WO2003022263A1 - Pharmaceutical composition comprising gamma-butyrobetaine for stimulating the sexual activity and potency - Google Patents

Pharmaceutical composition comprising gamma-butyrobetaine for stimulating the sexual activity and potency Download PDF

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Publication number
WO2003022263A1
WO2003022263A1 PCT/LV2002/000005 LV0200005W WO03022263A1 WO 2003022263 A1 WO2003022263 A1 WO 2003022263A1 LV 0200005 W LV0200005 W LV 0200005W WO 03022263 A1 WO03022263 A1 WO 03022263A1
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Prior art keywords
carnitine
gbb
butyrobetaine
gamma
sexual activity
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PCT/LV2002/000005
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French (fr)
Inventor
Ivars Kalvinsh
Maris Veveris
Anatolijs Birmans
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Ivars Kalvinsh
Maris Veveris
Anatolijs Birmans
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Priority to LVP-01-00133 priority Critical
Priority to LVP-01-133A priority patent/LV12978B/en
Application filed by Ivars Kalvinsh, Maris Veveris, Anatolijs Birmans filed Critical Ivars Kalvinsh
Publication of WO2003022263A1 publication Critical patent/WO2003022263A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/205Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10Drugs for genital or sexual disorders; Contraceptives for impotence

Abstract

New medical use for gamma-butyrobetaine is disclosed. Also disclosed are pharmaceutical compositions, containing gamma-butyrobetaine or combination thereof with L-carnitine or sildenafil for oral, parenteral, subcutaneous, transdermal, topical, sublingual, intrauetral, intranasal or rectal application, useful for stimulation of sexual activity and potency in mammals. The disclosed compositions, when applied orally for 6 weeks to non-narcotized male rats substantially increase their sexual activity, decreasing the arousal time, increasing the number of copulations and resultativeness of mounting attempts. When applied by intracavernous or intravenous route said pharmaceutical compositions increase intracorporeal pressure and duration of erection, as well as restore stimulation-induced reflectory erections in anesthetized animals.

Description

PHARMACEUTICAL COMPOSITION COMPRISING GAMMA-BUTYROBETAINE FOR STIMULATING THE SEXUAL ACTIVITY AND POTENCY

Invention relates to pharmaceutical composition, particularly to pharmaceutical composition for normalizing and stimulating of sexual activity and potency in mammals. The composition discloses novel effects of known substances, displaying unexpected pharmacological activity in combination. In particular, a pharmaceutical composition is disclosed, comprising as active ingredients gamma-butyrobetaine (GBB) in combination with L-carnitine (vitamin BT) or phosphodiesterase inhibitor.

GBB (actinine),' an intermediate in the synthesis of carnitine in mammalian organism, initially was characterised as a toxic substance, inducing tachypnea, salivation and lacrimation, mydriasis, vasoconstriction and cardiac arrest in diastole (Linneweh W. Z physiol Chem, 1929;42.T 81). Further research demonstrated that the toxicity of GBB is extremely low (LD50 = 7000 mg/kg subc.) (Rotzsch W, Lorenz I, Strack E. Acta biol med ger 1959;3:28-36). The cardiovascular effects of GBB were compared to that of acetylcholine (Hosein EA, McLennan H. Pharmacological action of γ-butyrobe aine. Nature I959;183:328), but later the data were renounced by the same author, who had in fact investigated the effects of the GBB methyl esther. Another investigators held, that GBB is pharmacologically inert (Hosein EA, Proulx P. Isolation and probable functions of betaine esters in brain metabolism. Nature 1960;187:321. Burgen ASV, Hobiger F. Brit J Pharmacol. 1949 4:229. Strack E, Foesterling K. Z physiol Chem. 1953 :295:377). Contrary to that, radical scavenger properties (Akahira M, Hara A, Abiko Y. Effect of MET-88, a gamma-butyrobetaine hydroxylase inhibitor, on myocardial derangements induced by hydrogen peroxide in the isolated perfused rat heart. Fundam Clin Pharmacol. 1997;11(4):356) and cardioprotective activity (Kalvins I, Veveris M. Latvian patent Nr. 11727) were later demonstrated for GBB. It was also disclosed, that pharmaceutical composition, comprising GBB as the active principle, is useful for treating of carnitine deficiency (Cavazza C. Pharmaceutical composition comprising gamma-butyrobetaine. UK Patent Application GB 2 091 101 (1982)). There are no data on the influence of GBB on sexual activity and . potency of mammals.

