U.S. patent application number 12/418339 was filed with the patent office on 2009-09-24 for use of oxicam compounds.
Invention is credited to Dieter Binder, Eva Binder.
Application Number | 20090239852 12/418339 |
Document ID | / |
Family ID | 33479909 |
Filed Date | 2009-09-24 |
United States Patent
Application |
20090239852 |
Kind Code |
A1 |
Binder; Dieter ; et
al. |
September 24, 2009 |
USE OF OXICAM COMPOUNDS
Abstract
Methods of treating and/or preventing arteriosclerosis are
disclosed. In certain methods, a composition containing at least
one lornoxicam or lornoxicam analogue that inhibits cyclooxygenase
1 and cyclooxygenase 2 (COX 1 and COX 2), cannot cross the
blood/brain barrier under physiological conditions, and reduces the
prostaglandin E2-induced induction of the amyloid precursor protein
(APP) is administered to a subject to treat and/or prevent
arteriosclerosis in the subject.
Inventors: |
Binder; Dieter; (Wien,
AT) ; Binder; Eva; (Wien, AT) |
Correspondence
Address: |
FULBRIGHT & JAWORSKI L.L.P.
600 CONGRESS AVE., SUITE 2400
AUSTIN
TX
78701
US
|
Family ID: |
33479909 |
Appl. No.: |
12/418339 |
Filed: |
April 3, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10558117 |
Mar 2, 2007 |
|
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PCT/AT04/00185 |
May 27, 2004 |
|
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12418339 |
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Current U.S.
Class: |
514/226.5 |
Current CPC
Class: |
A61K 31/4439 20130101;
A61K 31/54 20130101; A61P 43/00 20180101; A61P 25/28 20180101; A61P
9/10 20180101 |
Class at
Publication: |
514/226.5 |
International
Class: |
A61K 31/542 20060101
A61K031/542; A61P 9/10 20060101 A61P009/10 |
Foreign Application Data
Date |
Code |
Application Number |
May 27, 2003 |
AT |
A 819/2003 |
Claims
1. A method of treating and/or preventing arteriosclerosis in a
subject comprising: obtaining a composition comprising at least one
lornoxicam or lornoxicam analogue that inhibits cyclooxygenase 1
and cyclooxygenase 2 (COX 1 and COX 2), cannot cross the
blood/brain barrier under physiological conditions, and reduces the
prostaglandin E2-induced induction of the amyloid precursor protein
(APP); and administering the composition to a subject.
2. The method of claim 1, wherein practice of the method results in
undesired side effects in less than 1% of subjects.
3. The method of claim 2, wherein practice of the method results in
undesired side effects in less than 0.5% of subjects.
4. The method of claim 3, wherein practice of the method results in
undesired side effects in less than 0.1% of subjects.
5. The method of claim 4, wherein practice of the method results in
undesired side effects in less than 0.05% of subjects.
6. The method of claim 1, wherein the composition comprises a
lornoxicam-analogue further defined as
6-chloro-4-(1-(ethoxycarbamoyloxy)-ethoxy)-2-methyl-N-(2-pyridyl)-2H-thie-
no-(2,3-e)-1,2-thiazine-3-carboxylic acid amide-1,1-dioxide or
6-chloro-4-hydroxy-2-methyl-3-(2-pyridyl-carbamoyl)-2H-thieno[3,2-e]1,2-t-
hiazine-1,1-dioxide.
7. The method of claim 1, wherein the subject is a human.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a divisional of U.S. application Ser.
No. 10/558,117 filed on Mar. 2, 2007, which is a U.S. national
phase application under 35 U.S.C. .sctn. 371 of International
Application No. PCT/AT04/00185 filed May 27, 2004, which claims
priority to Austrian Application No. A 819/2003 filed May 27, 2003.
The entire text of each of the above-referenced disclosures is
specifically incorporated by reference herein without
disclaimer.
BACKGROUND
[0002] The invention relates to the production of pharmaceutical
compositions for the treatment of Alzheimer's Disease and
arteriosclerosis.
[0003] The etiology of Alzheimer's Disease (AD) has not yet been
clarified. According to the "amyloid hypothesis" of AD, a change
occurs in the cleavage of the amyloid precursor protein (APP). The
so-called .beta.-42 peptide is deposited, whereby cerebral plaques
form. Also as a consequence of the resultant hypoperfusion,
neuronal degeneration occurs.
