GB2058566A - Pharmaceutical composition comprising L-carnitine - Google Patents
Pharmaceutical composition comprising L-carnitine Download PDFInfo
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- GB2058566A GB2058566A GB8030373A GB8030373A GB2058566A GB 2058566 A GB2058566 A GB 2058566A GB 8030373 A GB8030373 A GB 8030373A GB 8030373 A GB8030373 A GB 8030373A GB 2058566 A GB2058566 A GB 2058566A
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
Abstract
Since D-carnitine exhibits an antagonistic effect versus the therapeutically advantageous effect of L-carnitine on free fatty acid levels and in treating cardiac disfunctions, a pharmaceutical composition is described for the treatment of hyperlipidaemias and hyperlipoproteinaemias and cardiac disfunctions, wherein substantially all the carnitine present therein is L-carnitine.
Description
SPECIFICATION
Pharmaceutical composition comprising L - carnitine
The present invention pertains to a pharmaceutical composition comprising L - carnitine for the treatment of hyperlipidaemias and hyperlipiproteinaemias and cardiac disfunctions and also to a therapeutical method comprising the administration of said compositions.
The use in therapy of carnitine (p - hydroxy - y trimethylamino butyric acid) for the treatment of hyperlimidaemias and hyperlipoproteinaemias has already been described and claimed in the Italian patent applications nos. 47900 A/78 and 49353 A/78 filed by this same applicant on February 3rd and May 15th, 1978 respectively.
It is likewise known that carnitine presents an asymmetrical centre and therefore exists in the D and L stereoisomer forms. In the aforementioned
Italian patent applications it is taught that either the racemateorthetwo individual isomers can be used indifferently. Although a certain preference can be given to the L form versus the D form in view of the known, slightly less toxicity of the L form versus the
D form, the optical isomers D and L are both considered active in the above patent applications.
If it is considered moreover that, as is well known, the resolution of a racemate into the respective optical antipodes generally involves complex and expensive procedures, as in fact occurs in the case of the separation of L - carnitine from D - carnitine, the slight difference in toxicity does not suffice to justify, at least for the aforementioned therapeutical purposes, the use of separated optical antipodes, particularly ofthe L form, since it is economically more advantageous to use carnitine in its racemic form.
It has now been surprisingly found and is the basis of the present invention, that in the treatment of hyperlipoproteinaemias D - carnitine is not only slightly more toxic than L - carnitine, but indeed exhibits a true and proper antagonistic effect versus the therapeutically advantageous properties of L carnitine, for instance on the lowering of the free fatty acid levels in the blood. It should be well understood that it has been discovered that the D form is not simply inactive compared to the L form, that is it does not act as a simple "diluent" of the active L form, but rather opposes the therapeutically advantageous effect of L - carnitine, at least partially blocking it.
Furthermore the therapeutical use of carnitine (ss hydroxy - y - trimethyl - amino - butyric acid) in the treatment of cardiac arrhythmias and impaired cardiac function associated with congestive heart failure and cardiogenic shock has already been disclosed in U.S. patents 3.830.931 and 3.968.241 issued to De Felice.
It is likewise known the ss - hydroxy - y -trimethyl amino butyric acid presents an asymmetrical centre and hence occurs in the two stereoisomer forms D and L. In the aforementioned U.S. patents it is taught that"... either the racemate or the individual isomers can be employed. While the racemate can be conveniently employed, it appears the L isomer is more active while the D isomer is slightly more toxic". The prior art teaches therefore that, in the treatment of the aforementioned cardiac dysfunctions, the L form and the D form are both active, although a certain preference may be given to the L form versus the D form.
If it is considered that, as is well known, the resolution of a racemate into the respective optical antipodes generally involves complex and expensive processes, as in fact occurs in the case of the separation of L - carnitine from D - carnitine, and that in the aforementioned patents it is affirmed that the racemic form can be suitably employed, it is evident that the prior art as a whole in no way suggests, at least in regard to the aformentioned therapeutical purposes, the separation of the optical antipodes for the employment of L - carnitine alone, but rather to simply use carnitine in its racemic form.
