IE51711B1 - Carnitine derivatives - Google Patents
Carnitine derivativesInfo
- Publication number
- IE51711B1 IE51711B1 IE217578A IE217578A IE51711B1 IE 51711 B1 IE51711 B1 IE 51711B1 IE 217578 A IE217578 A IE 217578A IE 217578 A IE217578 A IE 217578A IE 51711 B1 IE51711 B1 IE 51711B1
- Authority
- IE
- Ireland
- Prior art keywords
- carnitine
- cardiac
- acetyl
- effect
- derivatives
- Prior art date
Links
- PHIQHXFUZVPYII-ZCFIWIBFSA-O (R)-carnitinium Chemical class C[N+](C)(C)C[C@H](O)CC(O)=O PHIQHXFUZVPYII-ZCFIWIBFSA-O 0.000 title 1
- 230000000747 cardiac effect Effects 0.000 abstract description 13
- 229960004203 carnitine Drugs 0.000 abstract description 12
- -1 aliphatic saturated fatty acid Chemical class 0.000 abstract description 4
- 206010002660 Anoxia Diseases 0.000 abstract description 3
- 241000976983 Anoxia Species 0.000 abstract description 3
- 206010021143 Hypoxia Diseases 0.000 abstract description 3
- 230000007953 anoxia Effects 0.000 abstract description 3
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 206010019280 Heart failures Diseases 0.000 abstract description 2
- 230000002763 arrhythmic effect Effects 0.000 abstract description 2
- 208000028867 ischemia Diseases 0.000 abstract description 2
- 208000011580 syndromic disease Diseases 0.000 abstract description 2
- RDHQFKQIGNGIED-MRVPVSSYSA-N O-acetyl-L-carnitine Chemical compound CC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C RDHQFKQIGNGIED-MRVPVSSYSA-N 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 239000000546 pharmaceutical excipient Substances 0.000 description 6
- PHIQHXFUZVPYII-ZCFIWIBFSA-N (R)-carnitine Chemical class C[N+](C)(C)C[C@H](O)CC([O-])=O PHIQHXFUZVPYII-ZCFIWIBFSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 125000002339 acetoacetyl group Chemical group O=C([*])C([H])([H])C(=O)C([H])([H])[H] 0.000 description 4
- 125000004063 butyryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 230000001426 cardiotropic effect Effects 0.000 description 4
- 230000004907 flux Effects 0.000 description 4
- 230000010412 perfusion Effects 0.000 description 4
- 230000003288 anthiarrhythmic effect Effects 0.000 description 3
- 230000002929 anti-fatigue Effects 0.000 description 3
- PHIQHXFUZVPYII-UHFFFAOYSA-N carnitine Chemical compound C[N+](C)(C)CC(O)CC([O-])=O PHIQHXFUZVPYII-UHFFFAOYSA-N 0.000 description 3
- 239000012153 distilled water Substances 0.000 description 3
- 230000033764 rhythmic process Effects 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- QWYFHHGCZUCMBN-SECBINFHSA-N O-butanoyl-L-carnitine Chemical compound CCCC(=O)O[C@H](CC([O-])=O)C[N+](C)(C)C QWYFHHGCZUCMBN-SECBINFHSA-N 0.000 description 2
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 125000003074 decanoyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C(*)=O 0.000 description 2
- 230000010247 heart contraction Effects 0.000 description 2
- 125000003104 hexanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000002107 myocardial effect Effects 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 125000001312 palmitoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 230000009090 positive inotropic effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- DDMOUSALMHHKOS-UHFFFAOYSA-N 1,2-dichloro-1,1,2,2-tetrafluoroethane Chemical compound FC(F)(Cl)C(F)(F)Cl DDMOUSALMHHKOS-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 206010049565 Muscle fatigue Diseases 0.000 description 1
- 208000021642 Muscular disease Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 229960001009 acetylcarnitine Drugs 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000007900 aqueous suspension Substances 0.000 description 1
- 239000001110 calcium chloride Substances 0.000 description 1
- 235000011148 calcium chloride Nutrition 0.000 description 1
- 229910001628 calcium chloride Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000001451 cardiotoxic effect Effects 0.000 description 1
- 230000002057 chronotropic effect Effects 0.000 description 1
- 235000019404 dichlorodifluoromethane Nutrition 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000000302 ischemic effect Effects 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QELSKZZBTMNZEB-UHFFFAOYSA-N p-hydroxybenzoic acid propyl ester Natural products CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- LKPLKUMXSAEKID-UHFFFAOYSA-N pentachloronitrobenzene Chemical compound [O-][N+](=O)C1=C(Cl)C(Cl)=C(Cl)C(Cl)=C1Cl LKPLKUMXSAEKID-UHFFFAOYSA-N 0.000 description 1
- 230000004526 pharmaceutical effect Effects 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 229940107700 pyruvic acid Drugs 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 238000012353 t test Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
Landscapes
- Health & Medical Sciences (AREA)
- Emergency Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
I-Carnitine acylated with a C2-30 aliphatic saturated fatty acid optionally substituted by OH or CH3co may be used in the therapy of myocardic anoxia, of ischemia, of the arrhythmic syndromes and generally speaking, of the cardiac insufficiencies, as in all the cases where the energy demand at cardiac level is raised as a consequence of fatigue.
