 (en) | Compositions and methods for the modulation of hemoglobin (s) | |
| Keim Jr et al. | Amphotericin B methyl ester hydrochloride and amphotericin B: comparative acute toxicity | |
| CN113166060A (en) | Treatment of sickle cell disease with pyruvate kinase activating compounds | |
| Schorah | The transport of vitamin C and effects of disease | |
| EP0359256A2 (en) | The use of inositoltrisphosphate in the treatment of tissue damage | |
| US5486530A (en) | Use of torasemide for the treatment of brain oedemas | |
| JPH06503359A (en) | Use of AICA riboside compounds for the treatment and prevention of tissue damage resulting from decreased blood flow | |
| US5686475A (en) | Application of riluzole in the treatment of mitochondrial diseases | |
| Itskovitz et al. | Reciprocal renal effects of dopamine and 5-hydroxytryptamine formed within the rat kidney | |
| JP2002527383A (en) | Histochrome and its use in treating acute myocardial infarction and ischemic heart disease | |
| Jacobs et al. | Terminal renal failure due to oxalosis in 14 patients | |
| Seibert et al. | Hemoglobin potentiates oxidant injury in isolated rat lungs | |
| Chan et al. | Methemoglobinemia, Heinz bodies, and acute massive intravascular hemolysis in lysol poisoning | |
| Langslet | Cardiac effects of antiparkinson drugs, local anesthetics, and tranquilizers | |
| Hatt et al. | A comparative study of the activity of a new agent, indapamide, in essential arterial hypertension | |
| EP1787987A1 (en) | Substituted fullerenes and their use as antioxidants | |
| Inagaki et al. | Preparation and optical characteristics of hemoglobin-free isolated perfused rat head in situ | |
| Clabots et al. | Acute kidney injury, seizures, and hypertonic hyponatremia secondary to mannitol intoxication in a dog | |
| JPH0381219A (en) | Remedy for gastric mucosal disorder | |
| Serreau et al. | Placental transfer of drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |