LV12978B - Pharmaceutical composition - Google Patents
Pharmaceutical composition Download PDFInfo
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- LV12978B LV12978B LVP-01-133A LV010133A LV12978B LV 12978 B LV12978 B LV 12978B LV 010133 A LV010133 A LV 010133A LV 12978 B LV12978 B LV 12978B
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- Latvia
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- camitine
- gbb
- butyrobetaine
- pharmaceutical composition
- gamma
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic 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
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
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- Health & Medical Sciences (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Reproductive Health (AREA)
- Engineering & Computer Science (AREA)
- Endocrinology (AREA)
- Epidemiology (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
New medical use of 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, intrauretral, 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 erection in narcotized animals.
Description
LV 12978
Pharmaceutical composition
Invention relates to pharmaceutical composition, particularly to pharmaceutical composition for normalizing and stimulating of sexual activity and potency in mammals. The composition discloses novel efifects 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-camitine (vitamin BT) or phosphodiesterase inhibitor. GBB (actinine), an intermediate in the synthesis of camitine 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;42:181). 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 Y-butyrobetaine. Nature 1959;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 camitine 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 camitine, metabolically related to GBB, functions as vitamin, essential for the trasporting of long-chain fatty acids 1 across mitochondrial membranes, its deficiency resulting in myopathy (Engel AG, Angelini G, Nelson AR. Identification of camitine deficiency as a cause of human lipid storage myophathy; a new syndrome. Science 1973; 179:899). Camitine is widely used as physical performance enhancer or metabolic aģent in circulatory insufficiency and other cardiovascular conditions (Schofleld RS, Hill JA. Role of metabolically active drugs in the management of ischemic heart disease. Am J Cardiovasc Dmgs. 2001 ;1(X): 23).
There are no data on the influence of camitine on sexual activity and potency of mammals.
We have surprisingly discovered that pharmaceutical compositions, comprising GBB or combination thereof with camitine inducē substantial and long-lasting increase of sexual activity in laboratory animals. Moreover, the combination of both substances producē 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 camitine, exert a positive influence on intracorporeal pressure, induced by reflectory stimulation. Thus we have unexpectedly discovered that pharmaceutical compositions, comprising GBB or combination thereof with camitine, 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 camitine on the fatty acids tumover or other knovvn physiological effects of said substances.
The pharmacological effects of GBB, camitine (L-camitine) and their combination on the sexual activity was investigated by a modei 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 ķept in Standard crates in groups of 6. The feed was a standartized diet R70 (LABFOR, Lactamin AB, Sweden). The room temperature was ķept 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; 2 LV 12978
Group 3 (Camitine Group) - drinking water was supplemented by camitine (0.15% by weight), resulting in the average daily camitine intake of 150 mg/kg;
Group 4 (Camitine + GBB Group) - drinking water was supplemented by camitine (0.065% by weight) and gamma-butyrobetaine (0.02% by weight), resulting in the average daily camitine intake of 65 mg/kg and gamma-butyrobetaine intake of 20 mg/kg.
Group 5 (Camitine + GBB Group 2) - drinking water was supplemented by camitine (0.15% by weight) and gamma-butyrobetaine (0.03% by weight), resulting in the average daily camitine 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 copulatioa 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 ali animals were receiving drinking water without additives.
The tests were conducted betvveen 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 minūtes. 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 mārks: 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 tēst.
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 camitine 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 camitine resulted in hightened sexual interest and copulating activity during ali experimental period. After the 3 discontinuing of medication, only the GBB + Camitine Group displayed higher copulating activity compared with Controls.
