MXPA00005352A - Compositions and methods for increasing the concentration and/or motility of spermatozoa in humans - Google Patents
Compositions and methods for increasing the concentration and/or motility of spermatozoa in humansInfo
- Publication number
- MXPA00005352A MXPA00005352A MXPA/A/2000/005352A MXPA00005352A MXPA00005352A MX PA00005352 A MXPA00005352 A MX PA00005352A MX PA00005352 A MXPA00005352 A MX PA00005352A MX PA00005352 A MXPA00005352 A MX PA00005352A
- Authority
- MX
- Mexico
- Prior art keywords
- carnitine
- acetyl
- acid
- combination
- sperm
- Prior art date
Links
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- 230000004899 motility Effects 0.000 title claims description 18
- 210000003856 Spermatozoa Anatomy 0.000 title description 2
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- RDHQFKQIGNGIED-MRVPVSSYSA-N Acetylcarnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 claims abstract description 46
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Abstract
A method is disclosed for treating idiopathic asthenozoospermia and improving sperm quality which comprises orally or parenterally administering to a subject in need thereof a combination preparation comprising either an admixture of or separately packaged L-carnitine and acetyl L-carnitine, or a pharmacologically acceptable salt thereof, in molar ratios ranging from about 4.0:1 to 1:1.5.
Description
COMPOSITIONS AND METHODS FOR INCREASING THE CONCENTRATION AND / OR MOTILITY OF SPERMATOZOIDS IN HUMANS
BACKGROUND OF THE INVENTION
Field of the Invention The present invention relates to compositions and methods for increasing sperm concentration and / or motility in humans, including compositions and methods for treating humans affected by idiopathic asthenozoospermia.
Description of the Prior Art Sperm are produced in the testes and undergo post-gonadal modifications in the epididymis to acquire fertilizing ability. In epididymal plasma, high molecular weight proteins and similar small molecules such as free carnitine convert gametes into functional and "competent" cells. The free L-carnitine is taken from the blood plasma and concentrated in the epididymal lumen. This epididymal secretion is beneficial for sperm and is not just an excretory waste. Free carnitine passes through the spermal plasma membrane through
REF .: 120410 passive diffusion. Free L-carnitine is acetylated only in mature sperm. The excess of Acetyl-CoA from the mitochondria is probably stored as acetyl-L-carnitine and modulates the reserves of free CoA essential for the function of the tricarboxylic acid cycle. This property of L-carnitine buffering CoA in the mitochondrial matrix is known in somatic cells, but is accentuated in male germ cells. The relationship between the endogenous grouping of free and acetylated L-carnitine and the percentage of progressive motility in the spermatozoa indicates a metabolic function of greater importance related to the flagellar movement. Therefore, the potential to initiate sperm motility that takes place in the epididymis is probably independent of the carnitine system while the energetic properties of acetyl-L-carnitine are relevant in situations of "energy crisis". The taking of cytoplasmic free L-carnitine in mature sperm must be a protective form of mitochondrial metabolism useful for the survival of this isolated cell. Idiopathic asthenozoospermia, a disorder in sperm motility, is illustrative of certain conditions in this area. It is a post-testicular cause of infertility due to various etiologies, that is, congenital defects of the tail of sperm, defects in maturation, immune disorders or infection. Various drugs are known to treat idlopathic asthenozoospermia, none of which is completely satisfactory. Antiestrogen drugs (such as clomiphene citrate and tamoxifen) block sex hormones from inhibiting Follicle Stimulating Hormone (FSH) and Luteizing Hormone (LH) in the brain. This triggers an increased release of LH and FSH, which in turn stimulates the production of testosterone. The increased level of testosterone improves spermatogenesis, thus improving density and sperm motility. However, a recent randomized, double-blind, ulticentral study in 190 pairs by the World Health Organization (WHO) showed no effect of clomiphene citrate. Tamoxifen showed increased sperm concentration, but no change in motility was detected. As for clomiphene, recent studies did not confirm this efficacy. Testosterone Rebound therapy involves large doses of testosterone that suppress the activity of the patient's pituitary gland. This, in turn, reduces the