EP1200082A1 - Präparate mit sauerstoffsparender wirkung bei körperlicher leistung - Google Patents

Präparate mit sauerstoffsparender wirkung bei körperlicher leistung

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Publication number
EP1200082A1
EP1200082A1 EP00943512A EP00943512A EP1200082A1 EP 1200082 A1 EP1200082 A1 EP 1200082A1 EP 00943512 A EP00943512 A EP 00943512A EP 00943512 A EP00943512 A EP 00943512A EP 1200082 A1 EP1200082 A1 EP 1200082A1
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EP
European Patent Office
Prior art keywords
component
pharmaceutically acceptable
preparation
amino acid
thiamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Application number
EP00943512A
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German (de)
English (en)
French (fr)
Inventor
Oswald Wiss
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Individual
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Individual
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Publication of EP1200082A1 publication Critical patent/EP1200082A1/de
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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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541—Non-condensed thiazines containing further 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4415—Pyridoxine, i.e. Vitamin B6
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4418—Non condensed pyridines; Hydrogenated derivatives thereof having a carbocyclic group directly attached to the heterocyclic ring, e.g. cyproheptadine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A61K31/51—Thiamines, e.g. vitamin B1
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • 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
    • A61K31/33—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
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. clothiapine, diltiazem
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7135—Compounds containing heavy metals
    • A61K31/714—Cobalamins, e.g. cyanocobalamin, i.e. vitamin B12
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to the new use of certain compounds, in particular pharmaceutical active substances, for the production of preparations with an oxygen-saving effect in the case of physical performance, and to new preparations with this effect.
  • muscle glycogen is dependent on nutrition and that only certain nutritional components are suitable for its synthesis and are effective to varying degrees.
  • glucose or glucogenic metabolites must be formed in the course of their implementation in the metabolism.
  • the effectiveness is limited to carbohydrates and proteins, whereby a further prerequisite is that they are quickly broken down into their constituents in the nutritional tract, thereby releasing glucose and glucogenic amino acids, which can have a positive effect on muscular glycogen synthesis.
  • glycogen and fats differ in that, in contrast to the fats, the glycogen does not require oxygen for energy production because the formation of glucose from glycogen is subject to an anaerobic metabolic sequence, while the fatty acids released from fats are used aerobically.
  • the performance during physical activity, especially continuous performance, is limited by the individual oxygen intake capacity or the maximum individual heart rate. Only a part of the oxygen taken up is used for mechanical work, while a larger proportion is used for heat generation. The efficiency for mechanical work can vary within wide limits, but is on average only about 20%.
  • Table la shows the results obtained in the period from February 13 to March 6, 1999 with a male subject in good physical condition under standard conditions.
  • the test subjects were required to consume mechanical power of 100 W, 125 W and 150 W in succession (without interruption) for 10 minutes each (total test duration 30 minutes each).
  • a bicycle ergometer from Ergo Fit (Pirmasens, Germany) was used and the required power was regulated at 60 pedal revolutions per minute (controlled by a metronome from Seiko, Japan) using a Kirbel current brake.
  • Heart rate a heart rate computer from Polar Electro (Kempele, Finland) was used; the atmospheric pressure was measured using an electronic barograph from Altitude Instrumentation (Paris, France) with a resolution of 0.1 mbar; the temperature and relative humidity were measured using an electronic thermohygrometer. The heat generation induced by mechanical stress was calculated from the changes in the heart rate. Alternatively, it can also be due to the increase in humidity caused by perspiration (if the tests are carried out in a closed room) or decrease in weight. Table la
  • test subject received a carbohydrate-rich diet consisting mainly of pasta and meat from young animals (veal, chicken, fish) to achieve an adequate level
  • the oxygen uptake can be determined by measuring the heart rate as a function of the mechanical load.
  • This ergometric method is based on the determination of the oxygen transport volume through cardiac activity. Since the stroke volume is essentially constant regardless of the intensity of the mechanical output and the increased need for oxygen, due to the increase in output, results in an increase in the heart rate, the quantity of oxygen transported can be determined by determining the additional the performance-related heartbeats are determined.