[0004] The treatment methods currently employed all comprise the
administration of cholinergic agents, in particular of inhibitors
of acetylcholinesterase, since AD involves substantial losses of
cholinergic neurons, and acetylcholinesterase inhibitors increase
the acetylcholin level, so that the remaining neurons remain
activated ("firing"). However, the progressive loss of neurons
unfortunately cannot be stopped by this treatment.
[0005] Further target molecules, the influencing of which is
currently being discussed and tested in the context of an AD
therapy, are secretase-modulating substances, in particular .beta.-
and .gamma.-secretase inhibitors, inhibitors of cholesterol
biosynthesis, inhibitors of amyloid aggregation, immunological
methods, in particular with the A-.beta. peptide or antibodies
against this peptide, prevention of the APP expression, increase of
the APP clearance, modulation of the phosphorylation of tau protein
and lowering of the serum amyloid P level (Wolfe, Nat. Rev. Drug
Discov. 1 (2002) 859-866).
[0006] In US 2002/0052407 A1, U.S. Pat. No. 6,187,756 B1 and U.S.
Pat. No. 6,184,248 B1, substance mixtures are disclosed which
contain non-steroidal anti-inflammatory drugs (NSAID) for
inhibiting an abnormal expression of the amyloid precursor protein
(APP) which is known to be involved in Alzheimer's Disease. By
means of in vitro and in vivo tests it could be shown in the
examples that the inventive substances inhibit the over-expression
of APP. All three documents suggest the use of non-steroidal
anti-inflammatory drugs which only inhibit cyclooxygenase-2, yet
not cyclooxygenase-1, for the prevention or possible healing of
Alzheimer's Disease.
[0007] Furthermore, in these documents cyclooxygenase-2 inhibitors
exclusively are claimed. Oxicams and, in particular, lornoxicam or
analogous compounds are not disclosed therein.
[0008] In WO 93/24115 A1, a method for treating dementia, in
particular Alzheimer's Disease, by administering non-steroidal
anti-inflammatory drugs has been described. Besides a number of
other substances, also oxicams, in particular piroxicam, isoxicam
and sudoxicam have been suggested, yet not lornoxicam or analogous
compounds.
[0009] In WO 01/78721 A1, a method for the prevention and/or for
the healing of Alzheimer's Disease by administering substances that
reduce the content of the amyloid-.beta.-polypeptide (A.beta.)
A.beta..sub.42 is described. Since a high expression rate of
A.beta..sub.42 is held responsible for the development of
Alzheimer's Disease, the course of the disease can be positively
influenced by reducing this polypeptide. In this document,
moreover, a test is described in which the influence of various
NSAIDs on the expression rates of two A.beta.-polypeptides,
A.beta..sub.40 and A.beta..sub.42, are shown. From this it results
that oxicams, in particular meloxicam, peroxicam, isoxicam and
tenoxicam (lormoxicam or analogous compounds thereof are not
mentioned here) do not influence the expression of A.beta..sub.42
and even increase the expression thereof, respectively. From this
document, therefore, the person skilled in the art could derive
that oxicams have proven as not advantageous to be used for the
reduction of A.beta..sub.42.
[0010] From US 2002/0119193 A1, pharmaceutical compositions are
apparent which i.a. contain selective cyclooxygenase-2 inhibitors
and are used for the treatment of various diseases, among them
Alzheimer's Disease. According to this document, the inventive
cyclooxygenase-2 inhibitors have advantages over the conventional,
non-steroidal, anti-inflammatory active substances. Thus, also the
teaching of this document leads away from the use of oxicams which
inhibit both cyclooxygenase-1 and cyclooxygenase-2.
[0011] None of the previously described concepts, however, has
actually enabled a breakthrough in the efficient treatment and,
above all, in the prevention of AD. Therefore, medicinal treatment
and prevention measures for AD are still urgently needed.
SUMMARY OF THE INVENTION
[0012] Accordingly, the present invention relates to the use of
lornoxicam or lornoxicam analogues for producing a pharmaceutical
composition for the treatment or prevention of Alzheimer's Disease
(AD) or of arteriosclerosis.