intratesticular level of testosterone to systemic levels of normal level. Then the androgen therapy is discontinued in the hope that the system will make a rebound effect and result in improved spermatogenesis. This therapy is not recommended, since a large number of treated patients continue to exhibit azoospermia after treatment. Testolactone, an aromatase inhibitor, prevents the conversion of testosterone to estradiol. It has been studied in patients with idiopathic oligospermia, but the contrasting results have raised doubts about its efficacy. Mesterolone is a synthetic androgen widely used to treat idiopathic infertility in men. A recent study sponsored by the WHO failed to show any efficacy in this drug. Human Chorionic Gonadotropin (HCG) is administered empirically to patients in patients with defects in sperm count or motility to correct an intratesticular deficiency presumed in testosterone. Some patients actually experienced a depression in sperm count due to an increased production of estrogen by the testes. Human Menopausal Gonadotropin (HMO) has approximately one LH and FSH activity, but its use has produced increased sperm counts in only about 50% of cases. The combination therapy of FSH and HCG, or HCG and HMG does not seem to improve these results any better. Gonadotropin Releasing Hormone (GnRH) is expensive and unsatisfactory results have been obtained. Kalicrein can improve sperm motility that increases sperm concentration, but only in approximately 50% of cases. L-carnitine and acetyl-L-carnitine have also been studied as candidate drugs for the treatment of asthenospermia. Vitali G. et al. (Drugs Exptl. Clin. Res. XXI (4): 157-159, 1995) investigated the effectiveness of the administration of L-carnitine in a group of patients with idiopathic atenospermia. A favorable effect of the compound on sperm motility and rapid linear progression has been shown in 37 of 47 patients treated. The same results are obtained by Tordk L. (Dermatol, Monatsschr, 169: 572-575, 1983). Costa M. et al. (Andrology, 26: 155-159, 1994) shows a significant improvement, both in a quantitative and qualitative way, in sperm motility after the administration of L-carnitine. They speculate that in infertile patients the condition occurs, either in the epididymal function or in the sperm's ability to capture and use carnitine (Bartelloni M., Acta Eur. Fertile, 18: 29-31, 1987). Therefore, the administration of carnitine provides an additive substrate for the metabolism of sperm energy and its motility. Müller-Tyl E. (Fertilitat 4: 1-4, 1988) suggests that L-carnitine therapy may be successful in infrextile patients. In fact, the results show a continuous increase in sperm carnitine levels after a treatment with carnitine and a contemporary increase in motility and sperm cell count. Lournbakis P. (XII Congress of the European Association of Urology, Paris, September 1-4, 1996) provides preliminary data suggesting that the administration of carnitine can positively affect sperm quality. Finally, Moneada M. L. (Acta Eur. Fertile, 23 (5): 221-224, 1992) investigated the effect on the quality of the sperm of acetyl-L-carnitine administered to patients affected by idiopathic oligoasthenospermia. Acetyl-L-carnitine has no effect on sperm density, but progressively increases sperm motility.
BRIEF DESCRIPTION OF THE INVENTION Therefore, it is an object of the invention to provide various compositions and methods for increasing the concentration of sperm in humans. It is another object of the invention to provide various compositions and methods for increasing sperm motility in humans. It is another object of the invention to provide various compositions and methods for treating humans suffering from idiopathic asthenozoospermia. The above objectives and others which are apparent from the following description of the invention relate to the discovery that the administration of both L-carnitine and acetyl-L-carnitine, or pharmaceutically acceptable salts thereof, to a human is effective to increase the concentration and / or motility of sperm in humans, including the treatment of idiopathic asthenozoospermia, even in individuals who do not respond to known or conventional treatments mentioned above. It has been found that the compositions and methods of the present invention exhibit marked superiority in increasing sperm concentration and / or sperm motility in humans, including treating humans suffering from idiopathic asthenozoospermia, on the results obtained when administering L-carnitine or acetyl-L-carnitine. individually, that is, as monotherapies.