  • a 3-step ergometer test recommended by the World Health Organization (WHO) is used in physiological research institutes and fitness clubs worldwide. The working muscle uses glycogen and fatty acids together for energy. The muscle glycogen is broken down anaerobically. Fatty acid degradation is dependent on molecular oxygen.
  • the oxygen transport volume of the heart action can therefore be determined by determining the number of heartbeats or two different, but in each case constant physical stresses caused by mechanical work (e.g.
  • the muscle glycogen is used for energy supply during the test period in favor of the exclusive use is switched off from fats by either completely breaking down the muscle glycogen immediately before the determination method through physical stress on the muscles involved in the mechanical work, or by blocking its oxygen-saving effect by administering an effective dose of an anti-diabetic agent.
  • the oxygen transport volume per cardiac actuator 36 ml of oxygen, based on normal pressure, were determined in the test subject. The oxygen transport volume can then be calculated from the difference in the mechanical work and the corresponding difference in the number of heartbeats, although an efficiency of 20% was used in the context of the present invention, on the assumption that aass a fifth of the oxygen taken up for the mechanical work and the rest is used for heat production.
  • the metabolic oxygen requirement for the utilization of 1 kcal is 200 ml.
  • a fructose / glucose / protein mixture is described in US Pat. No. 5,292,538 which, in addition to glucose polyerrerene, fructose, partially hydrolyzed froteins and optionally a lipid source, contains a magnesium complex and vitamins such as vitamin A, Bi. B 2 , B 5 , B 6 , B i2 , C, D, E, folic acid, niacinamide and biotin, and which is said to improve endurance and anabolism.
  • FR-A-2 704 392 is an absorbable supplementary food for improving the physical and mental
  • EP-A-0 087 068 discloses a supplementary food which contains selenium, cysteine, L-tryptophan, L-tyrosm and, if desired, further constituents, such as fructose, vitamin Bi, vitamin C and calcium salts, and which is said to be suitable for the essential nutritional constituents to replace, which were exhausted as a result of excessive alcohol consumption.
  • US Pat. No. 5,039,668 describes a composition for the treatment of vitamin deficits and as a cough suppressant which, in addition to liquid honey, histidm, lysm, tryptophan and calcium or iron salts, contains vitamins such as vitamin B i2 and folic acid or the vitamins Bi, Be and B ⁇ 2 as well as Niacm.
  • EP-A-0 482 715 proposes a composition based on protein-free carbohydrates and vegetable fats together with essential amino acids, which should allow a balanced food supply and should have an immune-stimulating effect and which furthermore - thanks to specific ratios of the essential amino acids - unite enable higher NNU (Net Nitrogen Utilization) value.
  • the proposed composition contains - in addition to the amino acids isoleucine, leucm, lys, ethionm, phenylalan, threonm, tryptophan and ⁇ val - a coal hydrate from the group consisting of sucrose, maltose and sorbitol, a highly unsaturated vegetable fat from the group, consisting of safflower, sunflower oil and corn oil, and the Vitamins A, Bi, B 2 , B 6 , B i2 , C, D, K, biotin, folic acid, ⁇ -tocopherol, nicotinamide and pantothenic acid.
  • JP-A-07/330583 discloses a liquid preparation which is suitable as an enteric nutrient for patients after surgical interventions or burns and which, in addition to amino acids, preferably also mineral salts, dextrin, soybean oil and vitamin A, Bi, B 2 , B 6 , B ⁇ 2 , C, D, E, K, folic acid and biotin can contain.
  • JP-A-05/124974 proposes a preparation based on Fomes japonicus which is said to promote the breakdown of the glycogen stored in the liver. It can be prepared, for example, in the form of a beverage which, in addition to the mushroom extract, can also contain maltose, oligosaccharides, folic acid, vitamin C, vitamin B i2 and iron.