Thus we have experimentally demonstrated, that GBB alone and in combination with camitine after 6 week treatment period producēs 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 aģents on the number of mounting attempts of male rats
Duration of therapy 1 week 4 weeks 6 weeks Post-therapy Control 1.2±0.5 1.8±0.6 2.3±0.5 2.7±0.5 GBB 3.5*±0.8 3.7±0.7 3.5±0.6 3.2±0.5 Camitine 2.2±0.6 3.0±0.6 3.8±0.5 3.510.6 GBB+Camitine 3.3*10.7* 3.8*±0.5 4.0*±0.5 3.810.5 *) p<0.05 v.s. .control
Table 2. The influence of therapeutic aģents on the delay time before attempts of mounting (min) Duration of therapy 1 week 4 weeks 6 weeks Post-therapy Control 5.811.4 4.611.1 4.110.7 3.610.6 GBB 3.510.7 1.8*10.4 2.710.7 2.610.6 Camitine 4.711.2 2.310.6 2.310.5 2.510.6 GBB+Camitine 3.110.8 1.7*10.4 1.7*10.4 1.6*10.3 *) p<0.05 v.s. control
Table 3. The influence of therapeutic aģents on the number of copulations _
Duration of therapy 1 week 4 weeks 6 weeks Post-therapy Control 0.210.2 0.310.2 0.310.2 0.510.5 GBB 0.810.3 1.0*10.4 0.810.3 0.710.2 Camitine 0.510.2 0.710.3 1.0*10.3 0.810.3 GBB+Camitine 0.810.3 1.2*10.3 1.5*10.4 1.010.3 *) p<0.05 v.s. control 4 LV 12978
Table 4. The influence of therapeutic aģents 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 1.210.3 1.510.4 GBB 1.8±0.4 1.3±0.2 1.510.4 1.210.3 Camitine 1.0±0.3 1.510.4 2.010.4 1.210.3 GBB+Camitine 1.8*±0.3 2.2*10.3 1.810.3 1.710.4 *) p<0.05 v.s. control
In further experiments the changes in intracorporeal pressure induced by GBB, camitine, 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 modei, where measuring of intracavemous 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 ķept 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 cavemosum penis. Intracavemous 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 intracavemous introduction route. For the intracavemous 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-Camitine 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-camitine 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., camitine 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 intracavemous injection of GBB producēs a pronounced dose-dependent, but relatively short-termed increase of intracorporeal pressure (Table 5). Camitine did not producē any substantial changes of intracorporeal pressure, while the composition, consisting of camitine and GBB produced increase analogous to that, induced by GBB 5 alone, though more prolonged than induced by any of the two components alone. Although papaverine and sildenafil were most efficient aģents in this (intracavemous injection) modei, 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 camitine display little effect on intracorporeal pressure. Unexpectedly also influence of the well known preparation sildenafil was not expressed in ali animals, while GBB and GBB-camitine composition, as well as composition of GBB with sildenafil are highly efficient. The novel composition (GBB+camitine) producēs an increase of intracavemous pressure, lasting for 68% longer that the GBB effects. It is also essential to note that only the composition of GBB and camitine induced a positive response to reflex penis stimulation by increase of intracavemous 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 camitine or sildenafil, inducē increase of intracorporeal pressure both at intracavemous and intravenous administration.
Table 5. Influence of intracavemous injections of therapeutic aģents on intracorporeal pressure in narcotized rats Aģent GBB Camitine GBB+Camitine Papaverine Sildenafil GBB+Sildenafil Changes of intracavemous pressure (mmHg) 31.5*±5.1 1.1±0.7 31.0*17.8 36.8*±4.1 38.5*17.3 35.2*18.4 Duration of effect 4.3±0.9 0.6±0.4 7.0*11.2 8.3*±1.4 7.5±2.7 17.6*±4.3 *) p<0.05 v.s. camitine
Table 6. Influence of intravenous injections of therapeutic aģents on intracorporeal pressure in narcotized rats Aģent GBB Camitine GBB+Camitine Papaverine Sildenafil GBB+Sildenafil Reflectory increase of intracavemous pressure (mm Hg) 7.3*12.0 0.5±0.5 2.8±1.7 0.3±0.3 11.8*13.6 7.3*12.1 Changes of intracavemous pressure (mm Hg) 22.0*13.6 0.8±0.4 15.7*12.3 0.610.6 12.314.8 28.4*17.9 Duration of effect (min) 2.8±0.7 0.5±0.3 4.7*±0.9 0.910.9 2.511.1 15.3*14.2 *) p<0.05 v.s. camitine 6 LV 12978
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 camitine 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, pilis, granules, or powders, pharmaceutical composition contains gamma-butyrobetaine or combination thereof with camitine or sildenafil in the amount of 0.5 to 5 g by weight per tablet, caplet, capsule, pili, granule, or powder dosage unit.