DESCRIPTION OF SPECIFIC MODALITIES L-carnitine and acetyl-L-carnitine can be in any form suitable for oral or parenteral administration to a human. L-carnitine and acetyl-L-carnitine can be formulated together, as a mixture. Or they can be formulated separately (packaged separately), using known techniques. The L-carnitine and the acetyl-L-carnitine can be administered in such a manner to an individual either as a mixture or formulated separately.
1 The term "pharmacologically acceptable salts" is used herein simply to refer to those salts that are safe for use in food materials or prescription products. The term is not used to indicate or suggest a product that requires a prescription. Depending on several factors, such as the concentration of the active ingredient (s), the L-carnitine and the acetyl-L-carnitine according to the invention can be sold as food supplements, nutritional supplements, or as therapeutic products including prescription products on counter
Various molar proportions of L-carnitine for acetyl-L-carnitine, or the pharmacologically acceptable salts thereof, can be used in accordance with the invention, including molar proportions ranging from 4.0: 1 to 1: 1.5. Preferred proportions include molar proportions ranging from about 3.2: 1 to 2.8: 1 in molar proportions that correspond approximately to 1: 1. The combined proportions of the present invention, when in unit dosage form, comprise from 2.5 g to 0.22 g of internal salt of L-carnitine and from 0.28 g to 1.3 g of acetyl-L-carnitine or equimolar amounts of the pharmacologically acceptable salts this. Preferred combinations of the preparations in unit dosage forms comprise 1.0 g of L-carnitine inner salt and 0.5 g of acetyl-L-carnitine internal salt or equimolar amounts of the pharmacologically acceptable salts thereof. In addition, it was found that although the daily dose of the aforementioned active ingredients to be administered is determined from the age, weight and condition of the patient, using judicious professional judgment, it is generally advisable to administer a single dose or regimen of administration of multiple doses of approximately 0.8 to 2.5 g / day of L-carnitine and approximately 1.0 to 1.5 g / day of acetyl-L-carnitine or equivalent molar amounts of the pharmacologically acceptable salts thereof. The higher doses can be safely administered in view of the extreme low toxicity of the aforementioned active ingredients. A clinical study aims to evaluate whether supplementation with drug-associated therapy is effective in improving reduced motility of sperm on L-carnitine monotherapy and acetyl-L-carnitine monotherapy, respectively, is described here below. Thirty-six patients who responded to the following inclusion / exclusion criteria were enrolled. "Criteria for inclusion: infertile young men with idiopathic asthenozoospermia recognized as the only cause of infertility with at least two years duration; the semen parameters to be reached in at least two samples: the sperm concentration (M / ml) between 10-20, motility (%) > 20 < 40 for two hours, fast linear progression (%) < 20 to 2 hours. "Criterion of excision: testes without descending, variocele (grade 3), testicular atrophy related to trauma or infection, obstruction, inflammation and infection of the genital tract, any endocrine disorder that affects the hypothalamic-pituitary-gonadal axis; pubertals and evidence of anti-sperm antibodies All patients gave their informed consent to this open study Semen was obtained by masturbation after at least 4 days of sexual abstinence Samples were analyzed within one hour after ejaculation for all parameters using conventional methods recommended by WHO (1987) Sperm motility was studied using a computer-based motility analyzer in at least two specimens, semen analysis and motility assessment were carried out online 0 and after 4 months of treatment with L-carnitine (N = 12) or acetyl-L-carnitine (N = 12) or drug or in association (N = 12). L-carnitine is administered at a dose of 2g / day (2 x 500 mg tablet b.i.d., after meals) for 4 months. Acetyl-L-carnitine was administered at a dose of 4g / day (2 x 1 g in suborette b.i.d., after meals) for 4 months. The drug association treatment
(L-carnitine + acetyl-L-carnitine) is administered at a dose of 2 g / day (2 x 500 mg tablet composed of 220 mg of
L-carnitine and 280 mg of acetyl-L-carnitine, b.i.d., after meals) for 4 months.
The data were analyzed using the Student's "t" test for the paired data.
