WO2002069956A2

WO2002069956A2 - Use of carnitine for increasing testosteron

Info

Publication number: WO2002069956A2
Application number: PCT/EP2002/000464
Authority: WO
Inventors: Andrea Schaffhauser; Paula Gaynor
Original assignee: Lonza Ag
Priority date: 2001-01-22
Filing date: 2002-01-18
Publication date: 2002-09-12
Also published as: WO2002069956A3

Abstract

Use of carnitine or alkanoyl-carnitine administration to a human for increasing serum levels of testosterone.

Description

Use of carnitine for increasing testosteron

The present invention relates to the use of carnitine or an alkanoyl-carnitine or salts thereof for increasing the serum levels of testosteron in a human, preferably post-exercise. Another object of the present invention is the use of above said substances for increasing the serum levels of testosteron in a human in a period after a meal.

The steroid hormone testosterone is the sex hormone of human males; it is essential for proper functioning of the accessory sexual glands, for spermatogenesis and libido. Low endogenous testosterone levels reduce male fertility (Younes et al., Low plasma testosterone in varicocele patients with impotence and male infertility, Arch. Androl. 2000, 45:187 ff.). Equally important, testosterone has anabolic properties, it enhances the lean body mass/muscles, helps to fortify the skeleton and promotes erythropoiesis. This natural anabolic effect is accompanied by an important conditioning effect on the human/male psychis: From supplementation medication with exogenous testosteron for various reasons, it is known that testosterone is decisively enhancing important psychological qualities such as resistance to stress, self-esteem, optimism, agility/initiative, psychological dominance. Testosterone is supposed to have an important anti-depressive effect. In the body of the average adult male, approximately 7 mg testosterone are synthesized daily; small quantities (0,3 mg/day) are equally synthesized in the female body, subtly balancing the influence of oestrogens. The plasma form of testosterone, β⁴-Androsten-17β-ol-3-on, is not, however, the metabolically active form. Intracellularly, testosterone is converted by a specific steroid reductase to 5-β- dihydrotestosterone (DHT); the latter is the actual effector molecule binding to intracellular receptors.

Sports activities are a further important contribution to health and wellness, and are a necessary requirement to exploit said anabolic effect of testosterone. However, it has been observed that testosterone levels drop after physical exercise. This drop will be even sharper if the period of exercise is followed shortly after by a meal, as will often be the case (Chandler et al., Dietary supplements affect the anabolic hormones after weight-training exercise. J.

Appl. Physiol. 16: 839-845, 1994; Kraemer et al., Hormonal responses to consecutive days of heavy-resistance exercise with or without nutritional supplementation, J. Appl. Physiol. 85, 1544-1555, 1998). Given all the benefits of testosterone, it is obvious that such decrease in the level of testosterone is negatively influencing the recovery and performance of an individual after a period of exercise. This may be particularly important e.g. where employees or students seek recreation by sports activities in between working hours.

It is an object of the present invention to increase the resting level of testosteron in a human, in particular to alleviate the observed drop in testosterone levels after physical exercise. It is a further object of the present invention to alleviate the drop in resting levels of testosterone in a human after meals, in particular after fat-rich meals. This objects are achieved by administration of carnitine in accordance with claims 1 and 7.

By administration of carnitine, preferably by ingestion of a preparation comprising carnitine or an alkanoyl-carnitine or salts thereof, resting levels of testosterone are increased post- exercise. Carnitine according to the present invention may be (DL)-Carnitine or, preferably, essentially pure L-Carnitine. Such Carnitine may as well be an 3-Alkanoyl-Carnitine, in particular 3-Acetyl-Carnitine. Such Carnitine may be employed either as an inner salt or as a simple or complex salt together with other ionic substances such as, but not limited to, chloride, fumarate, tartrate, citrate, isocitrate, (-)-hydroxycitrate, magnesium, calcium, cholin, either alone or in suitable combinations, particularly as non-hygroscopic complex salts, e.g. L- Carnitine-magnesium-citrate, L-Carnitine-magnesium-(-)hydroxycitrate or L-Carnitine- cholin-tartrate. In even more preferred embodiments, Carnitine according to the present invention is either L-Carnitine-tartrate, L-Carnitine-magnesium-citrate or L-Carnitine- magnesium-(-)-hydroxycitrate. Carnitine is, in its L-form, a naturally occurring compound involved in energy metabolism in mitochondria that is widely used as a nutritional supplement, e.g. for slimming or cardiovascular health, for decades now and without adverse effects.