[0013] Only recently it has been found that peripheral platelets
are the primary source of the .beta.-42 peptide deposited in the
cerebral plaques. With this finding, AD is to be defined as a
vascular disease. The new etiological interpretation is supported
by the results of clinical studies which show that non-steroidal
anti-inflammatory drugs (NSAIDs) alleviate symptoms of AD. These
studies in turn were based on the hypothesis that AD were an
inflammatory disease of the brain, various causes for the
inflammatory symptoms having been mentioned. Thus, by administering
from 100 to 150 mg of indometacin per day, the cognitive
degradation could be reduced by approximately 9% over 6 months.
Likewise, it has been known that NSAIDs have an influence on APP
protein expression and processing in that they reduce the
prostaglandin E2-induced APP expression and at the same time cause
changes in the cleavage of APP.
[0014] In studies with Ibuprofen and Indometacin it could be
demonstrated that the portion of the amyloid .beta.-42 peptide is
lowered and that of the non-amyloidogenic soluble APP is increased.
From the fact that platelets are a primary source of the proteins
in amyloid plaques, there also results a correlation to
arteriosclerotic diseases.
[0015] Here, too, the NSAID-caused reduction of the APP expression
in platelets, the change in the cleavage of the platelet-APP with a
reduction of the plasma A-.beta. and an increase in the
non-amyloidogenic soluble APP, the reduction of the amyloid plaques
in the cerebral vessels and the reduced cerebrovascular
hypoperfusion are the basic mechanisms of the therapeutic
effect.
[0016] Therefore, the present invention is based on the idea that
the underlying cause of sporadic AD is a vascular disturbance and
that the primary source of the cerebrovascular deposition of
.beta.-42 are the peripheral platelets.
[0017] With the use according to the invention, the expression of
APP in platelets is selectively prevented, and the cleavage of
platelet APP is influenced, wherein the plasma A-.beta. level
decreases and the level of non-amyloidogenic soluble APP increases.
On account of the reduced plaque formation in the cerebral vessels,
cerebrovascular hypoperfusion does not occur, whereby the
neurodegeneration is reduced.
[0018] One of the essential pre-requisites for the use according to
the invention is that the inventive substance, i.e. lornoxicam or a
lornoxicam-analogue, inhibits both central isozymes of the
eicosanoid metabolism, i.e. COX-1 and COX-2. Particularly the fact
that the isozyme COX-2 is associated with inflammatory processes
has supported the prevailing opinion which suggested the use of
COX-2-selective brain-effective drugs. However, since according to
the above-mentioned new findings peripheral platelets expressing
COX-1 only are the primary source of the plaque protein, according
to the invention both inhibiting activities must be provided in an
efficient treatment and prevention agent.
[0019] Since in the brain COX-2 is also constitutively expressed,
with a view to the peripheral occurrence of the platelets, the
brain-effectiveness of an active substance must be considered not
only as undesirable, but, much rather, even as a disadvantage,
since the inhibition of a constitutively expressed enzyme as a rule
causes the inhibition of physiological processes and, thus, may
cause drug side effects. Thus, also the property of the agents to
be used according to the invention of not crossing the blood-brain
barrier is an important characteristic according to the
invention.
[0020] The effectiveness of lornoxicam or of lornoxicam analogues
within the scope of the present invention has also been surprising
in view of the prior art, in particular in view of the findings
provided in WO 01/78721 A1, since the oxicams described there, in
particular meloxicam, peroxicam, isoxicam and teroxicam, either
could not influence the expression of A.beta..sub.42 or even
increased them.
[0021] According to the present invention, however, lornoxicam and
its analogues have proved extremely advantageous in the treatment
and, above all, in the prevention or slowing down of AD and
arteriosclerosis. By "lornoxicam analogues" within the scope of the
present invention all substances are to be understood
which--derived from the lornoxicam structure--have the same basic
effect in the peripheral platelets as lornoxicam or an effect
comparable thereto with regard to A.beta.-42, which means that
they
[0022] inhibit cyclooxygenase-1 and cyclooxygenase-2 (COX-1 and
COX-2),
[0023] cannot cross the blood/brain barrier under physiological
conditions, and
[0024] reduce the prostaglandin E2-induced induction of the amyloid
precursor protein (APP).