It is also known, that carnitine, metabolically related to GBB, functions as vitamin, essential for the trasporting of long-chain fatty acids across mitochondrial membranes, its deficiency resulting in myopathy (Engel AG, Angelini G, Nelson AR. Identification of carnitine deficiency as a cause of human lipid storage myophathy; a new syndrome. Science 1973;179:899). Carnitine is widely used as physical performance enhancer or metabolic agent in circulatory insufficiency and other cardiovascular conditions (Schofield RS, Hill JA. Role of metabolically active drugs in the management of ischemic heart disease. Am J Cardiovasc Drugs. 2001 ;1(1): 23).

There are no data on the influence of carnitine on sexual activity and potency of mammals.

We have surprisingly discovered that pharmaceutical compositions, comprising GBB or combination thereof with carnitine induce substantial and long-lasting increase of sexual activity in laboratory animals. Moreover, the combination of both substances produce a more prolonged and higher increase of the intracorporeal pressure than each of the constituent substances separately. Moreover, the pharmaceutical compositions comprising GBB or combination thereof with carnitine, exert a positive influence on intracorporeal pressure, induced by refiectory stimulation. Thus we have unexpectedly discovered that pharmaceutical compositions, comprising GBB or combination thereof with carnitine, are useful for stimulating of both the sexual activity and potency of mammals. This activity can not be attributed to the known effects of GBB and/or carnitine on the fatty acids turnover or other known physiological effects of said substances.

The pharmacological effects of GBB, carnitine (L-carnitine) and their combination on the sexual activity was investigated by a model based on rat copulating behaviour.

Experiments were conducted on adult Wistar rats of both sexes with initial body weight of 300 - 350 g. During the experiment, the animals were kept in standard crates in groups of β. The feed was a standartized diet R70 (LABFOR, Lactamin AB, Sweden). The room temperature was kept at 20 - 23 °C, relative humidity at 65 ± 10%, 12 hour light/darkness cycle. During one week before the experiment it was established that the average water consumption by the rats was 8.2 - 12% (average - 10%) of their body mass. The experiment protocol was the following: male rats were distributed randomly into 5 groups, each of 6 animals, and supplied for 6 weeks with the following aqueous solutions: Group 1 (Control Group) - drinking water without any additives; Group 2 (GBB Group) - drinking water was supplemented by gamma- butyrobetaine (0.03% by weight), resulting in the average daily gamma- butyrobetaine intake of 30 mg/kg; Group 3 (Carnitine Group) - drinking water was supplemented by carnitine (0.15% by weight), resulting in the average daily carnitine intake of 150 mg/kg;

Group 4 (Carnitine + GBB Group) - drinking water was supplemented by carnitine (0.065% by weight) and gamma-butyrobetaine (0.02% by weight), resulting in the average daily carnitine intake of 65 mg/kg and gamma-butyrobetaine intake of 20 mg/kg.

Group 5 (Carnitine + GBB Group 2) - drinking water was supplemented by carnitine (0.15% by weight) and gamma-butyrobetaine (0.03% by weight), resulting in the average daily carnitine intake of 150 mg/kg and gamma- butyrobetaine intake of 30 mg/kg. Due to increasing aggressive behaviour of animals the experiment was discontinued.

The copulation activity of male rats was tested four times: after one week, after four weeks, after six weeks and 48 - 50 hours after the discontinuation of substance intake, when all animals were receiving drinking water without additives.