Results
LC + ALC = L-Carnitine + Acetyl-L-carnitine * p < 0.05 versus L-Carnitine # p < 0.05 versus Acetyl-L-Carnitine §§ p < 0.001 versus L-Carnitine + Acetyl-L-Carnitine at p < 0.01 versus L-Carnitine b p < 0.001 versus Acetyl-L-Carnitine p < cooling versus L-Carnitine Before the values for the treatment of the seminal parameters were lower than those of the WHO normal range. The associated drug treatment significantly increased the concentration of sperm motility, as well as the percentage of sperm with rapid linear progression compared to monotherapy treatments with L-carnitine and acetyl-L-carnitine. The medicament of the present invention can be prepared by mixing either separately or separately - the active ingredients (internal salt of L-carnitine and internal salt of acetyl-L-carnitine or a pharmacologically acceptable salt thereof) with suitable excipients for the formulation of compositions that are suitable for parenteral administration (particularly oral administration) or for parenteral administration
(particularly by the intramuscular or intravenous route). All of these excipients are readily apparent to someone who has an ordinary skill in this technique. The pharmaceutically acceptable salts of the above-mentioned active ingredients include all pharmaceutically acceptable salts which are prepared by the addition of an acid to the internal salts of L-carnitine and of acetyl-L-carnitine and which do not result in side or toxic effects unwanted The formation of addition salts has been pharmaceutically acceptable is well known in pharmaceutical technology. Non-limiting examples of suitable salts include chloride; bromide; I last; aspartate, particularly aspartate acid; citrate, particularly acid citrate; tartrate; phosphate, particularly acid phosphate; fumarate, particularly acid fumarate; glycerophosphate; phosphate in glucose; lactate; maleate, particularly acid maleate; orotato; oxalate, particularly oxalate acid; sulfate, particularly acid sulfate; trichloroacetate; trifluoro acetate and methanesulfonate. A preferred embodiment of the invention utilizes L-carnitine acid fumarate and acetyl L-carnitine hydrochloride, more preferably in a molar ratio of about 3: 1. This and other preferred embodiments may be illustrated by sachets containing the following composition:
Composition Composition Composition Composition 1 2 3 4 Acetyl-L- g 0.500 g 1.000 g 1.000 g 1.500 carnitine, HCl equivalent to internal salt g 0.424 g 0.848 g 0.848 g 1.272 Acetyl- (2.1 (4.2 (4.2 L-carnitine mMoles ) mMoles) mMoles) mMoles)
Fumarate of g 1,725 g 3,450 g 4,312 g 1,725 L-carnitine equivalent g 1,000 g 2,000 g 2,500 g 1,000 a salt (6.2 (12.4 (15.5 (6.2 internal mMoles) mMoles) mMoles) L-carnitine Proportion - 3 - 3 - 3.7 - 1 molar of L-carnitine / a cetyl-L-carnitine Fructose g 1,000 g 2,000 g 2,000 g 2,000
Acid g 0.050 g 0.050 g 0.050 g 0.050 g sodium Sodium 0.008 g 0.008 g 0.008 g 0.008 saccharine Flavor of g 0.050 g 0.050 g 0.050 g 0.050. tonic water D-mannitol g 0.666 g 0.441 g 0.579 g 1.666
Dioxide g 0.001 g 0.001 g 0.001 g 0.001 colloidal silicone The contents of a sachet can be mixed in at least 120 ml of water or another drink. Two sachets of the lowest composition (ie composition 1) should be taken per day, preferably one in the morning and one in the evening, preferably for at least six months. This request is a continuation in part of the serial request no. 08 / 980,821, filed December 1, 1997, pending. Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. Therefore, it should be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.
Claims (27)
1. A combination of L-carnitine and acetyl-L-carnitine in mixture or packed separately, able to increase the concentration and / or motility of sperm in humans, characterized in that the combination is in a form suitable for oral or parenteral administration.
2. A combination of L-carnitine and acetyl-L-carnitine in a form suitable for oral administration according to claim 1.
3. A combination of L-carnitine and acetyl-L-carnitine in a form suitable for parenteral administration according to claim 1.
