U.S. patent application number 10/510450 was filed with the patent office on 2005-05-19 for combined use of l-carnitine, acetyl l-carnitine and propionyl l-carnitine for the treatment of oligoasthenoteratospermia.
This patent application is currently assigned to Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. Invention is credited to Biagiotti, Giulio, Cavillini, Giorgio, Koverech, Aleardo, Sardelli, Francesca.
Application Number | 20050107470 10/510450 |
Document ID | / |
Family ID | 11456235 |
Filed Date | 2005-05-19 |
United States Patent
Application |
20050107470 |
Kind Code |
A1 |
Cavillini, Giorgio ; et
al. |
May 19, 2005 |
Combined use of l-carnitine, acetyl l-carnitine and propionyl
l-carnitine for the treatment of oligoasthenoteratospermia
Abstract
The use is described of L-carnitine and propionyl L-carnitine,
or of one of their pharmaceutically acceptable salts for the
preparation of a medicine for the treatment of
oglioasthenoteratospermia of any origin.
Inventors: |
Cavillini, Giorgio; (Roma,
IT) ; Biagiotti, Giulio; (Roma, IT) ;
Koverech, Aleardo; (Roma, IT) ; Sardelli,
Francesca; (Roma, IT) |
Correspondence
Address: |
NIXON & VANDERHYE, PC
1100 N GLEBE ROAD
8TH FLOOR
ARLINGTON
VA
22201-4714
US
|
Assignee: |
Sigma-Tau Industrie Farmaceutiche
Riunite S.p.A
Viale Shakespeare, 47
Rome
IT
1-00144
|
Family ID: |
11456235 |
Appl. No.: |
10/510450 |
Filed: |
January 7, 2005 |
PCT Filed: |
April 8, 2003 |
PCT NO: |
PCT/IT03/00214 |
Current U.S.
Class: |
514/547 ;
514/565 |
Current CPC
Class: |
A61K 31/205 20130101;
A61P 15/08 20180101; A61K 2300/00 20130101; A61K 2300/00 20130101;
A23L 33/175 20160801; A61K 31/22 20130101; A61K 31/205 20130101;
A61K 31/22 20130101; A61P 15/00 20180101 |
Class at
Publication: |
514/547 ;
514/565 |
International
Class: |
A61K 031/198; A61K
031/225 |
Foreign Application Data
Date |
Code |
Application Number |
Apr 9, 2002 |
IT |
RM2002A000194 |
Claims
1. Use of L-carnitine, acetyl L-carnitine and propionyl L-carnitine
inner salts, or of their pharmaceutically acceptable salts, for the
preparation of a medicine for the treatment of
oligoasthenoteratospermia.
2. Use according to claim 1, for the preparation of a medicine for
the treatment of oligospermia.
3. Use according to claim 1, for the preparation of a medicine for
the treatment of asthenospermia.
4. Use according to claim 1, for the preparation of a medicine for
the treatment of teratospermia.
5. Use of L-carnitine, acetyl L-carnitine and propionyl L-carnitine
or their pharmaceutically acceptable salts, for the preparation of
a nutritional composition for the treatment of
oligoasthenoteratospermia.
6. Use according to claim 5, for the preparation of a nutritional
composition for the treatment of oligospermia.
7. Use according to claim 5, for the preparation of a nutritional
composition for the treatment of asthenospermia.
8. Use according to claim 5, for the preparation of a nutritional
composition for the treatment of teratospermia.
9. Use according to claim 1 in which the pharmaceutically
acceptable salt is selected from the group consisting of chloride,
bromide, orotate, aspartate, acid aspartate, citrate, acid citrate,
magnesium citrate, phosphate, acid phosphate, fumarate, acid
fumarate, magnesium fumarate, glycerophosphate, lactate, maleate
and acid maleate, mucate, oxalate, acid oxalate, pamoate, acid
pamoate, sulphate, acid sulphate, glucose phosphate, tartrate, acid
tartrate, magnesium tartrate, 2-amino ethane sulphonate, magnesium
2-amino ethane sulphonate, methane sulphonate, choline tartrate,
trichloroacetate and trifluoroacetate.