It has now been surprisingly found, and is the basis of the present invention, that, conversely to what is taught by the known art, in the treatment of certain cardiac dysfunctions and particularly of those disclosed in the aforementioned patents to De Felice,
D - carnitine is not only slightly more toxic than L carnitine, but even exhibits a true and proper antagonistic effect against the therapeutical proper ties of L-carnitine. It must be well understood that it has been discovered that the D form is not simply inactive as compared to the L form, that is it does not act as a simple "diluent" of the active Lform, but rather it antagonizes, at least partially inhibiting, the therapeutically advantageous effect of L - carnitine.
Therefore the present invention provides a pharmaceutical composition for the treatment of hyperlipidaemias and hyperlipoproteinaemias comprising an effective amount of carnitine and by the fact that said carnitine is solely L - carnitine.
The invention includes a pharmaceutical formulation comprising L - carnitine in the substantial absence of D - carnitine formulated for pharmaceutical administration to human beings.
The invention also includes L - carnitine in the substantial absence of D - carnitine for use in a method of treatment of the human or animal body by therapy.
The present invention provides a pharmaceutical composition for the treatment of myocardial anoxia, myocardial ischaemia, arrhythmic syndromes and heart failure, comprising an effective amount of L carnitine in the substantial absence of D - carnitine.
By the term "the substantial absence of D - carnitine" is meant, for the purposes of the present invention, not only the case where component of the composition constituted by carnitine is substantiaily pure L - carnitine, thus disregarding incidental impurities or traces of D - carnitine, but also where the carnitine is prevailingly L - carnitine, that is clearly exceeding the quantity of D - carnitine pres
The drawings originally filed were informal and the print here reproduced is taken
from a laterfiled formal copy.
ent, for instance by an L:D ratio of 95:5.
It has also been found that a particularly suitable
pharmaceutical composition for the aforementioned
therapeutical uses, when in the unit dosage form, comprises from approximately 50 to 500 mg of L carnitine.
The scope of the present invention therefore also comprises a therapeutical method for the treatment of patients affected by hyperlipidaemias and hyperlipoproteinaemias, characterized by the fact of administering to said patients, via the oral or parenteral routes, a pharmaceutical composition compris-
ing an effective amountofcarnitine present solely in the Lform.
Although the daily dose to be administered depends, using sound professional judgment, upon bodyweight, age, general conditions and the specific affection exhibited by the patient, it has been found that it is generally suitable to administer to said patients from approximately 2 to approximately 10 mg/kg of body weight'davy of L - carnitine.
The antagonistic effect of D - carnitine versus L carnitine has been experimentally demonstrated by means of the following techniques.
A-Effectofcarnitine (DL, D and L) on the isolated rat liver.
Male Wistar rats weighing 250 t 10g g maintained at normal feeding and caging conditions were anaesthetized with pentobarbital and the liver
removed and after insertion of a canula perfused at the speed of 8 ml/min with free fatty acid (FFA) rich
medium from the blood of 20-hour fasted rats.
DL carnitine, L - carnitine and D - carnitine were
added respectively at the concentration of 0.5 mM/min equivalent to 80 y18 mllmin or the vehicle in
the case of the control group.
The uptake of FFA by the liver, considered expres
sion of the metabolic activity of the organ was
evaluated by measuring the FFA levels on the
medium at various times during the experiment.
At the end of perfusion the concentration of liver phospholipids, trigycerides and cholesterol was also determined.
The values given in Table 1 indicate that after 20 min of infusion (the phenomenon follows a linear pattern from 0 to 20 min) L - carnitine determines a considerable reduction in the half-life of the initial
FFA, while DL - carnitine and D - carnitine do not change the control group values.
The liver cholesterol and trigylceride values did not change, while the phospholipids resulted to be increased only by L - carnitine (Table 2).
In the perfused liver L - carnitine facilites the uptake of FFA's and utilizes them for increasing the phospholipid pool. Conversely, D - carnitine does not exert any metabolic action and experimental data show that it antagonizes the carnitine present in the racemic mixture.
