Title: Method for treating celiac disease
United States Patent: 6,348,495
Inventors: Cavazza; Claudio (Rome, IT); Mosconi; Luigi (Rome,
Assignee: Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
Appl. No.: 626151
Filed: July 26, 2000
Foreign Application Priority Data: Jun 06, 1996[IT]
A method for treating celiac disease comprising administration of a
composition containing an alkanoyl L-carnitine wherein the alkanoyl group
is straight or branched and has 2-6 carbon atoms and the pharmacologically
acceptable salts thereof.
Description of the Invention
The present invention relates to a new therapeutic use of
the lower alkanoyl L-carnitines and their pharmacologically acceptable
salts to produce pharmaceutical compositions for the treatment of chronic
intestinal disorders, in particular inflammatory bowel diseases, more
particularly, ulcerative colitis or celiac disease.
The present invention also relates to pharmaceutical compositions suitable
for rectal administration, particularly in the form of foams or enemas,
containing the above-mentioned alkanoyl L-carnitines.
Ulcerative colitis is an inflammatory, ulcerative disease of the colon of
unknown aetiology, very often characterised by haematic diarrhoea.
It usually originates in the recto-sigmoid area, from which it may spread
proximally with possible involvement of the entire colon. Alternatively,
it may attack a substantial portion of the large bowel right from the
The complications of ulcerative colitis are particularly severe: it has
been documented, in fact, that there is an enormous increase in the risk
of colon cancer in patients suffering from ulcerative colitis. The
incidence of colon cancer increases with both involvement of the entire
colon and with a duration of disease exceeding 10 years.
In both the mild-to-moderate forms and the moderately or distinctly severe
forms of the disease, corticosteroids constitute the drugs of choice,
namely hydrocortisone, betamethasone and prednisone.
In the mild-to-moderate forms, physiological solution containing
hydrocortisone is administered via an enema which is retained in the bowel
as long as possible.
In the moderately severe forms, systemic corticosteroid therapy is
necessary, consisting generally in 10-15 mg of prednisone t.i.d. or q.i.d.
per os, which is capable of inducing drastic remission.
In the more severe forms requiring admission to hospital, the
corticosteroid therapy is administered parenterally.
Both the systemic and topical administration of these drugs gives rise to
serious side effects, mainly related to interference with the hypothalamo-pituitary-adrenal
The side effects due to topical treatment of ulcerative colitis with these
traditional corticosteroids are, far instance, transient or prolonged
depression of adrenocortical function, weight gain, acne and moon face.
Though it is well known, particularly in the moderately severe forms of
the disease, that the daily corticosteroid dose can be gradually reduced
to 10-20 mg per week after 1-2 weeks of treatment, even such low
corticosteroid doses continue to induce harmful side effects, the
elimination or at least the drastic reduction of which constitutes a
therapeutic goal of primary importance.
Celiac disease (or celiac syndrome) is a chronic intestinal disorder
caused by a specific intolerance to gluten present in wheat, rye, barley
and oats proteins included in the diet leading to dramatic changes in the
small intestinal mucosa and subsequent impaired absorption. The celiac
syndrome can affect genetically susceptible subjects (around 3.Salinity.).
Symptoms comprise diarrhoea and other malabsorption symptoms, including
total atrophy of intestinal mucosa.
It is known that in humans said pathologic alterations are produced by the
action on the intestinal mucosa of digestion products of wheat gluten and,
in particular, by the 70% ethanol soluble gluten protein fraction. Said
protein fraction, generally name as "prolamin" (in wheat, in
particular, it is named as "gliadin"), is present in several
cereals in different proportions and is composed of numerous proteins with
different molecular weights, and having an high glutamine (one glutamine
residue every three amino acids) and proline (a proline residue every
seven amino acids) content, and a low ionic strength (due to few residues
able to ionise in solution).
Current treatment is effected by a well balanced gluten-gliadin-free diet
high in calories and proteins and normal in fat. This excludes cereal
grains with the exception of rice and corn. Patients affected by celiac
disease not responding to gluten-gliadin-free diet are treated with
glucocorticoid steroids. For example U.S. Pat. No. 4,958,418, assigned to
Glaxo Group Limited, teaches the use of fluticasone dipropionate, an
anti-inflammatory steroid, This patent clearly establishes that celiac
disease, ulcerative colitis and Crohn's disease are all embedded in the
category of bowel diseases which respond to treatment of glucocorticoid
Based on the study of toxic peptides obtained by different prolamins, WO
97/27217, in the name of Istituto Superiore di Sanita, provides a protein
compound having a sequence comprised in the proteins of durum wheat and
being not toxic for celiac subjects, in particular a protein of the
following sequence: QQPQDAVQPF.
WO 99/56698, in the name of Copenhagen University, discloses a method for
treating celiac disease comprising interfering with the deamidation of at
least one glutamine residue in a gliadin molecule. Practically, the
treatment comprises administering to a patient suffering from celiac
syndrome at least one of the following substances: a) a substance capable
of increasing the pH in the gastroduodenal tract, e.g. an antacid, an
anticholinergic agent, H2-receptor antagonists or a proton pump inhibitor,
b) an antibiotic or antimicrobial agent acting against deamidating
bacteria and/or a substance capable of interfering with deamidating
enzymes. In a wide sense, a method for treating celiac disease is
prospected in JP 1156927, to University Leland Stanford, by administering
an antagonist to IFN-65.