10. Use according to claim 1, in which the L-carnitine, acetyl
L-carnitine and propionyl L-carnitine inner salts or their
pharmaceutically acceptable salts are in a mixture or are packaged
separately.
11. Use according to claim 10, in which the molar ratio of
L-carnitine to acetyl L-carnitine and propionyl L-carnitine or of
their pharmaceutically acceptable salts ranges from
2.48:0.098:0.092 to 0.186:0.98:0.92.
12. Use according to claim 10, in cui the molar ratio of
L-carnitine to acetyl L-carnitine and propionyl L-carnitine or of
their pharmaceutically acceptable salts ranges from 2.48:0.49:0.46
to 0.62:0.49:0.46.
13. Use according to claim 10, in which the molar ratio of
L-carnitine to acetyl L-carnitine and propionyl L-carnitine or of
their pharmaceutically acceptable salts ranges from 2.48:0.98:0.92
to 1.24:0.49:0.23.
14. Use according to claim 11, in which the medicine or the
nutritional composition in unit dosage form contains L-carnitine
inner salt in amounts ranging from 4.0 g to 0.30 g, acetyl
L-carnitine inner salt in amounts ranging from 0.20 to 2.0 g, and
propionyl L-carnitine inner salt in amounts ranging from 0.20 g to
2.0 g, or equimolar amounts of their pharmaceutically acceptable
salts.
15. Use according to claim 14, in which the unit dosage form
contains 2 g of L-carnitine inner salt, 1 g of acetyl L-carnitine
inner salt and 0.5 g of propionyl L-carnitine inner salt or
equimolar amounts of their pharmaceutically acceptable salts.
Description
[0001] The invention described herein relates to the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine, in
combination, for the preparation of a medicine for the treatment of
oligoasthenoteratospermia of any origin: inflammatory, idiopathic,
hormonal, or associated with varicocele.
[0002] The final common pathway of all these forms of infertility
is the local accumulation of oxygen free radicals (Pasqualotto F.
F. et al., Fertil. Steril. 73:459-464, 1999). To combat this
accumulation antioxidant drugs can be used.
[0003] Most of the antioxidants currently available on the
pharmaceutical market (vitamin E, glutathione, NADH) act in a
manner unrelated to the Krebs cycle, and therefore in a manner
related solely to the drug dosage and not to cell metabolism.
[0004] The substantial topographical and temporal heterogeneousness
(within the same testicle) of human spermatogenesis (Silber S. J.,
Clin. Obstet. Gynaecol. 43:843-888, 1999) makes it impossible to
establish a "fixed" dosage of antioxidants, since this would lead
to over- and underdosing.
[0005] An excessive lowering of oxygen free radicals leads to
inhibition of the acrosome and capacitation reaction of the
spermatozoa (Ochendorf F. R., Hum. Reprod. Update. 5:399-402,1999),
whereas too high a concentration leads to morphological
abnormalities of the spermatozoon itself (Gattuccio F., et. al.,
Varicocele 2000, Cofese Editore, Palermo 2000).
[0006] In Human Reprod. 13:3090-3093, 1998, a semiquantitative
scoring sysem has been proposed based on US Doppler results to
distinguish between obstructive and non-obstructive
azoospermias.
[0007] In Human. Reprod. 15:2554-2558, 2000, it is reported that
the transmediastinic testicular artery has a significantly greater
resistivity index in non-obstructive azoospermic subjects than in
controls and in oligoasthenospermic subjects.
[0008] In Fertil. Steril. 75:1088-1094, 2001, it is reported that
the pulsatility index of the testicular artery is higher in
obstructive than in non-obstructive azoospermia.
[0009] In J. Urol. 163:135, 2000, it is reported that
intratesticular blood flow and blood flow rate are significantly
lower in subjects with arrested maturation of spermatogenesis, that
is to say with hypoplasia of the germ cells.
[0010] The spermatozoa are produced in the testicles and undergo
post-gonadal maturation in the epididymis in order to acquire their
fertilising capacity.
[0011] In plasma, high-molecular-weight proteins and small
molecules such as the free carnitines facilitate the maturation of
the gametes into competent, functional cells.