  • JP-A-02/078624 discloses the use of an extract from the fibers of bamboo shoots for the treatment of rheumatism and describes a preparation which, in addition to the extract, also contains ethanol, vitamin Bi and vitamin L.
  • JP-A-02/078625 describes the use of an extract from Adenophora triphylla together with vitamin Bi for the treatment of pollinosis and discloses a preparation in ethanol.
  • JP-A-52/143255 proposes a medicinal drink for masking the taste of medicinal substances which, in addition to a medicinal substance such as garlic, ginseng, cranesbill, vitamin A, Bi, B 2 and the like, contains a beer obtained by top fermentation and an alcohol content of Has 0.2 to 3 wt .-%.
  • pharmaceuticals which have a nitrogen-containing heterocycle and in which at least one nitrogen atom present in the ring has a methyl substitute and also midazolam reduce the oxygen consumption caused by mechanical work, and in particular also reduce the oxygen consumption counteracting an increase in oxygen consumption due to low atmospheric pressure or pressure drop. They are therefore suitable to significantly improve the efficiency for mechanical work, whereby the oxygen requirement can be significantly reduced with the same mechanical performance. Because increased oxygen demand an increase in heart rate and increased perspiration (which is caused by increased heat build-up), the above-mentioned pharmaceuticals can also reduce the heart rate and perspiration or heat build-up.
  • the invention therefore relates to the use of a pharmaceutical active ingredient from the group comprising midazolam and compounds having a methyl-substituted nitrogen atom, which is the ring atom of a nitrogen-containing heterocycle, for the preparation of a preparation for reducing the oxygen consumption during physical work. Due to the described relationship between heart rate, oxygen demand and heat generation (or perspiration), these active ingredients and preparations are not only suitable for reducing the physical activity induced increase in oxygen demand, but also to reduce the increase in heart rate induced by physical work and to reduce the increase in heat generation (or perspiration) induced by physical work.
  • the administration of the preparations which can be used according to the invention is indicated under all circumstances under which the oxygen requirement limits physical performance, in particular in the case of reduced oxygen absorption capacity due to pathological changes in the cardiovascular system and the lungs, in old age, during physical activity after eating and at high altitudes Fatigue due to increased oxygen demand due to weather influences and to prevent undesirable side effects of pharmaceuticals, in particular tranquilizers, hypnotics, antidepressants and neuroleptics, on the oxygen demand. They are suitable for prophylactic or therapeutic use and, depending on the form of administration, should preferably be taken at least about half an hour before the desired onset of action.
  • the pharmaceutical active substances suitable according to the invention can be, for example, alkaloids or alkaloio-analogous compounds.
  • alkaloids or alkaloio-analogous compounds.
  • What is decisive - apart from the surprisingly equally effective mizazolam - is that it has an N-heterocycle and min- at least have a methyl group on a ring nitrogen atom.
  • the effect found according to the invention is also independent of known therapeutic effects and is not restricted to compounds with a specific medical indication. It has been found that antitussives such as dihydrocodine, noscapine, codeine and dextromethorphan, analgesics such as morphine and dihydrocodeine, anesthetics such as cocaine, hypnotics such as midazolam and flunitrazepam, antihistamines such as cyproheptadin, clemolastin and clemolastin and clemastin and clemastin Diazepam, antidepressants such as dibenzepin and clothiapin, neuroleptics such as thioridazine, sedatives such as zopiclone, and the like are suitable.
  • the compounds suitable according to the invention are usually active even in very small amounts; for example, in the case of known active pharmaceutical ingredients, dosages which are approximately 2 orders of magnitude lower than for the previously known medical indications are often sufficient.
  • the pharmaceutical active substances suitable according to the invention can be used as such or in the form of their pharmaceutically acceptable salts. They can be monocyclic compounds or preferably have polycyclic ring structures with bridged and / or fused rings.
  • the suitable active compounds can in particular have an N-methyl-substituted amine or amide group in a ring.