[0025] Examples of such lornoxicam analogues are enolether of
6-chloro-4-hydroxy-2-methyl-N-(2-pyridyl)-2H-thieno(2,3-e)-1,2-thiazine-3-
-carboxylic acid amide-1,1-dioxide (as described in EP 0 313 935
A1, and in particular claimed by EP 0 313 935 B1),
4-hydroxy-2-methyl-3-(2-pyridylcarbamoyl)-6-trifluoromethyl-2H-thieno[2,3-
-e]-1,2 thiozine-1,1-dioxide (as described in EP 0 103 142 A1 and
in particular, claimed in EP 0 103 142 B1); thienothiazine
derivatives according to EP 0 001 113 A1 (B1) having the general
formula I
##STR00001##
wherein A together with the two carbon atoms of the thiazine ring
forms the group
##STR00002##
and the broken line indicates the double bond present in the first
and in the last instance, R.sup.1 represents lower alkyl, R.sup.2
represents 2-thiazolyl, 4-methyl-2-thiazolyl,
4,5-dimethyl-2-thiazolyl, 5-methyl-1,3,4-thiadiazolyl, 2-pyrazinyl,
2-pyrimidinyl, 1,2,4-triazin-3-yl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
3-methyl-2-pyridyl, 4-methyl-2-pyridyl, 5-methyl-2-pyridyl,
6-methyl-2-pyridyl, 4,6-dimethyl-2-pyridyl, 5-isoxazolyl,
5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl,
2,6-dimethyl-4-pyrimidinyl, 1,2,3,4-tetrazol-5-yl or a phenyl
residue optionally substituted by halogen, hydroxy, lower alkyl,
trifluormethyl or lower alkoxy, and R.sup.3 represents halogen, as
well as salts thereof, wherein the term "lower alkyl" means
straight-chain or branched saturated hydrocarbon groups with 1-4
carbon atoms, such as, e.g., methyl, ethyl, propyl, isopropyl and
t-butyl; the term "lower alkoxy" relates to hydrocarbonoxy groups
with up to 4 C atoms, and the term "halogen" refers to the 4
halogens chlorine, bromine, fluorine, iodine; particularly
preferably, R.sup.3 represents chlorine or bromine, wherein
chlorine is particularly preferred; R.sup.1 preferably represents
the methyl group; R.sup.2 preferably represents 2-thiazolyl,
5-isoxazolyl or 2-pyridyl; A preferably is the group
##STR00003##
further preferred are
[3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydropyrrolo[3',2':4,5]-cyclopen-
ta[1,2-c]pyridine derivatives of the general formula
##STR00004##
or [3a.alpha.,
8b.alpha.)]-1,2,3,3a,4,8b-hexahydropyrrolo[2',3':3,4]-cyclopenta[1,2-b]py-
ridine-derivatives of the general formula
##STR00005##
wherein: Z represents a single bond or CH.sub.2, R1 represents
hydrogen or a straight-chain or branched, optionally unsaturated
lower-alkyl residue which may also be perfluorinated, R2 and R3
independently represent hydrogen, a straight-chain or branched,
optionally unsaturated lower alkyl residue which may also be
perfluorinated, lower-alkoxy, lower-alkyl-thio or halogen, as well
as their optically pure antipodes and pharmaceutically usable
salts.
[0026] Compounds of the general formulas (II) and (III) can be
produced by reductively converting a compound
##STR00006##
wherein R2 and R3 are as defined above, into the compound of the
general formula II or III, wherein Z=single bond and R1=hydrogen,
optionally reacting it with enantiomerically pure
1-phenylethyl-isocyanate to the compound of the general formula
##STR00007##
recovering from the thus obtained diastereomeric mixture the less
readily soluble diastereomer by crystallization, cleaving the thus
obtained diastereomerically pure compound of the general formula
(Va) or (Vb) under suitable conditions to the enantiomerically pure
compound of the general formula (II) or (III), wherein Z=single
bond and R1=hydrogen, optionally reacting it under alkylating
conditions to compounds of the general formula (II) or (III),
wherein Z=CH.sub.2, and optionally converting the compound of the
general formula (II) or (III) as well as its racemic mixture into
its pharmaceutically usable salts, wherein the term "lower alkyl"
means a straight-chain or branched alkyl residue with 1-4 carbon
atoms, e.g. methyl, ethyl, n- and i-propyl, n-, i- and t-butyl; the
term "lower alkoxy" means a straight-chain or branched alkoxy
residue with 1-4 carbon atoms, e.g. methoxy, ethoxy, n- and
i-propoxy, n-, i- and t-butoxy; the term "lower-alkyl-thio" means a
straight-chain or branched alkyl-thio residue with 1-4 carbon
atoms, e.g. methyl-thio, ethyl-thio, n- and i-propyl-thio, n-, i-
and t-butyl-thio; and the term "halogen" means fluorine, chlorine,
bromine or iodine.
