U.S. patent application number 10/837370 was filed with the patent office on 2004-10-14 for use of 5ht3-receptor-antagonists.
Invention is credited to Welzel, Dieter.
Application Number | 20040204467 10/837370 |
Document ID | / |
Family ID | 7892223 |
Filed Date | 2004-10-14 |
United States Patent
Application |
20040204467 |
Kind Code |
A1 |
Welzel, Dieter |
October 14, 2004 |
Use of 5HT3-receptor-antagonists
Abstract
A method of treatment for Chronic Fatigue Syndrome (CFS)
comprising reducing the effect of serotonin by administering a
dosage unit comprised of 5HT.sub.3-receptor-antagonist in an amount
effective to decrease the effect of serotonin.
Inventors: |
Welzel, Dieter; (Nurnberg,
DE) |
Correspondence
Address: |
BACHMAN & LAPOINTE, P.C.
900 CHAPEL STREET
SUITE 1201
NEW HAVEN
CT
06510
US
|
Family ID: |
7892223 |
Appl. No.: |
10/837370 |
Filed: |
April 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10837370 |
Apr 30, 2004 |
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09868972 |
Sep 4, 2001 |
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6740672 |
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Current U.S.
Class: |
514/381 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 3/02 20180101; A61P 29/00 20180101; A61K 31/415 20130101; A61P
21/00 20180101; A61P 43/00 20180101; A61P 11/04 20180101; A61P
25/20 20180101 |
Class at
Publication: |
514/381 |
International
Class: |
A61K 031/41 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 22, 1998 |
DE |
198 59 406.2 |
Claims
1. A method of treatment for Chronic Fatigue Syndrome (CFS)
comprising reducing the effect of serotonin by administering a
dosage unit comprised of 5HT.sub.3-receptor-antagonist in an amount
effective to decrease the effect of serotonin.
2. The method of claim 1, wherein the
5HT.sub.3-receptor-antagonists is selected from the group
consisting of Alosetron, Tropisetron, Ondansetron, Granisetron,
Bemesetron, and mixtures thereof.
3. The method of claim 1, wherein said administering step comprises
administering said 5HT.sub.3-receptor-antagonist in an amount of 2
to 10 mg.
4. The method of claim 1, wherein said administering step comprises
administering a daily dosage of said 5HT.sub.3-receptor antagonist
in an amount from 2 to 20 mg.
5. The method of claim 1, wherein said
5HT.sub.3-receptor-antagonist is administered orally.
6. The method of claim 1, wherein said administering said dosage
unit comprises administering said dosage unit comprising
Tropisetron.
7. The method of claim 6, wherein said administering said dosage
unit comprises administering said dosage unit comprising
Tropisetron and at least one substance selected from the group
consisting of Alosetron, Ondansetron, Granisetron, Bemesetron and
combinations thereof.
8. The method of claim 1, wherein said
5HT.sub.3-receptor-antagonist is administered intravenously.
9. The method of claim 3, wherein said amount of said
5HT.sub.3-receptor-antagonist contained in said dosage unit is 5 to
8 mg.
10. The method of claim 4, wherein said daily dosage of said
5HT.sub.3-receptor-antagonist comprises an amount of said
5HT.sub.3-receptor-antagonist from 5 to 16 mg.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a continuation of U.S. patent
application Ser. No. 09/868,972, filed Sep. 4, 2001.
BACKGROUND OF THE INVENTION
[0002] The present invention relates to a new use for
5HT.sub.3-receptor-antagonists. CFS, chronic fatigue syndrome, was
defined as a diagnostic entity at the end of the eighties and has
been the subject of numerous studies and publications. Particularly
problematic with respect to the diagnosis of CFS is the fact that a
complex of symptoms of pathological fatigue and susceptibility to
fatigue is present, wherein the present symptoms are at least
partially also to be encountered in a number of other internistic
and psychiatric illnesses.
[0003] Thus, one must note the absence of symptoms, other than
those which can be attributed to other illnesses, useful when
diagnosing CFS.
[0004] Principally there is the question of what fatigue actually
is. Generally, it is referred to as a physiological lack of
capability, but may also be felt as lack of drive, lack of stamina
and physical weakness. Mental fatigue can be divided into a bad
ability to concentrate and remember, lack of interest in activities
and sleepiness throughout the day.
[0005] On the other hand, fatigue is a natural phenomenon occurring
after physical or psychological stress which goes away after
resting or sleeping. Thus, the differentiation between "normal" and
"abnormal" fatigue is of importance. It is helpful to note that
patients suffering from CFS usually also suffer from further
symptoms which can be employed for diagnosis.