  • the N-heterocycle carrying the N-methyl group can be a saturated, partially unsaturated or aromatic ring, active substances with a saturated or partially unsaturated, non-aromatic N-methyl-substituted N-heterocycle being mostly preferred.
  • N-methyl-substituted piperidine ring which may be saturated or partially unsaturated (for example N-methylpiperidine derivatives such as cyproheptadine, thioridazine and zopiclone) and / or part of a 2-methyl-2-azabicyclo [3.3.1] nonane structure (in particular N-methylmorphinane derivatives such as dihydrocodeine, codeine, morphine, thebaine and dextromethorphan) or 2-methyl-1,2,3-tetrahydroisoquinoline structure (such as noscapine) can be;
  • N-methylpiperidine derivatives such as cyproheptadine, thioridazine and zopiclone
  • 2-methyl-2-azabicyclo [3.3.1] nonane structure in particular N-methylmorphinane derivatives such as dihydrocodeine, codeine, morphine, thebaine and dextromethorphan
  • N-methyl-substituted diazepine ring in particular N-methylbenzodiazepines such as diazepa, flunitrazepam, dibenzepine and clobazam;
  • Particularly preferred active substances which can be used according to the invention are: dextromethorphan, cyproheptadine, clothipin, diazepam, midazolam, flunitrazepam, clemastine, dibenzepine, thioridazine, zopiclone, carbimazole, codeine and caffeine.
  • compositions can be produced in a known manner or in a manner known per se using customary auxiliaries. In principle, all common administration types and forms are suitable, but it should be noted that the commercially available preparations are usually overdosed for the present application.
  • the active pharmaceutical ingredients or their pharmaceutically acceptable salts can be administered in the form of an aqueous solution or suspension.
  • a gelling agent such as gelatin
  • the dose can often be reduced and the effectiveness is less influenced by the hydrophilic or lipophilic nature of the active ingredient, whereas in the absence of a gelling agent generally lipophilic active ingredients are preferably used.
  • Preparations containing gelling agents can be prepared in a manner known per se, for example by adding and gelling agent to an aqueous solution or suspension of the active ingredient or its salt or gelling or a solution or suspension of the active ingredient or its salt containing gelling agent by spraying to beadlets, preferably gelatin beadlets.
  • beadlets preferably gelatin beadlets.
  • Suitable methods for producing beadlets are known to the person skilled in the art, e.g. from the production of gelatine beadlet from vitamin A.
  • the beadlets can be administered as such or further processed in a manner known per se to form suitable forms of administration.
  • the preparations can preferably also contain the combinations of components disclosed in WO-A-98/08521 which counteract the increase in oxygen consumption caused by the reduction of the glycogen reserves. In this way it can be achieved that an optimal oxygen-saving effect can be achieved in every case, regardless of whether an increased oxygen consumption is due to the reduction of glycogen reserves, low atmospheric pressure or pharmaceuticals.
  • the invention therefore also relates to a preparation for reducing the oxygen consumption during physical work, comprising (a) as the first component an effective amount of an active pharmaceutical ingredient from the group comprising midazolam and compounds with a methyl-substituted nitrogen atom, the ring atom of a nitrogen containing heterocycle, (b) the second component is an effective amount of D-glucose, D-maltose, ethanol, a glucogenic amm, a glucogenic or amino acid metabolizable via glyoxylate or a dipeptide or pharmaceutically acceptable salt of such an amino acid and ( c) as a third component, an effective amount of thiamine, a pharmaceutically acceptable thiamine salt or a combination of folic acid and cyanocobalam, with the proviso that the third component of thiamine or a pharmaceutically acceptable thiamm salt is when the second component is D-glucose, D-maltose , a glucogenic amm, a gluc
  • dipeptide encompasses the dipeptides of amino acids which are glucogenic or metabolizable via glyoxylate, in particular dipeptides of two identical amino acids such as H-Gly-Gly-OH, H-Ser-S ⁇ r-OH and H-Glu-Glu-OH
  • the expression “monosacid metabolizable via glyoxylate” includes in particular the amino acids suitable for nucleic acid synthesis.