[0027] The reactions according to the invention are best carried
out by dissolving the compound of the general formula (IVa) or
(IVb) in a polar solvent, such as, e.g., acetic acid ethyl ester,
dioxane, ethanol or methanol, admixing 1-5 equivalents of a
suitable catalyst, such as, e.g., W2-Raney Nickel or Raney Cobalt
and the like, and hydrogenating at 40 to 70.degree. C. up to a
stoichiometric hydrogen uptake. For separation of the enantiomers,
the thus obtained racemic compound of the general formula (II) or
(III), wherein Z=single bond and R1=hydrogen, can be reacted in an
inert solvent, such as, e.g., tetrahydrofurane, dioxane or acetone,
with 1 equivalent (+) or (-) 1-phenylethylisocyanate to obtain a
compound of the general formula (Va) or (Vb), and from the
diastereomeric mixture thus obtained, the less readily soluble
diastereomer can be recovered by crystallization. For cleavage the
thus obtained diastereomerically pure compound of the general
formula (Va) or (Vb) is dissolved in a high-boiling alcohol, such
as, e.g., propanol, butanol, pentanol, glycol etc. or the aqueous
mixtures thereof, and heated for 1-24 hours to boiling with 5-20
equivalents of a base, such as sodium propanolate, -butanolate,
-pentanolate or sodium hydroxide. The thus obtained
enantiomerically pure compound of the general formula (II) or
(III), wherein Z=single bond and R1=hydrogen, as well as its
racemic form, optionally is dissolved for alkylation in an inert
solvent, such as, e.g., tetrahydrofurane, dioxane, acetonitrile or
dimethylformamide etc., admixed with 1-20 equivalents of the
compound of the formula
R1-CHO (VI),
wherein R1 is as defined above, and 1.5-4 equivalents of a reducing
agent, such as, e.g., sodium cyanoborohydride or the like, and
reacted at -20.degree. C. to 100.degree. C. for between 1 and 24
hours.
[0028] The compounds of the general formula (II) or (III) obtained
in this reaction are basic compounds and can be converted into
their pharmaceutically compatible salts in a conventional manner by
means of inorganic or organic acids. Salt formation can be effected
e.g. by dissolving the compounds of the formula (II) or (III) in a
suitable solvent, e.g. water, a lower aliphatic alcohol, THF,
dioxane, benzene, diethyl ether, DMF or DMSO, admixing an
equivalent amount of the desired acid, providing for a good mixing
and withdrawing the solvent under vacuum when the salt formation
has been completed. Optionally, the salt can be re-crystallized
after isolation.
[0029] Further preferred examples of the inventive lornoxicam
analogues are the subject matter of AT 400 567 B and of AT 400 437
B, in particular the substances described in claims 2, 3, 4, 5, 6,
7, 8, 9, 10, 11 or 12 of AT 400 567 B and in claims 2, 3 or 4 of AT
400 437 B. Further lornoxicam analogues preferred according to the
present invention are disclosed in EP 0 657 459 A1, in particular
the substances claimed in claims 2, 3 and 4 thereof.
[0030] Pharmaceutically usable salts are those of strong inorganic
acids, such as, e.g., hydrochloric acid, hydrobromic acid, sulfuric
acid etc., but also those of organic acids, such as, e.g., fumaric
acid, citric acid, sebacic acid, etc.