[0012] Epididymal L-carnitine, which comes from the plasma, has a
beneficial effect on the spermatozoa. It passes into the
spermatozoa by passive diffusion and is acetylated only in mature
spermatozoa.
[0013] The relationship between the endogenous pool of free and
acetylated carnitines and the progressive percentage of sperm
motility indicate a more important metabolic function related to
flagellar movement.
[0014] Thus, the start of sperm motility, in the epididymis, is
probably independent of the carnitine system, while the energy
properties of acetyl L-carnitine are relevant in "energy crisis"
situations.
[0015] The accumulation of free carnitines in the cytoplasm in
mature spermatozoa has to be regarded as a protective form of the
mitochondrial metabolism which is useful for the survival of these
isolated cells.
[0016] The use of L-carnitine, acetyl L-carnitine and propionyl
L-carnitine in combination is already known.
[0017] In European patent EP 0 973 415, a dietetic composition is
described consisting of L-carnitine, acetyl L-carnitine and
propionyl L-carnitine, which is useful for athletes subject to
intense physical effort, or for asthenic individuals.
[0018] In patent application WO 99/17623, a dietetic composition is
described consisting of L-carnitine, acetyl L-carnitine and
propionyl L-carnitine for the treatment of alcohol withdrawal
syndrome.
[0019] Also known is the use of L-carnitine and of the alkanoyl
L-carnitines for the treatment of male infertility.
[0020] In Drugs Exptl. Clin. Res. XXI(4):157-159, 1995, it is
reported that the administration of L-carnitine, in a group of
patients with idiopathic asthenospermia, improves sperm motility
and increases the sperm count in 37 out of 47 patients treated.
[0021] In Dermatol. Monatschr. 169:572-575, 1983, the same results
are confirmed.
[0022] In Andrologia, 26:155-159, 1994, it is reported that the
administration of L-carnitine in infertile patients brings about a
significant improvement of both a quantitative and qualitative
nature in sperm motility.
[0023] In Fertilitt 4:1-4, 1988, it is reported that L-carnitine
therapy in infertile patients brings about an increase in carnitine
levels in the spermatozoa and at the same time an increase in sperm
motility and sperm count.
[0024] Loumbakis P., et al. (12th Congress of the European
Asso-ciation of Urology, Paris, 1-4 Sep. 1996) report preliminary
data indicating that the administration of L-carnitine may have a
positive effect on sperm quality.
[0025] In Acta Eur. Fertil. 23(5):221-224, 1992, it is reported
that the use of acetyl L-carnitine in patients with idiopathic
oligoastheno-spermia has no effect upon sperm density, but induces
a progressive increase in sperm motility.
[0026] In U.S. Pat. No. 6,090,848, it is reported that the
combination of L-carnitine and acetyl L-carnitine is useful for the
treatment of oligoasthenoteratospermia.
[0027] The above-mentioned known compounds are certainly to be
regarded as good therapeutic agents, but nevertheless present a
number of disadvantages.
[0028] In fact, as mentioned above, in Drugs Exptl. Clin. Res. XXI
(4):157-159, 1995, it is reported that the administration of
L-carnitine to a group of patients with idiopathic
oligoasthenoteratospermia improves the sperm count and increases
sperm motility in 37 out of 47 patients treated, whereas, in Acta
Eur. Fertil. 23(5):221-224, 1992, it is reported that the use of
acetyl L-carnitine in patients with idiopathic oligoasthenospermia
has no effect upon sperm density.
[0029] The combination described in U.S. Pat. No. 6,090,848, which
is to be regarded as the best one known to date, was used as a
reference compound during the study of the activity of the
composition according to the present invention. The results
obtained, reported here below, confirmed the activity of the
composition described in U.S. Pat. No. 6,090,848, but also
demonstrated, surprisingly and unexpectedly, that the combination
according to the present invention is more active than the
composition described in U.S. Pat. No. 6,090,848.
[0030] In the medical field, there is still a strongly perceived
need for the availability of compositions useful for the treatment
of oligoasthenoteratospermia, which do not present the
disadvantages of the above-mentioned known compounds, or which
improve the results obtained with the best of the known
compositions currently in use.