  • the preparations can contain D-glucose, D-maltose, a glucogenic amm, a glucogenic amino acid or metabolizable amino acid via glyoxylate or a dipeptide or pharmaceutically acceptable salt of such an amino acid as the second component and can be gelled with a gelling agent.
  • a gellable polymeric carbohydrate in particular agar agar or pectin, is preferably used as the gelling agent, if the second component is D-glucose or D-maltose, or a gellable pro- tein, especially gelatin, when the second component is a glucogenic or glyoxylate metabolizable amino acid or a dipeptide or pharmaceutically acceptable salt of such an amino acid. Preparations with gelatin are particularly preferred.
  • the preparations can preferably also contain pyridoxin (vitamin Be) or a pharmaceutically acceptable pyridoxine salt, for example pydridoxine hydrochloride), ascorbic acid (vitamin C) or a pharmaceutically acceptable ascorbate such as sodium ascorbate and / or biotin (vitamin H).
  • pyridoxin vitamin Be
  • a pharmaceutically acceptable pyridoxine salt for example pydridoxine hydrochloride
  • ascorbic acid vitamin C
  • a pharmaceutically acceptable ascorbate such as sodium ascorbate and / or biotin (vitamin H).
  • a first embodiment of the combination preparation can be preferably used as second component of D-glucose, D-maltose, a glucogenic ⁇ amine, a glucogenic or metabolized via glyoxylate amino acid or a dipeptide or a pharmaceutically acceptable salt of such an amino acid, as a third component thiamine or a pharmaceutically acceptable thiamine salt and, if desired, contain a gelling agent, vitamin C and / or vitamin B i2 as further components.
  • fruits or fruit preparations can also be used.
  • glucogenic amino acids such as L-alanine, L-serine, L-cysteine, L-cystine, L-glutamic acid, L-aspartic acid, L-arginine, L-ornithin, L -Threonine, L-valine, L-isoleucine, L-proline, L-oxyproline, L-tryptophan, L-tyrosine, L-phenylalanine, L-methionine and L-histidine, amino acids convertible to glyoxylate, such as glycine, L -Srin and L-glutamic acid, dipeptide glucogenic or amino acids convertible into glyoxylate, such as H-Gly-Gly-OH, H-Ser-Ser-OH and H-Tyr-Tyr-OH, pharmaceutically acceptable salts of glucogenic or convertible to glyoxylate amino acids, such as L-monoso
  • the preparations can preferably additionally contain vitamin C, vitamin B ⁇ 2 and, if desired, gelatin and / or contain vitamin B 6 (pyridoxine).
  • vitamin C vitamin B ⁇ 2
  • gelatin if desired, gelatin and / or contain vitamin B 6 (pyridoxine).
  • glycine, L-serine, L-glutamic acid (or L-glutamate) and / or their dipeptides is generally preferred, and they can preferably be used together with folic acid, vitamin B i2 and / or glatin.
  • the combination preparation according to the invention can preferably contain ethanol as the second component, thiamine as the third component or pharmaceutically acceptable thiamine salt and as another component biotin or, according to an alternative embodiment, as the second component ethanol and as a third component a combination of folic acid and contain cyanocobalamin.
  • the preparation can preferably be in the form of an aqueous solution.
  • the combination preparations according to the invention can be a pharmaceutical active ingredient from the group comprising midazolam and compounds with a methyl-substituted nitrogen atom, which is a ring atom of a nitrogen-containing heterocycle, such as a caffeine group comprising a compound Gly-Gly-OH, H-S ⁇ r-S ⁇ r-OH, H-Glu-Glu-OH, glycine, ssrin and glutamic acid (or glutamate), and for folic acid, cyanocobalamin and gelatin.