[0031] Preferably, the administration of the substance should not
entail any severe undesired events, i.e. it should be free from
side-effects. By this, the prophylactic intake of this substance
for preventing AD or arteriosclerosis becomes possible without
confronting the patient with undesired side reactions. A
prophylactic treatment is primarily indicated for those persons who
have a high risk of AD or arteriosclerosis, be it by genetically
caused circumstances (familial accumulation of such diseases) or by
other parameters. For defining the freedom from side-effects
according to the present invention, the definitions provided in
relevant pharmaceutical textbooks and standard literature can be
resorted to. For example, the side-effects found during observation
of usage should be below 1%, preferably below 0.5%, more preferably
below 0.1%, in particular below 0.05%. Optionally, the substances
according to the invention can be combined with further drugs,
particularly those which counteract possible negative effects, such
as, e.g., gastric mucosa initiating properties, (e.g. antacids, H2
receptor antagonists, proton pump inhibitors, . . . ). This must be
considered primarily in case of long-term applications.
[0032] Besides lornoxicam, substances particularly preferred to be
used within the scope of the present invention are primarily [0033]
6-chloro-4-(1-(ethoxycarbamoyloxy)-ethoxy)-2-methyl-N-(2-pyridyl)-2H-thie-
no-(2,3-e)-1,2-thiazine-3-carboxylic acid amide-1,1-dioxide, [0034]
6-chloro-4-hydroxy-2-methyl-3-(2-pyridyl-carbamoyl)-2H-thieno[3,2-e]1,2-t-
hiazine-1,1-dioxide, [0035]
(+)-[3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydropyrrolo[2',3':3,4]cyclo-
penta[1,2-b]pyridine-dihydrochloride; [0036]
(+)-[3aS-(3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydropyrrolo-[3',2':4,5-
]cyclopenta[1,2-c]pyridine-dihydrochloride; [0037]
(-)-[3aR-(3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydropyrrolo-[3',2':4,5-
]-cyclopenta[1,2-c]pyridine-dihydrochloride; [0038]
(-)-[3a.alpha.,8b.alpha.]-1,2,3,3a,4,8b-hexahydropyrrolo-[2',3':3,4]-cycl-
openta[1,2-b]pyridine-dihydrochloride; [0039]
(-)-[(3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo-[2',-
3':3,4]-cyclopenta[1,2-b]pyridine-dihydrochloride; [0040]
(+)-[3aS-(3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo--
[3',2':4,5]-cyclopenta[1,2-c]pyridine-dihydrochloride; [0041]
(+)-[3a.alpha.,8b.alpha.]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo-[2',3'-
:3,4]-cyclopenta[1,2-b]pyridine-dihydrochloride; [0042]
(+)-[3aS-(3a.alpha.,8b.alpha.)]-1,2,3,3a,4,8b-hexahydro-1-methyl-pyrrolo--
[3',2':4,5]cyclopenta[1,2-c]pyridine-dihydrochloride.
[0043] The particular advantage according to the invention of the
application of lornoxicam as well as of the lornoxicam analogues
results from a particularly advantageous combination of the
pharmacodynamic and pharmacokinetic properties of this active
substance.
[0044] According to the present invention, the pharmaco-dynamic
particularities of lornoxicam or lornoxicam analogues causing the
invention are the following:
[0045] One particularly important property which causes the
particular inventive suitability of lornoxicam resides in the fact
that the substance inhibits both central isozymes of the eicosanoid
metabolism, i.e. COX-1 and COX-2. The henceforth established fact
that peripheral platelets expressing COX-1 only, are the primary
source of the plaque protein, is the reason for the superiority of
the inventive application of lornoxicam and its analogues,
respectively, which have a significant inhibition of COX-1.
[0046] Moreover, lornoxicam is an active substance with a
particularly high intrinsic activity. Since a therapy for the
prevention of AD and of arteriosclerosis, respectively, must last
over an extended period of time, a reduced load of active substance
on the body constitutes a further advantage.
[0047] Furthermore, lornoxicam is not capable of crossing the
blood-brain barrier (Pruss et al., 3. Interscience World Conference
on Inflammation, Monte Carlo (1989), Abstract 41).
[0048] In view of the extended duration of a preventive therapy of
AD with lornoxicam, the short plasma half-life of lornoxicam is a
special advantage since by this a cumulation in blood will not
occur. Likewise, the known good gastro-intestinal and other
tolerance of the active substance is of great importance. Thus, in
one million of prescriptions, less than 10 severe undesired events
have been reported, and the side-effects found during observation
of usage have been far below 0.05% (wherein so far all the side
effects could be repaired again).