[0006] Since comparatively short term conditions of fatigue may
occur during or after an illness or under strong and lasting
stress, one concludes the presence of CFS as chronic illness only
on the occasion of symptoms persisting for at least six months.
[0007] Generally, the presence of CFS is determined in a patient in
whom the fatigue is medically not explainable even after careful
clinical investigation. It is generally acknowledged that patients
with a defined organic illness are to be excluded from the group of
CFS patients. With respect to psychological illnesses, there is
less agreement in relation to a corresponding exclusion. Some
scientists are of the opinion that patients suffering from
depression and anxiety should be excluded since an appropriate
explanation for the fatigue in these patients is present. Other
scientists are of a different opinion.
[0008] In the presence of CFS, symptoms of chronic mental and
physical fatigue usually occur which grow worse with activity and
are often accompanied by pain in the muscles. In this respect,
patients frequently report that they are fit and capable for a
short period of time, but then suffer from heavy fatigue for hours
or days. Further symptoms that ordinarily are reported include
non-relaxing sleep, dizziness and breathlessness as well as head
aches and further symptoms. Depressive periods and conditions of
anxiety also occur in part of the patients. The diagnosis of CFS is
therefore always a diagnosis by means of exclusion.
[0009] Until now no effective way of treatment could be found for
treating CFS. Frequently antidepressants are employed for therapy,
but a first comprehensive, randomized placebo-controlled
investigation on antidepressants was negative in result (Vercoulen,
Jan H. M. M. et al., Lancet 1996, 347:858-61). The subject of the
referenced investigation was fluoxetin, wherein in the end not even
patients with accompanying symptoms of depression showed a positive
result in response to a daily dose of 20 mg fluoxetin. This already
points out a specific pathogenesis of CFS in contrast to depressive
illnesses.
[0010] Since fluoxetin is a selective serotonin reuptake inhibitor,
the referenced investigation concludes that an influence of
disorders in serotonin metabolism on the occurrence of depression
like symptoms in depressive CFS-patients is unlikely. In this
connection reference is made to an investigation relating to
serotonin processes in associaton with CFS (Yatham L. N. et al.,
Can. J. Psychiatry 1995, 40, 93-96).
[0011] Studies indicate there are concrete indications for
serotonic activity in the brain, such as is shown by the
significantly increased rise of prolactin in the serum after an
acute application of D-Feufluoroamin on patients with CFS.
[0012] It is generally to be noticed that indications of a
convenient and effective therapy for the treatment of CFS are
lacking.
SUMMARY OF THE INVENTION
[0013] It is object of the present invention to provide compounds
that are suitable for the manufacture of drugs for the treatment of
CFS.
[0014] The present object is achieved by the features of claim 1.
Advantageous embodiments of the invention form the subject matter
of the depending claims.
DETAILED DESCRIPTION
[0015] The present invention is based on the finding that the use
of antidepressants with CFS which amplify the action of serotonin
is not appropriate, which is also evidenced by the cited study with
respect to fluoxetin. First, this is a turn away from therapeutic
methods that were customary until now and which essentially were
focussed on the presence of depressive conditions. Thus, the use of
substances is suggested which reduces the effect of serotonin and
which are canalized by the subgroup of the so called
5HT.sub.3-receptors. According to the invention, the
pharmacologically known class of the highly specific
5HT3-receptor-antagonists, which for example find application in
the treatment of the emesis in the chemotherapy of cancer, are
suited for this purpose.
[0016] In an advantageous embodiment of the present invention
Alosetron, Tropisetron, Ondansetron, Granisetron, Bemesetron or
combinations of at least two of the foregoing, very selective
acting substances are employed as 5HT.sub.3-receptor-antagonists.
In this respect it is preferred that the amount of active substance
in one dosage unit amounts to 2 to 10 mg, an amount of 5 to 8 mg
active substance in one dosage unit being especially preferred. A
daily dosage comprises generally an amount of active substance of 2
to 20 mg, particularly preferred is an amount of active substance
of 5 to 16 mg. If necessary those skilled in the art also know how
to vary the active substance in a dosage unit or the level of the
daily dosage according to the requirements. The factors determining
this, such as body weight, overall constitution, response to the
treatment and the like will constantly be monitored by the artisan
in order to be able to react accordingly and adjust the amount of
active substance in a dosage unit or to adjust the daily dosage if
necessary.