  • a pharmaceutical active ingredient from the group comprising midazolam and compounds with a methyl-substituted nitrogen atom, which is a ring atom of a nitrogen-containing heterocycle, such as a caffeine group comprising a compound Gly-Gly-OH, H-S ⁇ r-S ⁇ r-OH, H-Glu-Glu-OH, glycine, ssrin and glutamic acid (or glutamate), and for folic acid, cyan
  • the N-methyl-N-heterocycles which can be used according to the invention are generally effective at doses of about 1-5 mg or less, even if they are not combined with a gelling agent, whereas in the case of caffeine, doses of about 10 are preferred -100 mg, in particular about 25-57 mg are administered. If the N-methyl-N-heterocycle is administered in combination with a gelling agent such as gelatin, the dose can be about 1-5 mg in the case of caffeine and usually about 0 in the case of other N-methyl-N-heterocycles , 1-1.0 mg or less can be reduced.
  • the preparations obtainable according to the invention can, in a manner known per se, in customary liquid, solid or semi-solid dosage forms, such as aqueous solutions or suspensions (for example as a drinking solution), effervescent powders, granules or tablets, beadlets and the like are brought and, if desired, contain customary pharmaceutically acceptable carriers, diluents or excipients such as sodium hydrogen carbonate, citric acid, mannitol, talc, maize starch, glycerin monostearate, food colors, flavorings and the like.
  • the pharmaceutical active ingredients, vitamins and energy-supplying Substances are also administered individually, since it is not decisive for the oxygen-saving or performance-increasing effect that the components are taken separately or together with a combination preparation.
  • the preparations which can be used according to the invention can be taken before or during physical work in order to reduce the oxygen requirement and thus to increase the performance achieve.
  • the present invention therefore offers a method for reducing the oxygen consumption during physical work by administering the preparation obtainable according to the invention before and / or during physical work, wherein in the case of the administration of several effective components, these as
  • the invention is further illustrated by the following example.
  • the relative values for oxygen consumption given in the examples were determined by the method mentioned in connection with Table 1.
  • Example 1 With a male test subject in good physical condition, the test series described below were carried out under standardized conditions. Unless otherwise stated, the tests were carried out in the morning in a sober state, with the test person obtaining mechanical power of 100 W, 125 W or 150 W during one or more 10-minute test phases. For this, a bicycle ergome t ⁇ r from Ergo Fit (Kaiserslautern, Germany) is used and the required power is regulated at 60 pedal revolutions per minute (controlled by a metronome from Seiko, Japan) using an eddy current brake. A heart rate computer from Polar Electro (K ⁇ mp ⁇ le, Finland) was used for the continuous measurement of the heart rate; the atmospheric pressure was measured using an electronic barograph from Altitude Instrumentation (Paris, France) with a resolution of 0.1 mbar; the temperature and relative
  • Humidity was measured by means of an electronic thermometer.
  • the "mean cardiac frequencies” given in the tables are average values over the respective test phase.
  • the test subject receives a carbohydrate-rich diet for the entire duration of the test series, consisting mainly of pasta and meat from young meat (veal, chicken, fish) in order to provide adequate protein Only 1 attempt was carried out per day.
  • the heartbeat was first registered during a 10-mm control test with a power of 100 W, then an active ingredient (as a dilute aqueous solution, 1st dosage) and 2.5 g Saccaros ⁇ at intervals of 10 minutes (2nd dose), further active ingredient (as a dilute aqueous solution, 3rd dose) and an Arr.mosaur ⁇ vitamin preparation, containing 100 mg sodium glutamate, 0.3 mg folic acid, 5 ⁇ g cyanocobalamin and 10 mg gelatin (4th Dosage), administered immediately after each administration the influence on heart rate and oxygen consumption during a 10-minute Table 4
  • Test phase was determined.
  • the active substances and amounts used and the effects of the four doses on heart rate and oxygen requirement are summarized in Table 4, the changes in oxygen consumption being based on the changes compared to the oxygen consumption measured according to the previous dose.