[0031] It has now been found that the use of L-carnitine, acetyl
L-carnitine and propionyl L-carnitine or of one of their
pharmaceutically acceptable salts, in combination, has proved
capable of exerting a surprising synergistic effect in the
treatment of all forms of oligoasthenoteratospermia.
[0032] One object of the present invention therefore is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine inner
salts or their pharmaceutically acceptable salts for the
preparation of a medicine for the treatment of
oligoasthenoteratospermia.
[0033] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine inner
salts or their pharmaceutically acceptable salts, for the
preparation of a medicine for the treatment of oligospermia.
[0034] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine inner
salts or their pharmaceutically acceptable salts, for the
preparation of a medicine for the treatment of asthenospermia.
[0035] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine inner
salts or their pharmaceutically acceptable salts, for the
preparation of a medicine for the treatment of teratospermia.
[0036] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine or their
pharmaceutically acceptable salts, for the preparation of a
nutritional composition for the treatment of
oligoasthenoteratospermia.
[0037] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine or their
pharmaceutically acceptable salts, for the preparation of a
nutritional composition for the treatment of oligospermia.
[0038] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine or their
pharmaceutically acceptable salts, for the preparation of a
nutritional composition for the treatment of asthenospermia.
[0039] A further object of the present invention is the use of
L-carnitine, acetyl L-carnitine and propionyl L-carnitine or their
pharmaceutically acceptable salts, for the preparation of a
nutritional composition for the treatment of teratospermia.
[0040] It has been found that the combination according to the
present invention is more active than the combination of
L-carnitine and acetyl L-carnitine mentioned above, in improving
both sperm count and sperm motility in man.
[0041] The L-carnitine, acetyl L-carnitine and propionyl
L-carnitine can be in any form suitable for oral or parenteral
administration in man. L-carnitine, acetyl L-carnitine and
propionyl L-carnitine can be formulated together, as a mixture, or
can be formulated separately (packaged separately), using known
methods. L-carnitine, acetyl L-carnitine and propionyl L-carnitine
can be administered to an individual either when fomulated in a
mixture or when formulated in separate packs.
[0042] On the basis of various factors, such as the concentration
of the active ingredients or the patient's condition, the
combination according to the present invention can be marketed as a
health food supplement, a nutritional supplement, or as a
therapeutic product on sale with or without the need for a medical
prescription.
[0043] According to the present invention, the molar ratio of
L-carnitine to acetyl L-carnitine and propionyl L-carnitine or of
one of their pharmaceutically acceptable salts ranges from
2.48:0.098:0.092 to 0.186:0.98:0.92.
[0044] Alternative molar ratios include the molar ratios ranging
from 2.48:0.49:0.46 to 0.62:0.49:0.46.
[0045] Alternative molar ratios include the molar ratios ranging
from 2.48:0.98:0.92 to 1.24:0.49:0.23.
[0046] The combination preparation according to the present
invention, when in unit dosage form, contains from 4.0 g to 0.30 g
of L-carnitine inner salt, from 0.20 to 2.0 g of acetyl L-carnitine
inner salt and from 0.20 g to 2.0 g of propionyl L-carnitine inner
salt, or an equimolar amount of one of their pharmaceutically
acceptable salts.
[0047] The preferred combination preparation, in unit dosage form,
contains 2 g of L-carnitine inner salt, 1 g of acetyl L-carnitine
inner salt and 0.5 g of propionyl L-carnitine inner salt, or an
equimolar amount of one of their pharmaceutically-acceptable
salts.
[0048] It has been found, however, that, although the daily dose of
the above-mentioned active ingredients to be administered depends
on the patient's age, weight and condition, using professional
experience it is generally advisable to administer, in a single
dose or in multiple doses, from 0.3 to 4.0 g/day approx. of
L-carnitine, from 0.20 to 2.0 g/day approx. of acetyl L-carnitine,
and from 0.20 to 2.0 g/day approx. of propionyl L-carnitina, or an
equimolar amount of one of their pharmaceutically acceptable
salts.
[0049] Larger doses can be administered thanks to the extremely low
toxicity of said active ingredients.
