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CA 02108794 2002-09-13
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.
CA 02108794 2002-09-13
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
-4-
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'~~~
5-
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~~
-9-
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,~
