U.S. patent application number 11/290944 was filed with the patent office on 2006-04-06 for treatment of inflammatory disorders.
Invention is credited to Robin Mark Bannister, Alan Rothaul, Benjamin Mark Skead.
Application Number | 20060074106 11/290944 |
Document ID | / |
Family ID | 9898880 |
Filed Date | 2006-04-06 |
United States Patent
Application |
20060074106 |
Kind Code |
A1 |
Skead; Benjamin Mark ; et
al. |
April 6, 2006 |
Treatment of inflammatory disorders
Abstract
A method of treating an inflammatory disease or an autoimmune
disease in a subject, comprises the administration of
mefloquine.
Inventors: |
Skead; Benjamin Mark;
(Cambridge, GB) ; Bannister; Robin Mark; (Essex,
GB) ; Rothaul; Alan; (Essex, GB) |
Correspondence
Address: |
SALIWANCHIK LLOYD & SALIWANCHIK;A PROFESSIONAL ASSOCIATION
PO BOX 142950
GAINESVILLE
FL
32614-2950
US
|
Family ID: |
9898880 |
Appl. No.: |
11/290944 |
Filed: |
November 30, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10362784 |
Aug 28, 2003 |
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PCT/GB01/03924 |
Aug 31, 2001 |
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11290944 |
Nov 30, 2005 |
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Current U.S.
Class: |
514/313 |
Current CPC
Class: |
A61P 19/02 20180101;
A61P 29/00 20180101; A61P 19/00 20180101; A61P 37/00 20180101; A61P
17/06 20180101; A61P 11/06 20180101; A61P 1/00 20180101; A61K 31/49
20130101; A61P 31/04 20180101; A61P 1/04 20180101; A61P 11/08
20180101 |
Class at
Publication: |
514/313 |
International
Class: |
A61K 31/47 20060101
A61K031/47 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 5, 2000 |
GB |
0021776.0 |
Claims
1. Use of (+)-erythro-mefloquine, substantially free of
(-)-erythro-mefloquine, for the manufacture of a medicament for the
treatment of an inflammatory disease selected from the group
consisting of rheumatoid arthritis, osteoarthritis, psoriatic
arthritis, psoriasis, Crohn's disease, systemic lupus
erythematosus, ulcerative colitis, COPD and asthma.
2. The use, according to claim 1, wherein the inflammatory disease
is rheumatoid arthritis.
3. The use, according to claim 1, wherein the inflammatory disease
is osteoarthritis.
4. A method for treating an inflammatory disease selected from the
group consisting of rheumatoid arthritis, osteoarthritis, psoriatic
arthritis, psoriasis, Crohn's disease, systemic lupus
erythematosus, ulcerative colitis, COPD and asthma, wherein said
method comprises administering, to a patient in need of such
treatment, (+)-erythro-mefloquine, substantially free of
(-)-erythro-mefloquine.
5. The method, according to claim 4, wherein the inflammatory
disease is rheumatoid arthritis.
6. The method, according to claim 4, wherein the inflammatory
disease is osteoarthritis.
7. The method, according to claim 4, further comprising first
identifying said patient in need.
Description
FIELD OF THE INVENTION
[0001] This invention relates to the treatment of inflammatory
disorders.
BACKGROUND OF THE INVENTION
[0002] Cytokines belong to a large group of polypeptide- or
glycopeptide-signaling molecules that act, at extremely low
concentrations, as regulators of cell growth and essential
mediators of inflammation and immune reactions. The production and
functions of cytokines are tightly regulated by cytokines
themselves and by several other factors. Most cytokines act locally
and are implicated in a number of inflammatory conditions. These
include rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic
arthritis, psoriasis, ulcerative colitis and Crohn's disease.
[0003] The antimalarial compounds chloroquine and
hydroxychloroquine are known as broadly active, modestly potent
inhibitors of cytokines. Such antimalarial agents have become
important disease-modifying antirheumatic agents (DMARD) in the
second line treatment of rheumatoid arthritis and other
inflammatory disorders. Other agents in this class include gold,
penicillamine, methotrexate and cyclosporins, all of which have
potent activity. However, the utility of these latter drugs for the
treatment of a chronic disease such as rheumatoid arthritis is
limited by serious side-effects. The antimalarial agents in the
DMARD class are recognised as having a more moderate side-effect
profile, while possibly lacking the potency of some of the other
agents. However, there is still concern about the ocular
side-effects of both chloroquine and hydroxychloroquine. Thus, it
may be postulated that a drug for the treatment of arthritis that
possesses an improved efficacy versus side-effect profile over
hydroxychloroquine, the most significant antimalarial drug in the
DMARD class, would be of significant clinical potential.