Table 1
Effect ofDL - carnitine HCL, D - carnitine HCI and L
carnitine HCI (0.5 mMolesiminuteJ on the half life of
FFA in the perfusion medium of the isolated and perfused rat ffver.
Mean values + SE calculated after 20 minutes of
infusion with the cornpounds.
after20 minutes
Control 20.92 + 3.07
(6)
DL-carnitine HCL 19.00 t 1.00
(3)
D-carnitineHCL 18.66+7.17 (3)
L-carnitine HCL 12.33 t 1.20
(3)
Number of tests in parenthesis.
Student's "t" tests forthe differences versus the control.
Table2
Effect ofDL - carnitine HCL, D - carnitine HCL and L - carnitine HCL (0.5
mMoles(min.) on triglycerides and phospholipids of isolated and perfused rat
liver.
Mean % values ~ SE after 120 minutes ofinfusion with the compounds.
Cholesterol Triglycerides Phospholipiifes % % % Control 0.229 0.009 1.309 0.17 2.519 + Q.06
(6) (6) (S) DL- carnitine HCL 0.192 j 0.016 1.125 +0.15 2.570 0.41 (3) (3) (3)
D - carnitine HCI 0.225 0.017 1.233 + 0.30 2.580 t 0.26
(3) (3) (3) L-carnitineHCl 0.227 0.005 1.187 i0.11 3.519 r 0.16"F (3) (3) (3)
Numberoftests in parenthesis.
Student's"t"testforthe differencesversusthe control.
* =5%.
B -- Metabolic activity (in vivo)
Effect of one administration ofcarnitine (DL, DandL) on free fatty acid (FFA) levels in the fasted rat
Male Wistar rats weighing 190-220 g, maintained in groups of 5 under normal caging conditions and fasted for 17 hours with access only to water, were thus treated: 20 mlikg pesos of water, control group, and with 1 g/kg per os of DL - carnitine, L - carnitine and D - carnitine respectively, the other groups.
1 hour aftertreatmentthe animals were sacrificed by decapitation and FFAwas determined in serum using the Dole method.
In similar experimental conditions 20-hr fasted rats in groups of 5 were thus treated: the control group with physiological saline, and the other groups with DL, D and L - carnitine respectively at the dose of 250 mg/kg i.p. After 15 min following treatment the animals were sacrificed and FFA was determined in serum using the Dole method.
The results in Tables 3 and 4 show that DL - carnitine given at the dose of 1 g/kg per os reduces the
FFA levels by 13-15%. Such levels increased in the rat after fasting. L - carnitine produces a 20-25% reduction while D - carnitine provokes a 6-9% increase versus control values.
The effect of reducing FFA provoked by L - carnitine is observed (-24%) also when the compound is given i.p. (Table 4).
In this experimental situation D - carnitine produces an increase (t' 34%) in FFA levels while DL carnitine shows poor activity. From this it is learnt that D - carnitine acts as an antagonist of the active laevorotatory form.
Table3
Effect ofDL - carnitine, L - carnitine and D - carnitine, 1 glkg per os,
on serum FFA levels in the 77-hr fasted rat % values versus
controls at 60 min. after treatment.
FFA: control% DL - carnitine L - carnitine D - carnitine 15t experiment -15 -37 +9 2"d experiment -13 -36 +6
Table 4
Effect ofDL - carnitine, L - carnitine, D - carnitine, 250 mglkg i.p., on serum FFA levels of the 20-hr fasted rat.Medium value t SE at
15 min after treatment
FFA Eqllitre Basal + 15 min. % reduction
Physiological 1190 + 69 1198 + 54 unmeasurable saline (27) (29) DL-carnitine 987+ + 50 931t 70 - 6 (10) (10)
L-carnitine 1350 a 136 1026 + 147 -24
(5) (5)
D-carnitine 1120 c 167 1412i159 +34
(5) (5)
C -Effectofcarnitine (D and L) on hyperlipoproteinaemia and hypertriglyceridaemia induced by administering oil to the rat
Male rats weighing 200t 5 g, maintained in
groups of 10 under normal caging and feeding con
ditions, were treated with triglyceride-loads by oral
administration of olive oil, 30 mg/kg, and 1 hour
afterwards with D- and L - carnitine, 500 mg/kg per os.