  • the pharmaceutical active ingredients which can be used according to the invention are not suitable on their own to compensate for the increase in heart rate and oxygen consumption caused by the administration of sucrose; a reduction only occurs after the preparation of a preparation according to WO-A-98/08521.
  • Example 2 In a further series of experiments, the dependency of the heart rate on the air pressure and the influence of diazepam at constant mechanical power of 125 W were examined under analogous test conditions as in Example 1. Only 1 test was carried out per day. The results summarized in Table 5 confirm that the heart rate and thus the oxygen consumption at low pressure levels are increased and that this influence of the air pressure can be compensated for by diazespam.
  • Example 3 200 parts by weight of Gly-Gly, 3 parts by weight of folic acid, 0.05 part by weight of cyanocobalamin, 1 part by weight of diazepam and 200 parts by weight of glatin are dissolved in 10,000 parts by weight of water while heating. By spraying the Solution, gelatin beadlets are produced, which can be further processed into pharmaceutical forms of use.
  • Example 4 100 parts by weight of tyrosine, 50 parts by weight of thiamine, 50 parts by weight of pyridoxine, 100 parts by weight of ascorbic acid, 0.05 part by weight of cyanocobalamin, 1 part by weight of dextromethorphan and 200 parts by weight of gelatin are dissolved in 10,000 parts by weight of water while heating. By spraying the solution, gelatin beadlets are produced which can be further processed into pharmaceutical use forms.
  • Example 5 150 mg of monosodium glutamate, 0.3 mg of folic acid, 5 ⁇ g of cyanocobalamin, 0.1 mg of codeine and 5 mg of gelatin are dissolved in 1 ml of water with heating and mixed with 9 ml of a 4% strength solution of ethanol in water , 10 ml of the solution corresponds to a single dose.
  • EXAMPLE 6 In analogy to example 1, the influence of ascorbic acid, sucrose, glibenclamide and H-Arg-Asp-OH was administered in 30-minute tests at a constant mechanical power of 125 W after administration alone or after administration together with a caffeine amino acid Vitamin combination preparation (containing 5 mg of H-Gly-Gly-OH, 250 ⁇ g of folic acid, 5 ⁇ g of cyanocobalamin, 1 mg of caffeine and 1 mg of gelatin and prepared in analogy to Example 3) was examined for the oxygen requirement and heat production. The results are compiled in Table 6, the oxygen consumption from the heart rate based on a predetermined value of 29 ml of oxygen (with normal Table 6
  • 1st dose 2nd dose mean heart rate (per minute) before after 1st dose. after 2nd dose
  • the combination preparation is suitable for compensating for the increase in oxygen consumption and heat production caused by the test substances.
  • Example 7 In tests analogous to example 1, the experiments given in table 7 were carried out with gelatin preparations which were prepared in analogy to examples 3-5. After a warm-up phase of 5 minutes, the heartbeats were first registered during a 10-minute control test with a mechanical power of 100 W, then the first dose was administered and then immediately afterwards in a 10-minute test phase with a performance of 100 W measured the heart rate. In the case of a second dosage, this further administration and a second, 10-minute test phase with a power of 100 W take place immediately after the first test phase. As the results in Table 7 show, the dosage of the active ingredient which can be used according to the invention can be reduced to clearly below 1 mg if these are used in combination with gelatin. In addition, the results show that the active ingredients in these low doses can balance the oxygen consumption and the heart rate-increasing effect of other medicaments, regardless of whether the latter are administered separately or together with the active substance which can be used according to the invention.

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US5132113A (en) 1990-10-26 1992-07-21 Maurizio Luca Nutritional composition containing essential amino acids
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US5292538A (en) 1992-07-22 1994-03-08 Metagenics, Inc. Improved sustained energy and anabolic composition and method of making
FR2704392B1 (fr) 1993-04-30 1995-06-02 Boiron Complément nutritionnel absorbable pour améliorer et optimiser les niveaux d'activité physique et cérébrale des individus.
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