Description
The present invention relates to carnitine derivatives and is more fully defined in the claims. The invention is concerned with the levorotatory acylated derivatives of carnitine and this is indicated by 1-.
The use of d,l-carnitine in the paediatric field in the therapy of diseases of the lipidic metabolism and in muscular diseases of dystrophic type is well known. d,lCarnitine has recently also been shown to have cardiotropic properties such that it had a favourable effect on pathologic conditions characterised by disturbances of the cardiac rhythm. Following these experimental observations, the applicants have carried out pharmacological research on the acetylated derivative of 1-carnitine, namely, acetyl-l-carnitine, in order to study the cardiotropic properties of this compound. The study was carried out by comparing its pharmacological activity with that of d,1-carnitine and disclosed the more evident cardiotropic properties and the good' tolerability of acetyl-l-carnitine. Similar studies were carried out with the other derivatives. -3Our Divisional Application No. 1850/85 is directed towards carnitine derivatives of the above formula in which R is acetyl or propionyl.
The invention also provides a use of a carnitine derivative 5 of the general formula + (CH3)3 . N - CHg - CH - CHgCOO" OR in a laevorotatory form wherein R is butyryl, hydroxy butyryl, 10 hexanoyl, octanoyl, decanoyl, palmitoyl, stearoyl or acetoacetyl or a pharmaceutically acceptable salt thereof for the preparation of a pharmaceutically formulation for the treatment or prophylaxis of a cardiac ailment in a mammal including humans. 5i7ii -4Typically the cardiac ailment is myocardial anoxia, ischemia, arrhythmic syndromes, cardiac insufficiency, cardiotoxemia or raised energy demand at cardiac level as a result of fatigue.
Preferably, R is butyryl, hydroxy butyryl or acetoacetyl.
Experimental study 1) Tests on acute toxicity The tolerability of the acetyl-1-carnitine (and the other derivatives) was tested by comparing the DLgg figures observed when administering the substance intravenously into male mice and into male rats, with the DLg0 figures observed under the same experimental conditions using intravenous administration of d, 1carnitine. DLgQ was determined by the method of Litchfield and Wilcoxon. As is shown by the values 1711 -5reported in Table 1 below, acetyl-l-carnitine, in mice as well as in rats, has a higher tolerability than d,lcarnitine. The other derivatives also showed good results. 2) Study of the cardiokinetic effect on isolated hearts.
Rabbit heart, isolated according to Langendorff, was perfused with oxygenated Ringer at 38.2°C and at a perfusion pressure of 50 cm HgO. The isometric contractions, the electrocardiograph and the coronary flux were registered by a Battaglia-Rangoni polygraph.
On removing oxygen from the perfusion liquid, metabolic damage was induced in the cardiac muscle, the damage gradually^increasing up to an 80% reduction of the cardiac contraction strength. Under these prolonged anoxic conditions, the aerobic glycolisis of the myocardium is reduced with a consequent accumulation of acid catabolites. These originate with the stanching (ristagno) of pyruvic acid, as well as its transformation into lactic acid, which cannot be utilized because of the depression (suppression) of the pyridinic enzymes such as lactic dehydrogenase. All this has an effect on the anaerobic glyolisis, influencing a rising number of enzymes, causing a progressive myocardial exhaustion, which becomes more and more critical. In this way all phases of cardiac -(,muscle fatigue are passed through. These may be seen in the behaviour of the observed parameters: contraction strength, coronary flux, cardiac frequency, cardiac rhythm.
Oxygen was then supplied again with normal Ringer (control) and with further Ringer which was treated by adding the substances under examination, at various concentrations • d — R (e.g. 10 g/1 to 10 g/1) the parameters are registered during the following 40 minutes.
In Table 2 the various percent values of the heart contraction strength are reported. They show a positive inotropic effect calculated 10 minutes after the interruption of the anoxic period (miocardium recovery).