The tests were conducted between 10 and 12 a.m. 6 male rats of one group were placed into a clean, well illuminated crate (box). After 5 min. adaptation period 2 female rats were placed into the box for 10 minutes. For each male rat the following data were collected:

1) copulating intensity (number of copulations during the exposition period);

2) arousal period, with separate registration of the delay time - the period until the male rat displays interest in the female rat, and number of approaching/mounting attempts during the exposition period;

3) postcoital period - the behaviour of male rats during 5 min. period after the removal of females. The postcoital behaviour was characterized by following marks: 0 - the animal is passive, lays down; 1 - the rat is quiet, grooming; 2 - the rat is mobile, rutting; 3 - the animal is active, aggressive.

The female rats used were in the estrus phase, induced by i.p. injection of 0.2 ml 0.1% estradiol dipropionate 48 h before the test.

There was no substantial changes in water consumption attributable to experimental substances, while the sexual behaviour of rats in experimental groups was substantially different from that of control group.

Already a week after the start of the experiment, animals receiving GBB and carnitine displayed substantially higher interest and activity in sexual contacts, as well as longer postcoital arousal period (Tables 1 - 4). The continuing application of GBB resulted in increase of sexual activity, reflected in higher copulation intensity, while rutting and general activity of animals was relatively less influenced.

The combined use of GBB and carnitine resulted in .lightened sexual interest and copulating activity during all experimental period. After the discontinuing of medication, only the GBB + Carnitine Group displayed higher copulating activity compared with controls.

Thus we have experimentally demonstrated, that GBB alone and in combination with carnitine after 6 week treatment period produces a substantial and lasting increase of copulating activity in male rats. Moreover, we found a surprising increase of efficiency for the combination of two substances as compared to their activity when used separately.

Table 1. The influence of therapeutic agents on the number of mounting attempts of male rats

Figure imgf000005_0001

!) p<0.05 v.s. control

Table 2. The influence of therapeutic agents on the delay time before attempts of mounting (min)

Figure imgf000005_0002

*) p<0.05 v.s. control

Table 3. The influence of therapeutic agents on the number of copulations

Duration of therapy 1 week 4 weeks 6 weeks Post-therapy

Control 0.2±0.2 0.3±0.2 0.3±0.2 0.5+0.5

GBB 0.8+0.3 1.0*±0.4 0.8±0.3 0.7+0.2

Carnitine 0.5±0.2 0.7±0.3 1.0*+0.3 0.8+0.3

GBB+Carnitine 0.8+0.3 '1.2*±0.3 1.5*±0.4 1.0±0.3

) p<0.05 v.s. control Table 4. The influence of therapeutic agents on rat post-coital agitation period

Duration of therapy 1 week 4 week 6 weeks Post-therapy

Control 0.8+0.3 1.0+0.4 1.2±0.3 1.5+0.4

GBB 1.8+0.4 1.3+0.2 1.5+0.4 1.2±0.3

Carnitine 1.0+0.3 1.5+0.4 2.0±0.4 1.2±0.3

GBB+Carnitine 1.8*+0.3 2.2*±0.3 1.8+0.3 1.7+0.4

*) p<0.05 v.s. control

In further experiments the changes in intracorporeal pressure induced by GBB, carnitine, phosphodiestherase inhibitors and combination thereof were investigated.

Adult male rats, weighing 300 - 410 g were used. The influence of the experimental substances on the penile erection was evaluated using the experimental model, where measuring of intracavernous pressure was measured (Chen KK et al. J Urol, 1992;147: 1124).

Rats were anesthetized by sodium pentobarbital (50 mg/kg i.p. plus additionally 8 mg/kg/h i.v.). Body temperature was kept at 37 - 37.4 °C (rectal control) by heating lamp. Endotracheal tube was inserted to assure adequate respiration under anesthesia. Number 25 needle filled with heparinized saline was connected to pressure transducer and introduced into corpus cavernosum penis. Intracavernous pressure and II standard lead on an ECG was continuously recorded on physiograph DMP-4B (Narco Bio-Systems, USA). In some experiments arterial pressure in common carotid artery was also recorded. The effects of experimental substances were determined both at intravenous and intracavernous introduction route. For the intracavernous injection the substances were dissolved in isotonic (0.9%>) NaCl solution and the dose introduced in 0.05 ml of liquid. Papaverine hydrochloride, used in clinics for potency testing, served as the positive standard. L-Carnitine and gamma-butyrobetaine were introduced separately and as combination including a combination with phosphodiesterase inhibitor, for example sildenafil.