The control animals received water. After 2,3 and
4 hours following oil administration sub-groups of animals were sacrificed. The serum percentage con centrations of chylomicrons, cs, pre-ss and p - lipopro- teins by lipidogram, triglyceride, cholesterol and
phospholipid serum levels and the serum content of
free carnitine, acyl carnitine (short chain), and total
carnitine were deternilned.
As shown in Fig. 1 the chylomicrons and pre - p lipoproteins were markedly reduced and the c lipoproteins were increased in the animals treated with L - carnitine.
Triglyceride and cholesterol levels were reduced (Fig. 2) and the formation of plasma acyl carnitine was increased. This effect was in no case present in the animals treated with D - carnitine, thus demonstrating the high selectivity of L - carnitine in the activities involving the mechanisms correlated to lipid metabolism, particularly lipoprotein metabolism.
CLINICAL CASES
Case 1.-Male patient, years of age, affected by primary hypertension; hypertriglyceridaemia accompanied by remarkably increased ss - lipoproteins was ascertained upon hospitalization. Hypertension was treated with a diuretic only. When normal pressure was re-established, hyperlipidaemia
was treated with L - carnitine 1 g per day in three
330-mg administrations. Prior to L - carnitine treat mentthe patient was given an appropriate isocaloric
diet in the attempt to change the hyperlipidaemic
pattern for the duration of the entire antihyperten
sive treatment, i.e. 29 days. The diet had moderately
lowered triglyceride. Therefore the patient was
defined as being resistant to the diet and L - carnitine
treatment was commenced.Blood was sampled in
basal conditions and on the 21sot day. The decrease in
triglyceride is evident and values are practically
normal. The p/a - lipoprotein ratio is substantially
normal.
basal values 2 1sot day
triglyceride 325 mg% 180 mg%
cholesterol 190 mg% 160 mg% pre-p-lipo 52% 37%
p-lipo 31% 43% an lip 17% 29.2%
Case 2. -- Female patient, 44 years of age, hospital
ized for ischaemic heart disease and treated with
nitro derivatives and a beta-blocker. The beta
blocker was suspended when ischaemia improved
and trinitrin was given as required. Successively,
since hyperlipidaemia was detected, L - carnitine
treatment was initiated, 1 g per day in three 330-mg
(approx.) administrations.
Blood samples were drawn in basal conditions,
and after 3 weeks of treatment a considerable reduc
tion in triglycerides and a decrease in the p/a - lipop
rotein ratio were observed.
basal values 21 days
triglyceride 395 mg% 205 mg%
cholesterol 249 mg% 219 mg% pre-p-lipo 52% 37% p-lipo 32% 41% cu-lipo 16% 21%
Case 3. - Male diabetic patient, 55 years of age,
hospitalized for sequelae of hemiplagia. Hypog Iycaemizing agents were administered to the patient via the oral route until a return to normal glyceamia and therapy was continued at minimum doses.
However, the lipid pattern was markedly pathological in spite of hypoglycaemizing and dietetic treatment The decision was taken to start L - carnitine therapy at the regimen of 1.33 g daily in four 330-mg (approx.) administrations. Treatment was continued for 4 weeks and blood was analyzed in basal conditions and on the 28h day. Triglyceride and total cholesterol were remarkably lowered with a decreased p/a lipoprotein ratio at the end of therapy.
basal values 28 days triglyceride 228 mg% 158 mg% cholesterol 267 mg% 160 mg% pre-p-lipo 35% 30% p-lipo 44% 45% an lip 21% 25%
Case 4. - Female patient, 57 years of age. Obese patient due to erraneous diet was hospitalized for investigation. She was put on a hypocaloric diet until normal bodyweight for her age and height was restored. Upon hospital admittance the lipid pattern was disordered: the triglycerides and cholesterol were above normal values. After the diet the lipid pattern showed a clear-cut deterioration and the trig
lycerides exhibited a further increase. The patient was given L - carnitine therapy at a daily dosage of 1 g in three 330-mg (approx.) administrations.