[0017] Preferably, the substances that are used for producing the
drug according to the invention, 5HT.sub.3-receptor-antagonists,
are processed to an oral or intravenous form of administration to
provide possibilities for variation in the application and for
providing a possibly most gentle administration for the respective
patient.
[0018] In the following, the present invention is further
illustrated by the way of examples. These examples serve to
illustrate and by no means to restrict the scope of the present
invention.
[0019] To revise the effectiveness of the inventive therapeutic
approach two groups of patients of ten patients were treated with
Tropisetron and Ondansetron, respectively.
[0020] In the preceding diagnostic the Chronic Fatigue Syndrom
(CFS) was confined by criteria of classification based on those of
the Center of Disease Control and Prevention, in the edition
revised 1994 (Fukuda K. et al., Ann Intern Med. 1994;
121:953-1959). In the judgement, it was set off from a clinically
proven etiologically unclear, persisting or relapsing fatigue
(duration >6 months) that has commenced newly or timely
delimited (not already existing for life), which is not the
consequence of a still lasting overload that does not improve with
rest and which leads two a considerable reduction of the earlier
level of activity in education and profession as well as in social
and personal areas. Prerequisite is that the occurrence of four or
more of the following symptoms which, all have had to exist
persisting or relapsing for at least six consecutive months of
illness and which may not have preceded the fatigue. These symptoms
are:
[0021] restriction of the short term memory or concentration severe
enough to cause a substantial reduction of the earlier level of
activity
[0022] a sore throat (Pharyngitis without pus)
[0023] axillary and lymph nodes of the neck reacting with pain on
pressure
[0024] muscle pain
[0025] arthalgia
[0026] headaches of a new quality
[0027] no relaxation by sleep
[0028] worsening of condition for more than 24 hours after
efforts.
[0029] By such diagnosis of exclusion according to the foregoing
criteria a group of patients may be confined the prevalence of
which is lying at about 3% and whose discomforts may not be named
differently. The group of patients treated with Tropisetron
received the active substance in the form of a capsule with an
amount of active substance of 5 mg/dosage unit, wherein the daily
dosage was also 5 mg. The second group of patients received the
active substance Ondansetron in form of tablets, wherein a dosage
unit contained 8 mg active substance and the daily dosage consisted
of twice a dosage unit, i.e. 16 mg daily.
[0030] The administration of the 5HT.sub.3-receptor-antagonists
took place for over 15 days, respectively. During the study
patients were monitored for the parameters listed as follows:
[0031] MARDS; days 0 and 15
[0032] VAS (Visual Analog Scale) susceptibility to fatigue/fatigue;
days 0, 8 and 15
[0033] VAS fitness; days 0, 8 and 15
[0034] daily recording of both of the VAS by the patient
himself
[0035] accompanying symptoms; days 0, 8 and 15
[0036] fitness during the test; day 15
[0037] final evaluation by physician and patient; day 15
[0038] The essential changes under therapy were recorded by visual
analog scales that documented the extent of the abnormal
susceptibility to fatigue/fatigue as well as the reduction of
fitness. In this respect the subjectively felt condition for
susceptibility to fatigue/fatigue or fitness were marked on a scale
comprising a range from 0 to 100, wherein 0 means normal
susceptibility to fatigue/fatigue or fitness and 100 for the
heaviest susceptibility to fatigue/fatigue or for a 100% reduction
in fitness.
[0039] With respect to two visual analog scales a significant
improvement in an amount of more than 35% could be determined in
one third of the patients. This related to both of the groups of
the patients similarly. Additionally, considering the patients
reporting of a pronounced improvement the response rate amounts to
about 66%.
[0040] The conducted studies show unambiguously that a pronounced
improvement in about a third of the patients occurred with regard
to the main symptoms of CFS, fatigue and reduction of fitness, a
further third feeling at least a minor improvement with respect to
the discomforts. Clinically this is a very significant success in
therapy, particularly on the background that other therapeutic
approaches have proven to be practically without effect.
[0041] Another important indication for the therapy of CFS with
respect to the effect of the suggested therapy is the fact that in
the studies described herein before a significant improvement of
the condition of the patients could be noted within the duration of
the study of 15 days which is very surprising in view of the
persistence of the determined symptoms, since the diagnostic
symptoms had to be present for more than 6 months according to the
definition.
[0042] The effect of the substances employed in the study,
Tropisetron and Ondansetron, on the inhibition of the
5HT.sub.3-receptor as the common highly specific principle of
action is based on the only common feature of the presence of a
structural element in form of a indol cycle, since these two
compounds differ considerably in their chemical structure.
* * * * *