GBB for intracorporeal administration was used in a dosage 0.02 to 0.1 mg per rat, usually 0.05 mg per rat, but L-carnitine and papaverine at a dose 0.2 mg and sildenafil at a dose 0.15 mg. For i.v. application GBB was used in a dose 2.0 mg/kg b.w., carnitine was applied in a dosage of 10.0 mg/kg b.w., papaverine in a dosage of 2.0 mg/kg b.w. and sildenafil in a dosage of 3.0 mg/kg b.w.

It was discovered that intracavernous injection of GBB produces a pronounced dose-dependent, but relatively short-termed increase of intracorporeal pressure (Table 5). Carnitine did not produce any substantial changes of intracorporeal pressure, while the composition, consisting of carnitine and GBB produced increase analogous to that, induced by GBB alone, though more prolonged than induced by any of the two components alone. Although papaverine and sildenafil were most efficient agents in this (intracavernous injection) model, this route is not acceptable clinically due to inconvenience of application.

Intravenous route was used for further evaluation (Table 6). It was demonstrated that papaverine and carnitine display little effect on intracorporeal pressure. Unexpectedly also influence of the well known preparation sildenafil was not expressed in all animals, while GBB and GBB-carnitine composition, as well as composition of GBB with sildenafil are highly efficient. The novel composition (GBB+carnitine) produces an increase of intracavernous pressure, lasting for 68% longer that the GBB effects. It is also essential to note that only the composition of GBB and carnitine induced a positive response to reflex penis stimulation by increase of intracavernous pressure, a response untypical for narcotized animals.

Also the composition of GBB+sildenafil demonstrated very long lasting effect, which was at least 5 times longer as that for each of ingradients (GBB or sildenafile) alone.

Thus we have unexpectedly discovered that pharmaceutical compositions, comprising GBB or combination thereof with carnitine or sildenafil, induce increase of intracorporeal pressure both at intracavernous and intravenous administration.

Table 5. Influence of intracavernous injections of therapeutic agents on intracorporeal pressure in narcotized rats

Figure imgf000007_0002

*) p<0.05 v.s. carnitine

Table 6. Influence of intravenous injections of therapeutic agents on intracorporeal pressure in narcotized rats

Figure imgf000007_0003
Figure imgf000007_0001
Considering the positive effects of the novel compositions on reflectory increase of intracorporeal pressure and activity displayed orally, they are useful for stimulation of sexual activity and erection both at norm and at physiological depression of erectile function, being introduced both enterally and parenterally.

In cases when the active ingredient(s) is (are) administered parentally by injections or orally as drops, syrup or beverage, the pharmaceutical composition contains gamma-butyrobetaine or combination thereof with carnitine or sildenafil in the amount of 0.5-40% by total weight of pharmaceutical form and distilled water, physiologic saline solution, glucose solution, or buffer solution as a pharmaceutically acceptable solvent.

In cases when the active ingredients are administered as tablets, caplets, capsules, pills, granules, or powders, pharmaceutical composition contains gamma-butyrobetaine or combination thereof with carnitine or sildenafil in the amount of 0.5 to 5 g by weight per tablet, caplet, capsule, pill, granule, or powder dosage unit.

In cases when the active ingredients are aclnxinistered transcutaneously, topically, sublingually, intrauretrally or intranasally their content is 0.5-40% by total weight of pharmaceutical form.

The pharmacutical composition, in addition, may include other pharmacutical agents, such, as for example, other known phosphodiesterase type V inhibitors (vardenafil, tadalafil and related).