The patient continued therapy for 3 weeks and
lipid values returned to nearly normal. The above case suggests the use of L - carnitine as a therapeuti- cal aid in slimming diets in orderto correct hypertrig
lyceridaemia probably due to lipid mobilization.
basal values 21 days triglycerides 409 mg% 219 mg%
cholesterol 313 mg% 190 mg% pre-p-lipo 48% 30% p - lipo 39% 52% a-lipo 13% 18%
Two examples pertaining to the tablet composition for the purposes of manufacture are given hereunder:
EXAMPLE 1.
L-carnitine 330 mg magnesium stearate * 50 mg microcrystalline cellulose 24 mg EXAMPLE 2.
L-carnitine 330 mg stearic acid 35 mg microcristalline cellulose 25 mg
It has likewise been found that a pharmaceutical composition particularly suitable forthe aforementioned cardiac therapeutical uses, when in the unit dosage form, comprises from approximately 50 mg to approximately 500 mg of L - carnitine.
Therefore the scope of the present invention also includes a therapeutical method for the treatment of patients affected by myocardial anoxia, myocardial ischaemia, arrhythmic syndromes and heart failure, characterized by the fact of administering to said patients, via the oral or parenteral route, a pharmaceutical composition comprising an effective amount of carnitine present solely in the L form.
Although the daily dose to be administered depends, according to sound professional judgment, upon bodyweight, age, general conditions and the specific affection exhibited by the patient, it has been found that it is generally suitable to administer to said patients from approximately 2 mg/kg to approx imately 10 mg/kg of bodyweight per day of L - carnitine.
The antagonistic effect of D - carnitine against L carnitine has been experimentally demonstrated by means of the following techniques.
(A) Behaviour of L- and D - carnitine on adrenalineinduced stress on isolated rabbit heart
Male rabbit hearts weighing 1.6-1.8 kg were isolated as per the method described by O. Fanelli, Life
Sciences, 23, 2563-2570 (1978).
The hearts were perfused as per the Langendorff method (0. Langendorff, Pflügers Arch. Ges. Physiol.
61,291-333, (1895) using a Ringer solution (which was not recycled) maintained at 38"C and at a pressure of 54 cm of water bubbled with pure oxygen.
The isometric contractions were recorded by a transducer attached via a pulley to a clip on the apex of the ventricles and regulated in such a manner as to exert a tension force of 4 grammes. By means of another transducer connected to a volume displacement recorder the coronary flow was moni
tored giving normal values: 22 t 4 ml/min.
The ECG was monitored using surface electrodes.
Only hearts which initially showed a rate of at least
140 beats per minute were used. After a period of
acclimatization lasting 25-30 minutes under the
aforementioned experimental conditions, the basal
values of the hearts to be treated with blank Ringer
solution (controls) and standard Ringer solution containing L - carnitine or D - carnitine at the same con
centration of 1.10-5 g/l were recorded for 15 minutes taking care to discard hearts exhibiting some
irregularities.
Cardiac stimulation was achieved by injecting 0.5
ml of Ringer solution containing 0.5 mcg of
adrenaline using a lateral canula inserted into the
aortic bulb. This stimulation was repeated four timers at 5-minute intervals.
The stress tolerated bythe heartforeach injection of adrenaline was calculated by the formula: [J Ag tj M were Ag is the increasing tension force (in grammes) and Af is heart rate (number of beats) during the period of time (in seconds) wherein the increase in tension force occurs.
The values referring to the control hearts were compared to the respective yalues obtained with the hearts perfused with Ringer solution containing Lcarnitine or D - carnitine, using Student's and
Cochran-Cox's "t" test.
Results Coronary flow
The basal values given in Table 1 a show that L carnatine slighly increases coronary flow, whereas D - carnitine does not.