The results evaluated with the t test of Student show that with the same concentration in the perfusion liquid, the acetyl-l-carnitine induces a higher positive inotropic effect than the one induced by d,l-carnitine, with statistically significant differences. Similar results were observed with butyryl - 1 -carnitine, hydroxy butyryl-l-carnicine and acetoacetyl-1 -carnitine. The coronary flux and the cardiac frequency are not sensibly affected by the perfusion with the examined substances . -7Therefore, the cardiotropic action of these substances is different from that of digitalic drugs. Moreover a clear antlarhythmic effect has been observed. In fact the sinusal rhythm which was altered by the induced anoxia, was restored with acetyl-l-carnitine in 80% of the cases, whereas using d,1-carnitine the restoration was observed in 50% of the cases. 3) Research on the anti-fatigue effect.
The anti-fatigue effect was studied by intraperitoneally 10 administering to female rats, either acetyl-l-carnitine, or d,1-carnitine or a physiological solution (for the controls). After treatment, the animals were placed, every 15 minutes (session) on a 6 cm diameter bar, which was rotating at a speed of 16 revolutions per minute.
The percent number of animals able to remain on the rotating bar for more than 180 seconds was determined.
In Table 3, the percent values, session after session, are reported. The results evaluated with the squared chi test, show that at dosage parity, the acetyl-l-carnitine gives a significantly higher anti-fatigue activity than d,1-carnitine. It is also superior to the other substances. Analogous results were observed on other derivatives of 1-carnitine, having the formula: (CH3)3 . N - CHg CH - CH.COO I 2 OR -8where Rrepresents, butyryl, hydroxy butyryl, hexanoyl, octanoyl, decanoyl, palmitoyl, stearoyl or acetoacetyl or a pharmaceutically acceptable salt thereof.
It is evident that butyryl-l-carnitine and acetoacetyl -1- carnitine are better tolerated and show a better pharmaceutical effect at cardiac level, than d,l-carnitine and are therefore preferred compounds. Therefore acetyl-1carnitine (and also the other above-mentioned derivatives) is particularly indicated in the therapy of cardiac diseases 10 of the anoxic, ischemic type in particular cardiac, antiarrhythmic and cardiotoxic effect as well as in all cases where the energy demand at cardiac level is raised because of fatigue. 4) Coronary vasodi1atator effect.
All the examined substances when compared to controls, induce a more or less higher coronary flux, which is statistically not significant.
) Chronotropic effect.
AU the examined substances do not significantly modify the cardiac frequency» when compared to controls. 6) Antiarrhythmic effect.
By means of the rat's isolated auricle method, which was described by M.Libonati and G.Segre, it was observed that among the various substances studied, acetyl-1carnitine and butyryl-l-carnitine show the most evident antiarrhythmic properties.
EXAMPLES 1) Sterile aqueous solutions or suspensions containing acetyl-l-carnitine (or any other derivative under examination) in concentrations of 50 mg to 600 mg per each ml. a) The excipient for vials used for injections and for ready for use syringes is prepared according to the following non-limitative example: - sodium carboxymethylcellulose of low viscosity mg/ml 51711 -10- polysorbate 80 - propylparaben mg/ml 0.4 mg/ml - distilled water for injectable use sufficient to produce 1 ml, 2 ml, 5 ml, and 10 ml vials. b) The excipient for phleboclysis bottles containing ml, 100 ml, 250 ml, 500 ml and 1000 ml is prepared according to the following non-limitative example: NaCl 8.6 g/1 KC1 0.3 g/1 CaCl2 0.33 g/1 H20 sterilized for injection use sufficient to produce 1 litre. c) The excipient for bottles for oral use of 5 ml 15 and 100 ml, is prepared according to the following non-limitative example: manni to! 11 mg/ml sorbitol 600 mg/ml sodium benzoate 3 mg/ml -Ilorange extract 200 mg/ml with or without vitamin B^23 mcg/ml sterilized distilled water q.s. 2) Tablets containing between 20 and 500 mg of acetyl-15 carnitine (or any other derivative under examination).