In cases when the active ingredients are administered 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 aģents, such, as for example, other known phosphodiesterase type V inhibitors (vardenafil, tadalafil and related).
We 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-camitine 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 inhibitor. 6. The pharmaceutical composition of Claim 5 wherein the phosphodiesterase inhibitor of type V is selected from the group consisting of sildenafil, vardenafil, tadalafil 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. 7 LV 12978
ABSTRACT
New medical use for gamma-butyrobetaine is disclosed. Also disclosed are pharmaceutical compositions, containing gamma-butyrobetaine or combination thereof with L-caraitine or sildenafil for oral, parenteral, subcutaneous, transdermal, topical, sublingual, intrauretral, 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 intracavemous or intravenous route said pharmaceutical compositions increase intracorporeal pressure and duration of erection, as well as restore stimulation-induced reflectory erections in anesthetized animals. 8
Claims (7)
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-01-133A LV12978B (en) | 2001-09-07 | 2001-09-07 | Pharmaceutical composition |
| PCT/LV2002/000005 WO2003022263A1 (en) | 2001-09-07 | 2002-03-04 | Pharmaceutical composition comprising gamma-butyrobetaine for stimulating the sexual activity and potency |
| UA2004042511A UA78235C2 (en) | 2001-09-07 | 2002-04-03 | Pharmaceutical compositions, containing gamma-butyrobetaine for treating impotence in males of mammals |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| LVP-01-133A LV12978B (en) | 2001-09-07 | 2001-09-07 | Pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| LV12978B true LV12978B (en) | 2003-05-20 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| LVP-01-133A LV12978B (en) | 2001-09-07 | 2001-09-07 | Pharmaceutical composition |
Country Status (3)
| Country | Link |
|---|---|
| LV (1) | LV12978B (en) |
| UA (1) | UA78235C2 (en) |
| WO (1) | WO2003022263A1 (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050234068A1 (en) * | 2004-04-19 | 2005-10-20 | Baldwin Dalton D | 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 |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1198434B (en) * | 1981-01-06 | 1988-12-21 | Sigma Tau Ind Farmaceuti | PHARMACEUTICAL COMPOSITION INCLUDING BUTYROBETAIN RANGE FOR THE TREATMENT OF SYNDROMES FROM CARNITIN DEFICIENCIES |
| LV11728B (en) * | 1995-08-21 | 1997-08-20 | Kalvins Ivars | Pharmaceutical composition |
| IT1293539B1 (en) * | 1997-07-16 | 1999-03-01 | Sigma Tau Ind Farmaceuti | NUTRITIONAL COMPOSITION FOR SUBJECTS IN A STATE OF DEBILITATION CAUSED BY STRESS |
| US6090848A (en) * | 1997-12-01 | 2000-07-18 | Sigma-Tau Healthscience S.P.A. | Compositions and methods for increasing the concentration and/or motility of spermatozoa in humans |
| GT199900061A (en) * | 1998-05-15 | 2000-10-14 | Pfizer | PHARMACEUTICAL FORMULATIONS. |
-
2001
- 2001-09-07 LV LVP-01-133A patent/LV12978B/en unknown
-
2002
- 2002-03-04 WO PCT/LV2002/000005 patent/WO2003022263A1/en not_active Ceased
- 2002-04-03 UA UA2004042511A patent/UA78235C2/en unknown
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| Publication number | Publication date |
|---|---|
| WO2003022263A1 (en) | 2003-03-20 |
| UA78235C2 (en) | 2007-03-15 |
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