Testosteron according to the present invention is β⁴-Androsten-17β-ol-3-on. The resting level of testosterone according to the present invention refers to the total testosterone concentration measurable from blood samples with techniques well known in the art. Resting refers to the absence of physical strain, i.e. the person from whom the blood is taken is in a relaxed state. In contrast, physical exercise is known to promote an increase in the level of testosteron during exercise (Kraemer et al., 1998, ibd.). Total testosterone means blood-born free testosterone and testosterone bound to protein carriers in blood such as sex hormone binding globulin (SHBG). A suitable technique for testosterone analytics from blood according to the present invention is the determination by radioimmunoassay (Anderson et al., Radioimmunoassay of plasma testosterone.., Clin. Chem. (1975) 25:708-714).

Physical exercise according to the present invention means a bout of resistance exercise. Such resistance exercise promotes, during exercise, at first an increase in total testosterone concentration in the blood, followed by a graded decline in total testosterone concentration immediately after the exercise ended (Kraemer et al., 1998, ibd.). Such decline will be maximal approximately 30 min. after the exercise ended and may last at least for 60 min. Preferably, the post-exercise period according to the present invention relates to the period of 30 to 120 min., more preferably to the period of 30 to 60 min. after the exercise ended.

Such post-exercise decline will be much more pronounced if, immediately or shortly after exercise, the exercise is followed by a meal; then the total testosterone concentration can be lowered significantly below its pre-exercise value for an extended period of time, i.e. up to 6 to 8 hours post exercise. Preferably, such a meal is a fat-rich meal.

This effect of a meal on resting levels of total testosterone is not bound, but more pronounced, in case of a preceding physical exercise. Such a drop in total testosterone concentration is also observable after a meal without preceding exercise. It is another object of the present invention to increase the level of total testosterone in a human in the period after a meal. Preferably such period is in the range of 30 min to 8 hours, more preferably in the range of 30 min to 4 hours, most preferably in the range of 30 min to 2 hours after the meal has been taken. The embodiment described in the foregoing and following sections apply likewise to this object of the present invention.

Such effect of physical exercise and/or meals on the level of total testosterone as well as its effect on the wellness may, qualitatively and quantitatively, depend on the constitution or susceptibility of the individual. Preferably, the use of carnitine according to the present invention is limited to humans in need thereof. More preferably, humans in need of adminstration of carnitine are those having a meal shortly or up to one hour post-exercise. In a preferred embodiment, the carnitine is a 3-alkanoyl-carnitine, more preferably a 3- alkanoyl-carnitine with a alkanoyl-moiety comprising one to four C-atoms, most preferably 3- acetyl- (ALC) or 3-propionyl-carnitine. Uptake of ALC, in contrast to non-acylated carnitine, occurs also in the central nervous system (Burlina et al., Uptake of acetyl-carnitine in the brain, Neurochem. Res. 14:489 ff.(1989)). In the brain, ALC is probably involved in control of hormone levels at the hypothalamic/pituitary level.

Carnitine according to the present invention may not only be ingested, i.e. taken orally, but may be applied in any way, e.g. intravenously or subcutaneously by means of injection or infusion. Preferably, a suitable pharmaceutical or nutritional composition comprising carnitine incorporates the carnitine or alkanoyl-carnitine in a pharmaceutically acceptable carrier. In a preferred embodiment, the pharmaceutically acceptable carrier is a tablet, capsule, microbead, emulsion, powder, granule, suspension, syrup, an effervescent preparation or elixir. Such compositions may comprise carnitine in admixture with one or more of the following agents: sweeteners, flavoring agents, coloring agents, pharmaceutical excepients and preservatives. "Pharmaceutically acceptable" means that the agent should be acceptable in the sense of being compatible with the other ingredients of the formulation (as well as non-injurious to the individual). Such excipients include inert diluents such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch and alginic acid; binding agents such as starch, gelatin or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc. Tablets or capsules may be uncoated or may be coated with known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. For example, a time delay material such as glyceryl monostearate or glyceryl stearate alone or with a wax may be employed.

