Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-12-10
2001-04-10
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S259500, C514S556000
Reexamination Certificate
active
06214884
ABSTRACT:
Pharmaceutical composition for the treatment of Chronic Regional Pain Syndrome
The present invention relates to L-carnitine and lower alkanoyl L-carnitines or the pharmacologically acceptable salts thereof in combination with ketanserin, for the therapeutic treatment of Chronic Regional Pain Syndrome (CRPS).
CRPS is a pain syndrome, which affects several subjects after a trauma, even a mild entity trauma.
To CRPS are associated disturbs of blood circulation with ischemia and pain, wherein, ischemia gives pain and pain causes ischemia.
Other important symptoms shown by patients affected by CRPS are hyperpathia and allodinia.
CRPS origin is still not clear; for several years it has been considered that the sympathetic nervous system is involved.
For this reason the most effective therapy was effected by blocking the sympathetic innervation with phenol, thermolesion or treating with guanethidine.
The circulation restoration with ketanserin, a serotonine antagonist, constituted an improvement in the treatment of such disease.
With this drug it is possible to treat most of symptoms, but not those caused by hyperpathia and allodinia [A. Moesker et al., in Konservative Therapie Arterieller Durchblutungsstoerungen, Georg Thieme Verlag (Stuttgart, New York), 148-152, 1986; A. Moesker et al., The pain Clinic vol. 8,n
o
.1, 31-37 (1995); A. Moesker et al., ibid.vol 12, 269-302 (1991)].
More recently, following to the identification of the oxygen free radical during CRPS, dimethyl sulfoxide has been utilised (R. J. A. Goris et al. Free Rad. Res. Comm. 1987, 13-18; W. W. Zuurmond et al., Acta Anaesthesiol. Scan.) without any therapeutic result for the symptoms caused by hyperpathia and allodinia.
The therapeutic treatment with dimethyl sulfoxide proved to be efficacious only during acute CRPS.
Ketanserin is a well known synthetic drug (The Merck Index 11
th
Ed., pag. 834), having formula
and is a specific S2receptor antagonist with hypotensive properties, first described in EP application n
o
13.612.
Ketanserin has been utilised for evaluating its effect on central haemodynamics and coronary circulation [J. Cardiovasc Pharmachol 1998 Dec;
32(6):983-7
]; and in the treatment of intermittent claudicatio [J. De Cree et al., Lancet 2, 775 (1984)].
L-carnitine and alkanoyl L-carnitines are well known compounds. US Pat. No. 4,255,449 and US Pat. No. 4,268,524 describe the use of L-carnitine and alkanoyl L-carnitines, respectively, for normalising abnormally high ratios of low-density lipoproteins (LDL)+very low- density lipoproteins (VLDL) to high-density lipoproteins (HDL), which constitute an etiological factor in various cardiovascular diseases. Through beta-oxidation of fatty acids, L-carnitine is capable of preventing their accumulation and of supplying the cell energy requirement (Bremner Y, TIBS 2, 207, 1977) via modulation of extra-and intra-mitochondrial CoA.
L-carnitine and particularly propionyl L-carnitine or acetyl L-carnitine can act by varying the lipid substrate from which the various vasoconstrictor and aggregation-promoting factors derive as a result of the effects of cyclo-oxygenase and lipo-oxygenase, by reducing their formation and by promoting the synthesis of antiaggregant and vasodilators factors.
Carnitine contain a single centre of asymmetry and therefore may exist as two enantiomers, designated D(+)-carnitine and L(-)carnitine-and, obviously in form of racemate. Of these only L(-)-carnitine is found in living organism, were it functions as a vehicle for transporting fatty acids across mitochondrial membranes. Moreover, L-carnitine may be in form of inner salt or in form of pharmacologically acceptable salt.
For the sake of simplicity in the following reference will be made only to L-carnitine or alkanoyl L-carnitine, it should be understood that the compositions described herein apply to L-carnitine or alkanoyl L-carnitines inner salt, or pharmacological acceptable salts thereof.