Conversely, when adrenaline is injected D - carnitine increases the coronary-dilator effect of adrenaline, whereas L - carnitine reduces it
Tension force peak
The data given in Table 2a show that adrenalineinduced tension force peak is decreased bv L - carnitine, while D - carnitine practically does not modify it.
Duration of increased tension force induced by adrenaline
The data given in Table 3a show that the duration of increased tension force induced by adrenaline is shortened by L - carnitine, whereas D - carnitine lengthens it.
Heart rate
The data given in Table 4a show that adrenalineinduced tachycardia is reduced by L- carnitine and increased by D - carnitine.
Stress effect
The data given in Table 5a show that the stress effect is decreased by L - carnitine, whereas D - carnitine increases it.
Examination of the stress index (Fig. la) shows that L - carnitine has an antagonizing effect on adrenaline-induced stress, while D - carnitine enhances it.
From the above experimental results it appears evident that L - carnitine reduces the three effects of stimulation on the heart exerted by adrenaline (see
Tables 2a, 3a and 4a), whereas D - carnitine even heightens the adrenaline effect on the duration of
tension force and heart rate. Consequently (see
Table 5a and Fig 1 a) the stress index is low in the
presence of L - carnitine and much higher in the pre
sence of D - carnitine.
The antagonistic effect of the two optical isomers
of carnitine is also made evident by the fact that L
carnitine reduces the coronary-dilator effect induced
by adrenaline, whereas D - carnitine increases it.
(B) Effect on adriamycin cardiotoxicity
in vitro study
The action of L - carnitine and D - carnitine against
adriamycin-induced cardiotoxicity was investigated
using isolated rat heart perfused as per the Langen
dorff method, with Tyrode's solution at the rate of
0.1 ml/min.
The perfusion medium containing adriamycin at
the concentration of 0.2 mg/ml was perfused on the
heart until heart rate was reduced by 30% compared to the basal value. This reduced heart rate was
accompanied by reduced contractile force and coro
nary flow rate.
Successiveiy, Tyrode's solution containing L - car
nitine or D - carnitine art a concentration of 5.08 mM or Tyrode's blank solution (control group) was perfused on the heartfor90-120 min.
The graphs appearing in Figs. 2a, 3a and 4a show that the repairing effect against cardiac damage caused by adriamycin administration is exclusively exerted by L - carnitine, whereas D - carnitine exhibits an opposite effect antagonizing that of L cernitine. D - carnitine appears incapable of even partially restoring cardiac function.
(C) EEBece- on etparimental infarctions (contml Thiarn- eiGn and itest in7arctionJ induced in the same heart by Occlusion or efVO coronary arteries in the dog.
The technique described by W. Shaper, M. Hofmann, K. D. MOller, K. Genth and-M. Carl in Basic
Res. Cardiol., 76,224-229(1979) was employed, with simultaneous occlusion olFtNo coronary arteries in the same heart, for producing ischaemic areas with equal dimensions in identical heemodynamic conditions.
Successively, one of the ischaemic areas was per fused with a D - carnitine solution and the other with L - carnitine. Both soiutions had the same concentration of carnitine (approx. 5 millimoles).
It was determined that, while the e)stension of the ischaemic area perfused with the D - carnitine solution remained unchanged, the extension of the ischaemic area perfused with the L - carnitine solution was reduced by approximately 60% as compared to the pre-infusion value.
Table la
Isolated rabbit heart. Four adrenaline injections {0.5 mcg) with 5-minute intervals between injections.