[0049] The said combination of pharmaco-dynamic and
pharmaco-kinetic properties of the active substance lornoxicam in a
constellation which is particularly favorable for the purpose of
the therapy of AD and of arteriosclerotic diseases is not found in
any other hitherto known substance in a comparable way.
[0050] The invention will be explained in more detail by way of the
following examples as well as the drawing figures to which,
however, it shall not be restricted.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] Therein,
[0052] FIGS. 1, 2 and 3 show the arachidonic acid pathway and its
correlation with COX-1 and COX-2;
[0053] FIG. 4 shows the COX-inhibiting effect of some
substances;
[0054] FIG. 5 shows the lornoxicam pharmaco-kinetics in healthy
young volunteers after an oral single dose;
[0055] FIG. 6 shows the inhibition of COX-1-derived TXB2 from whole
blood during coagulation by lornoxicam;
[0056] FIG. 7 shows the inhibition of the eicosanoid formation in
HEL cells (COX-1) and LPS-stimulated Mono Mac 6-cells (COX-2) by
lornoxicam.
DETAILED DESCRIPTION OF THE ILLUSTRATIVE EMBODIMENTS
Examples
Example 1
Effect of Lornoxicam on APP Processing In Vitro and In Vivo
[0057] 1.1. Characterization of a specific influence on APP
cleavage in vitro: [0058] 1.1.1. Influence of lornoxicam on APP
processing in neuronal cell line (SH-SY5Y) [0059] Release of the
amyloid .beta.-42 peptide (lowered by NSAIDs) [0060] Release of the
non-amyloid sAPP.alpha. protein (increased by NSAIDS) [0061]
Expression of the APP holoprotein (lowered by NSAIDs)
1.2. Characterization of Human Thrombocytes as Peripheral Model for
the Effect of Lornoxicam on Nerve Cells
[0062] In peripheral thrombocytes of patients suffering from
Alzheimer's Disease it has been demonstrated that the non-amyloid
sAPP.alpha. protein is also produced in a reduced amount (Colciaghi
et al., Mol. Med. 8 (2002), 67-74). The expression of the
non-amyloid sAPP.alpha. can be increased in nerve cells by NSAIDs
(Avramovich et al., J. Biol. Chem. 277 (2002), 31466-73). The
results of these two studies lead to the expectation that the
non-amyloid sAPP.alpha. protein is very well suited to peripherally
observe the specific activity of lornoxicam.
1.2.1. Influence of Lornoxicam on APP-Processing in Human
Thrombocytes In Vitro
[0063] Release of non-amyloid sAPP.alpha. protein of activated
thrombocytes
1.2.2. Influence of Lornoxicam on APP-Expression of Human
Thrombocytes of Alzheimer's Disease Patients In Vivo Expression of
APP-holoprotein
[0064] (This parameter is meaningful if lornoxicam does not have a
specific influence on APP processing, since APP holoprotein is
expressed in increased amounts in the frontal cortex (Golde et al.,
Nueron 4 (1990), 253-267) and NSAIDs can reduce its expression. In
an ongoing study, also increased APP holoprotein expression has
been demonstrated on thrombocytes of Alzheimer patients). [0065]
APP ratio of the thrombocytes of Alzheimer's Disease patients
before and after treatment with lornoxicam. [0066] Release of the
non-amyloid sAPP.alpha. protein of activated thrombocytes These
investigations are aimed at the in vivo-monitoring on peripheral
blood thrombocytes for the postulated effect of lornoxicam on nerve
cells. 2.2. Protein-Profiling (Proteomics) of Human Thrombocytes
after In Vivo Administration of Lornoxicam
[0067] Comparison of the thrombocyte proteome of Alzheimer's
Disease and healthy individuals before and after lornoxicam
medication.
[0068] These investigations were aimed at the in vivo-protein
profiling of the effect of lornoxicam on human thrombocytes.
2.3. Influence of Lornoxicam on the Pharmacoproteomics of Human
Thrombocytes In Vitro: Protein-Profiling (Proteomics) of Human
Thrombocytes After In Vitro Incubation with Lornoxicam
[0069] Comparison of the thrombocyte proteome of lornoxicam-treated
thrombocytes with non-treated control thrombocytes.
[0070] This example is aimed at the characterization of the
thrombocyte proteins which are directly affected by the
cyclooxygenase-inhibitor lornoxicam.
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