There is still a strong need to make available a method for the treatment
of celiac disease using a simple therapeutic scheme, with an easily
managed drugs, with low or null side effects. The cost of the drug is also
Celiac patients, children in particular, proved to have low serum L-carnitine
levels, most likely due to the damaged bowel mucosa (Lerner A. et al.,
Gut; 34: 933-935; Ceccarelli M. et al. Minerva Pediatr. 1992; 44:401-5).
Indeed, celiac patients do, not absorb hexogenous L-carnitine. From a
clinical point of view, L-carnitine deficiency cannot be associated to
celiac disease. To date, it has never been demonstrated that L-carnitine
deficiency may give celiac disease.
Therefore, it was totally unexpected to find that an alkanoyl L-carnitine
is effective in the treatment of celiac disease according to is the
teaching of the present invention. The object of the present invention is
to provide a method for treating and pharmaceutical compositions useful
for the treatment of chronic intestinal disorders, in particular
inflammatory bowel diseases, more particularly, ulcerative colitis or
celiac disease. The aim of the present invention is to provide
compositions and methods for the treatment of the above disease, which,
while affording equivalent therapeutic benefit, make it possible to use a
lower daily dose of corticosteroid drug, with a consequent distinct
reduction in the side effects induced by such drugs.
A further object of the present invention is to provide a composition of
the above-mentioned type which enables complete remission of symptoms to
be achieved and which lends itself to oral or, if necessary, to rectal
administration, in the form of a foam or enema, thus making it possible to
avoid corticosteroid administration via the parenteral route even in the
most severe cases.
These objects are achieved according to the present invention by means of
the use of lower alkanoyl L-carnitines in which the alkanoyl group,
straight or branched, has 2-6 carbon atoms and of their pharmacologically
acceptable salts to produce the aforementioned compositions. The preferred
alkanoyl L-carnitines are acetyl, propionyl, butyryl, isabutyryl, valeryl
and isovaleryl L-carnitine. Propionyl L-carnitine, butyryl L-carnitine and
their pharmacologically acceptable salts are particularly preferred.
What is meant by a pharmacologically acceptable salt of an alkanoyl L-carnitine
is any salt of the latter with an acid which does not give rise to
unwanted toxic or side effects. These acids are well known to
pharmacologists and pharmacy experts.
Non-limiting examples of such salts are, for instance, chloride, bromide,
orotate, acid aspartate, acid citrate, acid phosphate, fumarate and acid
fumarate, lactate, maleate and acid maleate, acid oxalate, acid sulphate,
glucose phosphate, tartrate and acid tartrate.
Though, according to the present invention, the alkanoyl L-carnitine and
the reduced dose of corticosteroid can be administered orally, it might be
necessary that the preferred alkanoyl L-carnitine administration route is
rectal. In particular, those forms of rectal administration, such as foams
and enemas, are preferred, which allow prolonged contact between the
alkanoyl L-carnitine and the intestinal tract affected by the inflammatory
The preparation of these foams and enemas and the choice of appropriate
vehicles and excipients are well known to pharmacy experts.
These compositions capable of being administered by the rectal route may
contain additional active ingredients such as anti-diarrhoea agents,
antibiotics, anaesthetics, stool softeners and lubricants.
For example, an enema composition comprises from approximately 3 to
approximately 15 grams, preferably 6-12 grams, of alkanoyl L-carnitine and
possibly 400-600 mg of hydrocortisone or 20-50 mg of prednisone per litre
of physiological solution.
Though the daily dose will depend, according to the judgement of the
primary care physician, on the subjects weight, age and general condition,
it is generally advisable to administer 1-4 g/day--preferably 2-3
g/day--of alkanoyl L-carnitine or a stoichiometrically equivalent amount
of one of its pharmacologically acceptable salts. In the preferred rectal
administration form, an enema of 500 mL physiological solution containing
5-10 g of alkanoyl L-carnitine--e.g. 6 g of propionyl L-carnitine--is
administered twice daily.
Larger doses can safely be administered in view of the substantial
non-toxicity of the alkanoyl L-carnitines.
In the embodiment relating to the treatment of celiac disease, the
alkanoyl L-carnitine, among which propionyl L-carnitine is preferred, may
be used alone or in combination with at least one active agent used in the
treatment of celiac disease. Active agents for the treatment of celiac
disease are well-known in the art and the skilled person will be able to
determine the suitable agent. Glucocorticoids, such as hydrocortisone,
prednisone or prednisolone may be used as well as other active agents.
Preferably, the method according to the present invention is associated
with the proper gluten-free diet.
In a further embodiment of the invention, the alkanoyl L-carnitines, and
in the particularly preferred embodiment, propionyl L-carnitine, are
combined with short chain fatty acids. The latter are used in celiac
disease therapy. It is important that the alkanoyl L-carnitine and the
short chain fatty acid be combined in a physical form and not bound in a
chemical entity (such as, for example an ester). Though the inventors do
not wish to be bound to any theory, it is believed that alkanoyl L-carnitines
exert a protective effect toward the cells against potential damaging
effects of short chain fatty acids.
In a still further embodiment of the invention, the alkanoyl L-carnitines,
and in the particularly preferred embodiment, propionyl L-carnitine, are
combined with amino acids, preferably glutamine. The latter are used in
celiac disease therapy, where they exert a protective effect towards
intestinal epitelial cells.
Claim 1 of 20 Claims
What is claimed is:
1. A method of treating celiac disease comprising administration of a
composition containing an alkanoyl L-carnitine wherein the alkanoyl group
is straight or branched and has 2-6 carbon atoms or a pharmacologically
acceptable salt thereof.
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