4. A combination of L-carnitine and acetyl-L-carnitine according to claim 1.
5. The L-carnitine and acetyl-L-carnitine packaged separately, according to claim 1.
6. The combination according to claim 1, characterized in that it comprises a pharmacologically acceptable salt of L-carnitine or acetyl-L-carnitine, the salt is selected from a group consisting of chloride, bromide; I last; aspartate; citrate; tartrate; phosphate; fumarate; glycerophosphate; phosphate in glucose; lactate; maleate; orotato; oxalate; sulfate; trichloroacetate; trifluoroacetate and methanesulfonate.
7. The combination according to claim 1, characterized in that it comprises a pharmacologically acceptable salt of the group consisting of acid aspartate, acid citrate, acid phosphate, acid fumarate, acid maleate, acid oxalate and acid sulfate.
8. The combination according to claim 6 and 7, characterized in that it comprises L-carnitine fumarate acid and acetyl-L-carnitine hydrochloride.
9. The combination according to claim 6, characterized in that it comprises pharmacologically acceptable salts of both L-carnitine and acetyl-L-carnitine.
10. The combination according to claim 1, characterized in that it is capable of increasing the concentration of sperm in a human.
11. The combination according to claim 1, characterized in that it is capable of increasing the motility of sperm in a human.
12. The combination according to claim 1, characterized in that it is capable of treating idiopathic asthenozoospermia in a human.
13. The mixture of L-carnitine and acetyl-L-carnitine according to claim 4, characterized in that it is in a form suitable for oral administration.
14. The mixture of L-carnitine and acetyl-L-carnitine according to claim 4, characterized in that it is in a form suitable for parenteral administration.
15. The combination according to claim 1, characterized in that it comprises L-carnitine and acetyl-L-carnitine with a molar ratio of 4.0: 1 to 1: 1.5.
16. The combination according to claim 15, characterized in that it comprises L-carnitine acid fumarate and acetyl L-carnitine hydrochloride.
17. A method for increasing the concentration and / or motility of sperm in a human in need of this, characterized in that it comprises administering to this human each of L-carnitine and acetyl L-carnitine in an amount that provides this increase in concentration and / or motility of the sperm.
18. The method according to claim 17, characterized in that it comprises administering to this human which is a mixture of L-carnitine and acetyl L-carnitine.
19. A method for treating idiopathic asthenozoospermia in a human, in accordance with claim 17.
20. The method according to claim 17, characterized in that it comprises administering a pharmacologically acceptable salt of L-carnitine or acetyl L-carnitine, this salt is selected from a group consisting of chloride, bromide; I last; aspartate; citrate; tartrate; phosphate; fumarate; glycerophosphate; phosphate in glucose; lactate; maleate; orotato; oxalate; sulfate; trichloroacetate; trifluoroacetate and methanesulfonate.
21. The method according to claim 20, characterized in that it comprises administering a salt selected from the group consisting of acid aspartate, acid citrate, acid phosphate, acid fumarate, acid maleate, acid oxalate and acid sulfate.
22. The method according to claim 20, characterized in that it comprises administering L-carnitine acid fumarate and acetyl L-carnitine.
23. The method according to claim 17, characterized in that it comprises administering to this human 'L-carnitine and acetyl L-carnitine in a molar ratio of 4.0: 1 to 1: 1.5.
24. The method according to claim 22, characterized in that it comprises administering L-carnitine fumarate acid and acetyl L-carnitine hydrochloride in a molar ratio of 4.0: 1 to 1: 1.5.
25. The combination according to claim 1, in the form of a unit dose, characterized in that it comprises from 0.22 to 2.5 g of internal salt of L-carnitine and from 0.28 to 1.3 g of internal salt of acetyl-L-carnitine or equimolar amounts of the pharmacologically acceptable salts of this.
26. The use of a combination of L-carnitine and acetyl L-carnitine or the pharmacologically acceptable salts thereof is mixed or packaged separately to prepare a composition for increasing the concentration and / or motility of sperm in humans.
27. The use according to claim 26, characterized in that the L-carnitine and the acetyl L-carnitine or the pharmacological salts thereof are in a molar ratio of 4.0: 1 to 1: 1.5.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08980821 | 1997-12-01 | ||
| US09122897 | 1998-07-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA00005352A true MXPA00005352A (en) | 2001-07-03 |
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