[0004] In terms of antimalarial potency, mefloquine is one of the
most effective drugs indicated for both prophylaxis and treatment
and has particular utility for use in chloroquine-resistant
malaria. Chloroquine has been the mainstay of antimalarial
treatment and prophylaxis, but the emergence of chloroquine
resistance in Plasmodium falciparum, the most lethal strain, has
started to limit its utility. Thus mefloquine has emerged as the
preferred compound for the prophylaxis and treatment of malignant
malaria.
[0005] Mefloquine enantiomers have been evaluated in animal models
for efficacy against Plasmodium species. These studies concluded
that there was no difference in antimalarial potency of the
enantiomers.
SUMMARY OF THE INVENTION
[0006] Surprisingly, it has been found that (+)-mefloquine
possesses potent anti-rheumatic properties. The use of the
substantially pure enantiomer may maximise efficacy and reduce
unwanted side-effects. (+)-Erythro-mefloquine is a more potent
inhibitor of cytokines implicated in the inflammatory response.
(+)-Erythro-mefloquine suppresses human lymphocyte
proliferation.
DESCRIPTION OF THE INVENTION
[0007] The present invention is based, at least in part, on the
finding that mefloquine shows a broad profile of cytokine
inhibition, consistent with antimalarial RA therapy. In addition,
it has been shown that the isomers of mefloquine show good activity
against Interleukin-8 (IL-8). Both chloroquine and
hydroxychloroquine are inactive against IL-8, and this cytokine is
implicated in the progression of inflammation and tissue
destruction inherent in the progress of RA and OA. This is a
significant aspect of the enhanced profile of mefloquine isomers in
the treatment of inflammatory conditions. In addition, as shown in
Table 1, the isomers of mefloquine have superior activity over
chloroquine and hydroxychloroquine against IL-2, a cytokine
implicated in the destruction of connective tissue in RA and OA.
TABLE-US-00001 TABLE 1 Inhibition Profile (IC.sub.50, .mu.M) T-cell
prolifer- IFN TNF IL-1 IL-6 IL-8 IL-2 ation gamma Hydroxy- 32.2 21
90 Inactive 94 16 94 chloroquine Chloroquine 21 6.3 81 Inactive 66
13 63 (-)Mefloquine 18 79 43 63 17 10 18 (+)Mefloquine 24 68 53 41
17 11 17
[0008] This inhibition profile has shown significant activity in a
preclinical, ex vivo assay of tissue destruction in the bovine
nasal cartilage model. The results are shown in Table 2.
TABLE-US-00002 TABLE 2 Inhibition of IL-2-stimulated bovine nasal
cartilage destruction 1 .mu.M 10 .mu.M 100 .mu.M Hydroxychloroquine
4 3 36 Chloroquine 3 6 35 (+/-)Mefloquine 20 (-)Mefloquine 37 45 82
(+)Mefloquine 32 44 71
[0009] For use in the invention, the active agent may be
formulated, e.g. together with a carrier, excipient or diluent, and
administered, by procedures that are known in the art, including
those already proposed for the racemate. Suitable compositions will
depend on the intended route of administration, which may be, for
example, oral, topical, nasal, rectal, sublingual, buccal or
transdermal. Sustained, delayed, timed or immediate release
compositions may be used.
[0010] The amount of the agent that should be administered can
readily be determined by the skilled man, taking into account the
usual factors such as the type of patient, the nature of the
condition being treated, and the route of administration. The
amount of enantiomer may be higher or the same as that for the
racemate, or may be modified depending on the co-administration of
other drugs.
[0011] Conditions that may be treated include conditions involving
cartilage destruction, inflammatory conditions and those mediated
by IL-2 and IL-6, e.g. rheumatoid arthritis, asthma, psoriasis,
psoriatic arthritis, Crohn's disease, irritable bowel syndrome and
systemic lupus erythematosus. Other relevant conditions are
ulcerative colitis, COPD and asthma. The patient may be disposed to
CNS side-effects, and/or may be undergoing concomitant therapy with
another drug.
[0012] Depending on the relative activities of the individual
enantiomers, it may be preferred to administer a mixture, e.g.
racemate, or substantially one enantiomer. The desired enantiomer
may be in at least 50%, 70%, 90%, 95% or 99% excess, with respect
to any other. The active agent may be used in any active form, e.g.
salt or non-salt.
[0013] The use of (+)-erythro-mefloquine is preferred. It appears
that this compound is particularly useful in providing the desired
effect, without tissue destruction, and can be safely administered
at a relatively high dosage.
* * * * *