Claims

Claim.
1. Use of gamma-butyrobetaine as free base or pharmaceutically acceptable salt in the production of a medicament for normalizing and stimulating of sexual activity and potency in mammals.
2. A pharmaceutical composition for stimulation of sexual activity and potency in mammals comprising gamma-butyrobetaine in association with pharmaceutically acceptable diluent or carrier.
3. The parmaceutical composition of Claim 2 further comprising L- carnitine as free base or pharmaceutically acceptable salt.
4. The pharmaceutical composition of Claim 2 further comprising a phosphodiesterase inhibitor.
5. The pharmaceutical composition of Claim 4 wherein the phosphodiesterase inhibitor is type V ώhibitor.
6. The pharmaceutical . composition of Claim 5 wherein the phosphodiesterase inhibitor of type V is selected from the group consisting of sildenafil, vardenafil, tadalafϊl and related.
7. Use of the pharmaceutical composition of any of Claims 2 to 6 in the production of a medicament for normalizing and stimulating of sexual activity and potency in mammals.
PCT/LV2002/000005 2001-09-07 2002-03-04 Pharmaceutical composition comprising gamma-butyrobetaine for stimulating the sexual activity and potency WO2003022263A1 (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006041922A2 (en) * 2004-10-08 2006-04-20 Dara Biosciences, Inc. Agents and methods for administration to the central nervous system
EP1737465A1 (en) * 2004-04-19 2007-01-03 Loma Linda University Composition and method of decreasing renal ischemic damage

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2091101A (en) * 1981-01-06 1982-07-28 Sigma Tau Ind Farmaceuti Pharmaceutical composition comprising gammabutyro-betaine for the treatment of syndromes induced by l-carnitine deficiency
WO1997006794A1 (en) * 1995-08-21 1997-02-27 Ivars Kalvinsh Pharmaceutical composition for treating cardiovascular diseases containing 3-(2,2,2-trimethylhydrazinium) propionate and gamma-butyrobetaine
WO1999003364A1 (en) * 1997-07-16 1999-01-28 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Nutritional composition for subjects under stress
WO1999027925A1 (en) * 1997-12-01 1999-06-10 Sigma-Tau Healthscience S.P.A. Compositions and methods for increasing the concentration and/or motility of spermatozoa in humans
EP0960621A2 (en) * 1998-05-15 1999-12-01 Pfizer Inc. Pharmaceutical formulations comprising sildenafil

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2091101A (en) * 1981-01-06 1982-07-28 Sigma Tau Ind Farmaceuti Pharmaceutical composition comprising gammabutyro-betaine for the treatment of syndromes induced by l-carnitine deficiency
WO1997006794A1 (en) * 1995-08-21 1997-02-27 Ivars Kalvinsh Pharmaceutical composition for treating cardiovascular diseases containing 3-(2,2,2-trimethylhydrazinium) propionate and gamma-butyrobetaine
WO1999003364A1 (en) * 1997-07-16 1999-01-28 Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. Nutritional composition for subjects under stress
WO1999027925A1 (en) * 1997-12-01 1999-06-10 Sigma-Tau Healthscience S.P.A. Compositions and methods for increasing the concentration and/or motility of spermatozoa in humans
EP0960621A2 (en) * 1998-05-15 1999-12-01 Pfizer Inc. Pharmaceutical formulations comprising sildenafil

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BOHMER T: "ACCUMULATION OF CARNITINE IN RAT EPIDIDYMIS AFTER INJECTION OF TRITIATED BUTYRO BETAINE IN-VIVO QUANTITATIVE ASPECTS AND THE EFFECTS OF ANDROGENS AND ANTI ANDROGENS", MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 11, no. 2, 1978, EN, pages 213 - 224, XP001078749, ISSN: 0303-7207 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1737465A1 (en) * 2004-04-19 2007-01-03 Loma Linda University Composition and method of decreasing renal ischemic damage
EP1737465A4 (en) * 2004-04-19 2007-10-03 Univ Loma Linda Composition and method of decreasing renal ischemic damage
WO2006041922A2 (en) * 2004-10-08 2006-04-20 Dara Biosciences, Inc. Agents and methods for administration to the central nervous system
WO2006041922A3 (en) * 2004-10-08 2006-07-27 David Crockford Agents and methods for administration to the central nervous system

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LV12978B (en) 2003-05-20

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