Use of carnitine and of lower acyl-carnitines in the therapeutic treatment of the pathology of the veins

Based on the discovery that carnitine and some lower acyl-carnitines act on the phospholipids in the wall of erythrocytes restoring the elasticity of the erythrocytic membrane, a new therapeutic use of the compounds mentioned above in the treatment of the pathology of the veins, typically venous stasis, is disclosed.

The present invention relates to a new therapeutic use of carnitine and 
lower acyl-carnitines. More particularly, this use pertains to the 
treatment of peripheral vasculopathy and, even more specifically, to the 
treatment of pathology of the veins. The present invention also relates to 
orally or parenterally administrable pharmaceutical compositions for use 
in said treatment. 
Previous uses of carnitine and of some acyl-carnitines in the treatment of 
peripheral vasculopathies are already known. 
In the Italian patent application Serial number 49353 A/78, filed Mar. 15, 
1978, in the name of the same applicant as the present application, the 
use of carnitine was described in the therapeutic treatment of some 
arterial vasculopathies whose etiologies can be traced to an altered ratio 
between low density lipoproteins + very low density lipoproteins and high 
density lipoproteins. 
In the Italian patent application Serial number 47976 A/79, filed Feb. 12, 
1979, in the name of the same applicant as the present application, the 
use of some acyl-carnitines (for example, acetyl-carnitine) was described 
in the therapeutic treatment of functional peripheral vasculopathies of 
the arteries, for example, Raynaud's disease and acrocyanosis. As known, 
the etiology of this last group of vasculopathies is not correlated to the 
previously mentioned lipoprotein ratio but seems to be dependent on an 
altered activity of the neurovegetative system. 
In any case, a previous therapeutic use of carnitine and acyl-carnitine in 
the treatment of pathology of the veins has never been described. 
It has now been discovered that carnitine and the lower acyl-carnitines 
wherein the acyl radical contains from 2 to 4 carbon atoms 
(acetyl-carnitine, propionyl-carnitine, butyryl-carnitine, 
hydroxybutyryl-carnitine and acetoacetyl-carnitine) act on the 
phospholipids in the erythrocyte wall restoring the elasticity of the 
erythrocytic membrane in cases in which this elasticity has been 
compromised or altered by pathological factors. Particularly effective are 
the levo optical isomers of the foregoing compounds: L-carnitine, acetyl 
L-carnitine, propionyl L-carnitine, butyryl L-carnitine, hydroxybutyryl 
L-carnitine and acetoacetyl L-carnitine. Also the pharmaceutically 
acceptable salts of the foregoing compounds (e.g. L-carnitine 
hydrochloride) can be used. 
It has also been found that several pathological phenomena which concern 
the microcirculation are largerly provoked, not so much by the decreased 
size of the lumen of the capillaries consequent to dyslipidemic phenomena, 
but rather by the decreased elasticity of the erythrocytic membrane which 
does not permit the erythrocytes to change shape in order to adapt 
themselves to the shape and dimensions of the capillary lumens. Therefore, 
carnitine and the lower acyl-carnitines mentioned previously can be used 
effectively in the treatment of all those pathological states whose 
etiology is ascribed to decreased elasticity of the erythrocytic wall. 
A non-limitative example of such a new therapeutic use of carnitine and the 
lower acyl-carnitines mentioned above is the treatment of venous stasis. 
Carnitine and the previously mentioned acyl derivative of carnitine or the 
pharmacologically acceptable salts thereof are administered either via the 
oral route or via the parenteral route. 
The dose to be administered will be determined by the attending physician 
taking the age, weight and general conditions of the patient into account, 
in accordance with an appropriate professional assessment. Although 
effective results may be noted at doses as low as 5-8 mg/kg of body weight 
per day, a dose between approximately 10 and 50 mg/kg of body weight is 
preferred. Should it be deemed necessary, larger doses can be 
administered, in view of the remarkably low toxicity of carnitine and its 
acyl derivatives. 
In practice, carnitine and the acyl-carnitines (in the racemic form or, 
preferably, in the separated stereoisomer L form) are administered either 
orally or parenterally, in any of the usual pharmaceutical forms prepared 
by means of conventional processes well known to those skilled in the art. 
These forms comprise forms of oral unit dosages, either solids or liquids, 
such as lozenges, capsules, solutions, syrups and the like, and injectable 
forms such as sterile solutions for ampoules and vials.