To date, the combined use of L-carnitine and ketanserin is not known for any therapeutic indication.
It has now unexpectedly been found that the co-ordinated use, a term which will be precisely defined here below, of L-carnitine or of an alkanoyl L-carnitine in which the linear or branched-chain alkanoyl has 2-6 carbon atoms, or one of their pharmacologically acceptable salts, in combination with ketanserin show a potent synergistic effect in the treatment of CRPS.
With the composition of the invention patients are able either to recover from blood circulation symptoms or from hyperpathia and allodinia symptoms.
This pharmacological activity is very important because for the first time it is possible to cure these symptoms in patients affected by CRPS.
The well known lack of toxic and side effects of L-carnitine or of the alkanoyl L-carnitines and ketanserin makes their co-ordinated use, according to the invention, particularly useful and safe for the treatment of CRPS.
In the context of the invention described herein, what is meant by “co-ordinated use” of the afore-mentioned compounds is either their co-administration, i.e. the substantially simultaneous administration of L-carnitine or one of the alkanoyl L-carnitines, or one of their pharmacologically acceptable salts, and ketanserin or, indifferently, the administration of a composition containing a combination or mixture of the aforesaid active ingredients, in addition to any excipient included.
The scope of the present invention therefore encompasses both the co-administration of L-carnitine or of an alkanoyl L-carnitine, or one of their pharmacologically acceptable salts, together with ketanserin and pharmaceutical compositions, which can be administered orally, parenterally or per intravenous infusion, containing a mixture of the two active ingredients.
In a preferred embodiment of the invention, the alkanoyl L-carnitine will be selected from the group consisting of acetyl, propionyl, butyryl, valeryl and isovaleryl L-carnitine or one of their pharmacologically acceptable salts.
What is meant by pharmacologically acceptable salt of L-carnitine or of an alkanoyl L-carnitine is any salt with an acid that does not give rise to unwanted toxic or side effects.
These acids are well known to pharmacologists and to experts in pharmacy.
Examples of pharmacologically acceptable salts of L-carnitine or alkanoyl L-carnitine, though not exclusively these, are chloride, bromide, orotate, aspartate, acid aspartate, acid citrate, acid phosphate, fumarate and acid fumarate, lactate, maleate and acid maleate, mucate, acid oxalate, acid sulphate, glucose phosphate, tartrate and acid tartrate.
One preferred composition, in unit dosage form, is a composition containing 5-100 mg of ketanserin and 500-3000 mg of L-carnitine or an equivalent amount of alkanoyl L-carnitine.
This pharmaceutical composition is useful for the treatment of symptoms related to CRPS.
Here below are given, by way of example, the pharmacological results of experimental studies aimed at providing evidence of the surprising and unexpected synergistic effect achieved with the combination of the invention.
In the following description, reference will be made only to L-carnitine, it being understood that the compositions described also apply to the above-mentioned alkanoyl L-carnitines and to the pharmacologically acceptable salts of both L-carnitine and the above-mentioned alkanoyl L-carnitines.
METHOD OF DIAGNOSIS OF CRPS
The diagnosis of chronic regional pain syndrome was made in the presence of at least five of the following symptoms:
Persistent pain at rest;
Increasing pain during exercise;
Abnormal feeling of pain like hyperpathia or allodinia;
Cold skin;
Glancing skin;
Hyperhidrosis;
Oedema;
Impaired mobility.
These symptoms were scored at the start of the treatment and after 3 months of oral treatment.
All patients gave their informed consent. Patients data are listed in the following table 1.
TABLE 1
Skin
Age
Delay
Tempera-
patient
M/F
(Years)
(months)
ture
Area
A
F
37
13
28.1
Foot
B
F
38
6
29.1
Foot
C
F
39
3
33.6
Hand
D
F
40
30
31.4
Ha
Calvani Menotti
Cavazza Claudio
Criares Theodore J.
Kim Jennifer
Nixon & Vanderhye
Sigma-Tau Industrie Farmaceutiche Riunite S.p.A.
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