[0050] Reported here below is a clinical trial conducted in order
to assess whether or not the combination according to the present
invention improves sperm motility as compared to combined therapy
with L-carnitine plus acetyl L-carnitine.
[0051] The patients recruited had to fulfil the following
inclusion/exclusion criteria.
[0052] Inclusion criteria: young infertile males with
astheno-zoospermia recognised as being the sole cause of
infertility over the preceding period of at least two years; the
semen criteria that had to be fulfilled in at least two samples
were: sperm concentration (M/ml) from 10 to 20, motility (%)
>20<40 at 2 hours, rapid linear progression (%) <20 at 2
hours. The patients were subjected to history taking, bilateral
scrotal echo-colour Doppler, physical examination, hormone assays
(free and total testosterone, FSH, LH, 17 beta oestradiol,
progesterone, prolactin), and a spermiogram (WHO 1999).
[0053] Exclusion criteria: acute genital inflammation, sperm
concentration <5,000,000/ml. All patients gave their informed
consent for participation in this open trial. In all, the patients
examined were 8 patients with varicocele (6 grade II, 2 grade III),
12 parients with chronic inflammation of the sex glands, 12
patients with varicocele (8 grade II, 4 grade III)+chronic
inflammation of the sex glands, 25 with cryptogenetic
oligoasthenospermia, 2 with hypogonadotropic hypogonadism, 1 with
hyperprolactinaemia, 4 with a history of surgery (unilateral
cryptorchidia in 3 cases, bilateral in 1 case) and 2 with bilateral
testicular trauma.
[0054] Semen was obtained by masturbation after at least 4 days of
sexual abstinence. Semen samples were analysed within one hour of
ejaculation for all parameters, using the standard methods
recommended by the WHO (1987). Sperm motility was studied using a
computerised motility analyser on at least two samples.
[0055] Semen analysis and the motility assessment were carried out
before treatment with the study compounds and after 4 months'
treatment with the latter.
[0056] L-carnitine was administered at the dose of 2 g/day
(2.times.500 mg tablets twice daily, after lunch) for 4 months;
acetyl L-carnitine was administered at the dose of 1 g/day for 4
months, while propionyl L-carnitine was administered at the dose of
500 mg/day for 4 months. The combination according to the present
invention significantly increases the sperm concentration and
motility as well as the percentage of spermatozoa with a rapid
linear progression as compared to treatment with the L-carnitine
plus acetyl L-carnitine combination, regardless of the cause of the
oligoasthenoterato-spermia, even in patients with hormonal
abnormalities.
[0057] In the latter, the combination according to the invention
has permitted a reduction in the posology of gonadotropins and
antiprolactinaemia drugs compared to the data reported in the
literature.
[0058] The medicine according to the invention described herein can
be prepared by mixing the active ingredients (L-carnitine inner
salt, acetyl L-carnitine inner salt and propionyl L-carnitine inner
salt or one of their pharmacologically acceptable salts) with
suitable excipients for the fomulation of compositions for enteral
(particularly oral) or parenteral (particularly intramuscular of
intravenous) administration. Experts in pharmaceutical technology
are familiar with said excipients.
[0059] The pharmaceutically acceptable salts of the above-mentioned
active ingredients include all the pharmaceutically acceptable
salts that are prepared by addition of an acid to the L-carnitine,
acetyl L-carnitine and propionyl L-carnitine inner salt, and that
do not give rise to unwanted toxic or side effects. The formation
of salts by addition of an acid is well known in pharmaceutical
technology.
[0060] Examples of such salts, though not exclusively these, are:
chloride, bromide, orotate, aspartate, acid aspartate, citrate,
acid citrate, magnesium citrate, phosphate, acid phosphate,
fumarate, acid fumarate, magnesium fumarate, glycerophosphate,
lactate, maleate and acid maleate, mucate, oxalate, acid oxalate,
pamoate, acid pamoate, sulphate, acid sulphate, glucose phosphate,
tartrate, acid tartrate, magnesium tartrate, 2-amino ethane
sulphonate, magnesium 2-amino ethane sulphonate, methane
sulphonate, choline tartrate, trichloroacetate and
trifluoroacetate.
* * * * *