Changes in coronary flow mllmin. (mean r S.E.)
no. of adrenaline 0.5mcg - % values Groups hearts basal values 1st injection 2nd injection 3nd injection 4h injection Controls 9 23.6 1.50 -0.76 6.65 --5.86 5.45 +7.858.24 +12.74 5.06 (a) L-carnitine 1.10-5g/l 9 27.00.91 -14.6 6.43 +5.97 5.38 +3.73 6.08 +0.21 4.05 D-carnitine 1/10-5 g/l 11 23.4 1.02 -3.09 3.01 +6.63 6.15 +10.6 3.48 +9.83 2.62 Statistically significant values versus controls (a) 0.05 - - p '- 0.02, (b) 0.02 > p : 0.01, (c) 0.01 3-- p p 0.001 Table 2a
As in Table 1a, Tension force increase peak (grammesJ (mean t S.E.) no. of adrenaline 0.5 mcg
Groups hearts 1 injection 2nd injection 3rd injection 4h injection
Controls 9 2.82 0.41 2.92 + 0.32 3.17 t 0.35 3.43 + 0.59
L - carnitine 1.10-5 gll 9 1.73 0.23 2.23 + 0.08 2.68 + 0.23 3.02 t 0.33
(a)
D - carnitine
1.10-5g/l 11 2.48 0.30 3.12t0.27 3.130.30 3.220.29 Statistically significant differences versus controls (a) 0.05 > p p > 0.02 Table 3a
As in Table la Tension force duration (seconds) induced by adrenaline (mean S.E.) no. of adrenaline 0.5 mcg
Groups hearts 1st injection 2nd injection 3rd injection 4th injection
Controls 9 49.2 j 5.15 61.4 j 9.81 61.0 6.63 71.0 10.1
L - carnitine
1-10-5 g/l 9 37.8 3.66 50.4 4.48 55.7 5.93 50.6 5.31
D - carnitine
1.10-5 9/l 11 73.58.70 84.011.2 83.5t9.05 86.211.4
(a)
Statistically significant differences versus controls (a) 0.05 p > 0.02
Table 6a As in Table la. Increase in heart rate, beats/minute (mean t S. E.J no. of adrenaline 0.5 mcg Groups hearts basal values 1St injection gd injection 3rd injection 4th injection
Controls 9 184t6.5 +22+13.5 +29+ 3.5 +29+ 6.8 +26+11.8 L - carnitine 1.10-5 g/l 9 178 + 4.6 +33 6.7 +32t10.0 +4410.0 +33 13.4
D - carnitine 1.10-5 g/l 11 177 4.4 +53 4.1 +46 6.1 53 9.8 +46 4.7 (*) Statistically significant differences versus controls 0.05 > p > 0.02.
Table 5a As in Table la. Effect ofstress.
{J#g tj AfI100(meanS.E.) no. of adrenaline GJ.5mcg Groups hearts 1st injection 2nd injection 3rd injection 4h injection
Controls 9 105.8+ 16.5 182.5 r 40.6 203.5 j 41.5 294.6 89.1
L - carnitine 1.10 -5 gll 9 48.0 + 9.4 94.4t14.6 153.0 31.2 31.2 183.3t 43.5 (c)
D - carnitine 1.10' 9/i 11 255.4 + 44.2 432.4 t 95.6 425.2 + 85.4 492.0 + 123.3
(b)
Two composition examples for the manufacture of tablets are given hereunder
Example 3
L-carnitine 330.0 mg
Magnesium stearate 50.0 mg
Microcrystalline cellulose 240.0 mg
620.0 mg
Example 4
L - carnitine 330.0 mg
Stearic acid 35.0 mg
Microcrystalline cellulose 230.0 mg
595.0 mg
Claims (14)
1. A pharmaceutical composition for the treatment of hyperlipidaemias and hyperlipoproteinaemias comprising an effective amount of L carnitine, in the substantial absence of D - carnitine.
2. A pharmaceutical composition for restoring the ratio between p - lipoproteins and a - lipoproteins from an abnormally high value to a normal value, comprising L - carnitine in the substantial absence of D - carnitine.
3. A pharmaceutical formulation comprising L carnitine in the substantial absence of D - carnitine formulated for pharmaceutical administration to human beings.
4. A pharmaceutical composition adapted for administration to human beings containing as an active ingredient L - carnitine in the substantial absence of D - carnitine.
5. A pharmaceutical composition or formulation as claimed in any preceding claim in a unit dosage form containing approximately 50 mg to approximately 500 mg of L - carnitine.