The carnitine according to the present invention may as well be administered as an ingredient of a nutrional supplement such as a beverage, a cookie, an energy/cereals bar and the like.

Preferably, the amount of carnitine to be administered is 0.1 g to 8 g, more preferably 0.5 to 4 g of carnitine according to the present invention. Preferably, the carnitine is taken before or during exercise and the meal, respectively. More preferably, irrespective of the individual exercise or meal, the carnitine is to be administered on a regular base, most preferably on a daily base, expediently for an extended period of time. The most preferred amount for a daily dose of carnitine, given piecemeal or at a single instance over the day, is 1 g to 4 g of carnitine.

Examples

Example 1 Pharmaceutical dosage form for Acetyl-carnitine

A hard gelatine capsule is filled with a powder mixture. The particle size is <0.8 μm. The powder has been mixed by addition of the fine-milled, solid compounds in a conventional knedding machine. The composition of the powder mixture is given below:

Acetyl-L-Carnitine (Carnitine-tartrate) 1 g

Sodium-stearate 1.5 mg microcrystalline cellulose 40 mg

Vitamine E 2 mg Lactose 37 mg

Talcum 5 mg

Sodium-carboxymethyl-starch 10 mg

Polyvinylpolypyrrolidon 10 mg

Two such capsules may be ingested per day to achieve a daily dose of 2 g, for instance.

Example 2

Administration of carnitine post-exercise.

Six healthy, adult men are supplemented with a daily dose of 2 g carnitine (by means of a capsule according to example 1) for 2 weeks. An equally sized control group obtains a placebo without carnitine. During a bout of resistance exercise of 30 min., the pre-exercise concentration of total testosterone from blood raises from 20 nM to 25 nM. Immediately after the exercise, a meal consisting of hamburgers and french fries is taken. Beginning preexercise, the blood total testosteron concentration is monitored in both groups in 15 min. intervals. 30 min. after the exercise ended, the testosterone concentration in the control group is stable at 17.5 nM for at least 50 min. and thus below the pre-exercise threshold. The testosterone concentration is significantly higher in the carnitine treated group during that same period of time and shows earlier recovery to the pre-exercise value.

Example 3 Administration of carnitine post-meal.

Six healthy, adult men are supplemented with a daily dose of 2 g carnitine (by means of a capsule according to example 1) for two weeks. An equally sized control group obtains a placebo without carnitine. The resting, pre-meal concentration of total testosteron from blood is 20 nM. A meal consisting of hamburgers and french fries is taken (approx. 600 kcal).

Beginning pre-meal, the blood total testosteron concentration is monitored in both groups in 15 min. intervals. During the meal, the testosterone level begins to drop in both study groups. 0.5- lh after the meal ended, the mean testosterone concentration in the control group is stable at 15.5 nM for at least 60 min.; it begins to rise incrementally again thereafter, but remains below the pre-meal threshold for the entire 8-hour postprandial period of measurement. The testosterone concentration is significantly higher in the carnitine treated group during that same period of time and shows earlier recovery to the pre-meal value.

Claims

1. Use of carnitine or an alkanoyl-carnitine or salts thereof for the manufacture of a preparation for increasing the levels of testosteron in a human, preferably post-exercise.

2. Use ace. to one of the preceding claims, characterized in that the carnitine or alkanoyl- carnitine is the L-enantiomer thereof.

3. Use ace. to one of the preceding claims, characterized in that the alkanoyl-carnitine is acetyl-L-carnitin or a salt thereof.

4. Use ace. to one of the preceding claims, characterized in that the human is in in need thereof.

5. Use ace. to claim 4, charcterized in that the human is having a post-exercise meal, preferably a meal within one hour after exercise.

6. Use ace. to one of the preceding claims, characterized in that the carnitine is administered before and/or during exercise and/or before the meal.

7. Use of carnitine or an alkanoyl-carnitine or salts thereof for the manufacture of a nutritional supplement for increasing the resting levels of testosteron in a human in a period after a meal.

8. Use ace. to claim 7, characterized in that the meal is a fat-rich meal.

9. Use ace. to claim 8, characterized in that the carnitine is adminstered orally before or during the meal.

10. Use ace. to one of the preceding claims, characterized in that the carnitine is administered in a daily dose of 100 mg to 8 g, preferably 0.5 - 4 g.