The excipient is prepared according to the following nonlimitative example: starch 45% avicol 45% 10 talc 10% 3) Capsules containing from 20 mg to 500 mg of acetyl-lcarnitine (or any other derivative under examination) without excipients in a non-limitative sense. 4) Aerosol and spray preparation containing from 50 mg to g of 1-acetyl-carnitine (or any other derivative under examination). The excipient is prepared according to the following non-limitative example: - ethanol 30% - distilled water 30% - Freon 12/114 (50 parts/50 parts) q.s. -1 2- Table -14CO UJ co «X o to o o 20,0 * o o in 50,0(*) * o o io o 10,0 25,0 25,0 tn „—. QJ * * * +J •>w* χ-ρ* 3 o o o O o o o Γ-* C A A A A A * at • © © o o © o o in tn ε CM m in to © 1—' CM *" in •ie * * >3 s- O © o © o © r-» QJ A * A » * * * > o o o o o in © Φ CM in in in o o CM r— Vt c * o *—»* O o o o co r* (Z) * n « • co ·* tn o o o o Λ © Φ co o r—· «0* in o o CO to o O o r*» A A A * © o © © OJ o o CM CM co o o o r— o o o O o o o o o cn J»* • o. cn • o o © o © o o © o ε r— o © o o © © o o CM «0· to CM co *0· © ω μ o o © o © © o CM CM • fO cu p— r— r— r— r"- r- z: S- Φ •r" «Ρ ·»» C Φ s_ c to *r— u -μ •p— c £_ tn t— ea >» υ C μ <0 φ r— u • _Q CO -σ in o © V ex «Ρ <0 •μ Φ s(0 o S+> c o u ε o s«*iu u Φ 4— (o) Number of rats % able to pass the test sessions after session.
Claims (1)
1. CLAIW5
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IE1850/85A IE51712B1 (en) | 1977-11-03 | 1978-11-03 | Pharmaceutical compositions containing carnitine derivatives |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT51663/77A IT1143611B (en) | 1977-11-03 | 1977-11-03 | APPLICATION OF ACETYL-CARNITINE IN THE THERAPY OF CARDIAC AFFECTIONS OF / ANOXIC, ISCHEMIC, CARDIOTOXIC AND IN ARITHMIC SYNDROMES |
| IT4767678A IT1155772B (en) | 1978-01-18 | 1978-01-18 | Acylated L-carnitine derivs. - useful for treating myocardial anoxia, ischaemia, arrhythmic syndromes, cardiac insufficiencies, etc. |
| IT4789978A IT1155814B (en) | 1978-02-03 | 1978-02-03 | Acylated L-carnitine derivs. - useful for treating myocardial anoxia, ischaemia, arrhythmic syndromes, cardiac insufficiencies, etc. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE782175L IE782175L (en) | 1979-05-03 |
| IE51711B1 true IE51711B1 (en) | 1987-03-04 |
Family
ID=27273641
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE217578A IE51711B1 (en) | 1977-11-03 | 1978-11-03 | Carnitine derivatives |
Country Status (2)
| Country | Link |
|---|---|
| GB (1) | GB2008578A (en) |
| IE (1) | IE51711B1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4897355A (en) * | 1985-01-07 | 1990-01-30 | Syntex (U.S.A.) Inc. | N[ω,(ω-1)-dialkyloxy]- and N-[ω,(ω-1)-dialkenyloxy]-alk-1-yl-N,N,N-tetrasubstituted ammonium lipids and uses therefor |
| US5545412A (en) * | 1985-01-07 | 1996-08-13 | Syntex (U.S.A.) Inc. | N-[1, (1-1)-dialkyloxy]-and N-[1, (1-1)-dialkenyloxy]-alk-1-yl-n,n,n-tetrasubstituted ammonium lipids and uses therefor |
| IT1299544B1 (en) * | 1998-07-03 | 2000-03-16 | Sigma Tau Ind Farmaceuti | SOLID COMPOSITIONS SUITABLE FOR ORAL ADMINISTRATION INCLUDING NON-HYGROSCOPIC SALTS OF L-CARNITINE AND L-CARNITINE ALCANOYLS |
| WO2000030637A1 (en) * | 1998-11-26 | 2000-06-02 | Sigma-Tau Industrie Farmaceutiche Riunite S.P.A. | Use of fumarate salt of l-carnitine or its alkanoyl derivatives in ischaemia |
| CN101573326B (en) | 2006-11-09 | 2013-05-01 | 三菱丽阳株式会社 | Process for production of betaine |
| WO2012142474A2 (en) | 2011-04-13 | 2012-10-18 | Thermolife International, Llc | N-acetyl beta alanine methods of use |
| US11865139B2 (en) | 2020-11-12 | 2024-01-09 | Thermolife International, Llc | Method of treating migraines and headaches |
-
1978
- 1978-11-03 GB GB7843156A patent/GB2008578A/en not_active Withdrawn
- 1978-11-03 IE IE217578A patent/IE51711B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| IE782175L (en) | 1979-05-03 |
| GB2008578A (en) | 1979-06-06 |
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