6. Atherapeutical method for the treatment of patients affected by hyperlipidaemias and hyper lipoproteinaemias characterized by the fact of administering to said patients, orally or parenterally, a pharmaceutical composition comprising an effective amount of carnitine present solely in the L form.
7. Atherapeutical methodfortreating patients exhibiting an abnormally high value of the ratio between p - lipoproteins and a - lipoproteins comprising administering to said patients of an effective amount of L-carnitine, sufficientto restore said ratio to normal values.
8. The therapeutical method according to claim 4 or 5, characterized by the fact of administering to said patients from approximately 2 mg/kg to approximately 10 mg/kg of bodyweight per day of L - carnitine.
9. A pharmaceutical composition substantialily as hereinbefore described in Example 1 or Example 2.
10. L - carnitine in the substantial absence of D carnitine for use in a method of treatment of the human or animal body by therapy.
11. A pharmaceutical composition for the treatment of myocardial anoxia, myocardiai ischaemia, arrhythmic syndromes and heart failure, comprising an effective amount of L - carnitine, in the substantial absence of D - carnitine.
12. A pharmaceutical composition as claimed in claim 1, in a unit dosage form, comprising from approximately 50 mg to approximately 500 mg of L carnitine.
13. A therapeutical method for the treatment of patients affected by myocardial anoxia, myocardial ischaemia, arrhythmic syndromes and heart failure, characterized by the fact of administering to said patients, via the oral or parenteral route, a pharmaceutical composition comprising an effective amount of L - carnitine in the substantial absence of
D - carnitine.
14. Atherapeutical method according to claim 3 characterized by the fact of administering to said patients approximately 2 mg to approximately 10 mg/kg of bodyweight per day of L - carnitine.
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IT50332/79A IT1119854B (en) | 1979-09-21 | 1979-09-21 | PHARMACEUTICAL COMPOSITION INCLUDING L-CARNITINE FOR THE TREATMENT OF HEART DYSFUNCTIONS |
IT50331/79A IT1119853B (en) | 1979-09-21 | 1979-09-21 | PHARMACEUTICAL COMPOSITION INCLUDING L-CARNITINE FOR THE TREATMENT OF DYSLIPIDEMIA AND HYPERLIPO PROTEINEMIE |
Publications (1)
Publication Number | Publication Date |
---|---|
GB2058566A true GB2058566A (en) | 1981-04-15 |
Family
ID=26329402
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB8030373A Withdrawn GB2058566A (en) | 1979-09-21 | 1980-09-19 | Pharmaceutical composition comprising L-carnitine |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2058566A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2132085A (en) * | 1982-10-29 | 1984-07-04 | Sigma Tau Ind Farmaceuti | Pharmaceutical composition containing l-carnitine |
EP0232227A1 (en) * | 1986-01-13 | 1987-08-12 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Phosphorylalkanolamide derivatives of L-carnitine and pharmaceutical compositions containing same |
US4883672A (en) * | 1988-04-29 | 1989-11-28 | Shug Austin L | Method for preventing diet induced carnitine deficiency in domesticated dogs and cats |
EP0434088A1 (en) * | 1989-12-22 | 1991-06-26 | Lonza Ag | Pharmaceutical compositions containing L-carnitine |
-
1980
- 1980-09-19 GB GB8030373A patent/GB2058566A/en not_active Withdrawn
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB2132085A (en) * | 1982-10-29 | 1984-07-04 | Sigma Tau Ind Farmaceuti | Pharmaceutical composition containing l-carnitine |
EP0232227A1 (en) * | 1986-01-13 | 1987-08-12 | Sigma-Tau Industrie Farmaceutiche Riunite S.p.A. | Phosphorylalkanolamide derivatives of L-carnitine and pharmaceutical compositions containing same |
US4883672A (en) * | 1988-04-29 | 1989-11-28 | Shug Austin L | Method for preventing diet induced carnitine deficiency in domesticated dogs and cats |
EP0434088A1 (en) * | 1989-12-22 | 1991-06-26 | Lonza Ag | Pharmaceutical compositions containing L-carnitine |
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