Some non-limitative examples of suitable compositions for oral and 
parenteral administration are given below. 
EXAMPLE 1 
Solution or sterile aqueous solution containing carnitine or an acyl 
carnitine in concentrations from 50 mg to 500 mg per ml. 
(a) The excipient for injectable ampoules/vials is prepared in accordance 
with the following non-limitative composition: 
sodium carboxymethyl cellulose (low viscosity): 10 mg/kg 
polysorbate 80: 4 mg/kg 
propylparaben: 0.4 ml/ml 
sufficient water for injections for 1-ml, 2-ml, 5-ml and 10-ml 
amoules/vials. 
(b) The excipient for drip bottles containing 50 ml, 100 ml, 250 ml, 500 ml 
or 1000 ml, is prepared in accordance with the following non-limitative 
composition: 
NaCl: 8.6 g/lt 
KCl: 0.3 g/lt 
CaCl.sub.2 : 0.33 g/lt 
sufficient water for injections to produce 1 liter. 
(c) The excipient for bottles for oral administration containing from 5 ml 
to 100 ml is prepared in accordance with the following non-limitative 
composition: 
mannitol: 11 mg/ml 
sorbitol: 600 mg/ml 
sodium benzoate: 3 mg/ml 
orange extract: 200 mg/ml 
vitamin B.sub.12 : 3 mcg/ml 
sufficient purified water. 
EXAMPLE 2 
Lozenges containing from 25 mg to 500 mg of carnitine or an acyl-carnitine. 
The excipient is prepared in accordance with the following non-limitative 
composition: 
starch: 45% 
avicel: 45% 
talc: 10% 
EXAMPLE 3 
Capsules containing from 25 mg to 500 mg of carnitine or an acyl-carnitine 
without excipients. 
The efficacy of the therapeutic method of the present invention has been 
confirmed by numerous clinical cases, some of which are hereinbelow 
described. 
Patient 1: female--42 years--venous stasis due to valvular insufficiency of 
the right inner saphenous vein. Feeling of intolerable weight and evident 
edema. Treated with phlebotonic drugs with little success. Acetylcarnitine 
was administered orally at a dose of 1.6 g for 4 days and 1 g for 18 days. 
Preceeding therapy was suspended. After 4 days of therapy the sensation of 
local weight was markedly reduced and the edema started to decrease. On 
the 12th day local discomfort disappeared and the edema was reduced by 
50%. Simultaneously diuresis increased without the use of diuretics. On 
the 20th day the edema was further reduced leaving some liquid content in 
the malleoli. 
Patient 2: female--28 years--venous stasis due to valvular insufficiency of 
the right external saphenous vein and bilateral varicose veins. At the 6th 
month of pregnancy. Feeling of weight, heavy legs and edema of the legs 
and feet. The patient was not under any therapy for fear of endangering 
pregnancy. Oral treatment with acetylcarnitine was begun at a dose of 1 g 
per day. Treatment was protracted for 21 days. After 8 days of therapy the 
subjective symptoms started to regress. The maximum effect was observed on 
the 14th day. The edema gradually decreased starting from the 5th day of 
treatment and was reduced by 90% on the 21st day. Slight increase in 
diuresis without diuretic treatment. 
Patient 3: female--48 years--obese with light signs of cardiac 
insufficiency. Venous stasis due to valvular insufficiency in the left 
external saphenous vein and bilateral varicose veins possibly complicated 
by cardiac insufficiency. Heavy legs, asthenia, formication and notable 
edema of the foot and leg. The patient was given digitalis and diuretics 
to improve cardiac performance. After 12 days the edema was reduced by 20% 
and the signs of cardiac insufficiency (dyspnea) disappeared. Venous 
insufficiency, heavy legs, formication and edema continued. Diuretic 
treatment was suspended. A small dose of digitalis was maintained. Oral 
treatment with acetylcarnitine at a dose of 1 g per day was initiated. 
After 8 days of treatment pain and the sensation of heavy legs were 
notably diminished and the edema was further reduced. After another 13 
days of treatment the subjective symptoms disappeared as did the edema. 
Patient 4: female--second pregnancy at the 9th month. Varicose veins in the 
legs and malleolar edema had been present for 2 months. Feeling of heavy 
legs. No treatment in progress. Acetyl-carnitine was given orally at a 
dose of 1 g per day. After two weeks heaviness of the legs and edema 
disappeared. 
Patient 5: male--60 years--post-phlebitic syndrome with left venous 
insufficiency. Small bilateral varicose veins. Feeling of weight, pain, 
burning; intense edema on the left. Slight malleolar edema on the right. 
The patient received antibiotic therapy only. Oral treatment with 
propionylcarnitine was begun at a dose of 1 g per day. On the 12th day 
there was improvement in the subjective and objective symptomatology. 
Subjective symptoms disappeared on the 18th day. Regression of the edema 
on the 28th day. 
Patient 6: male--56 years--post-phlebitic syndrome with left venous 
insufficiency. Bilateral varicose veins. Feeling of heaviness of both 
legs. Pain and cramps on the left. Evident edema on the left, and slight 
edema on the right. Propionylcarnitine was given orally at a dose of 1 g 
per day. Duration of treatment 3 weeks. Subjective and objective 
improvement starting from the 4th day. Regression of syptoms on the 18th 
day.