Composition comprising ketanserin and L-carnitine or an alkanoyl L-carnitine for the treatment of CRPS

This invention relates to L-carnitine and lower alkanoyl L-carnitines in combination with ketanserin, for the therapeutic treatment of Chronic Regional Pain Syndrome (CRPS).

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.sup.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.sup.th Ed.,
 pag. 834), having formula
 ##STR1##
 and is a specific S2receptor antagonist with hypotensive properties, first
 described in EP application n.sup.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 Hand
 E F 24 3 28.5 Foot
 F M 48 108 25.9 Foot
 G M 37 192 23.1 Foot
 H M 42 6 29.2 Knee
 I F 55 6 33.0 Hand
 J F 50 3 31.7 Hand
 K F 36 16 25.3 Hand
 L F 42 9 32.5 Foot
 Mean 40.7 32.9
 S.D. 7.5 55.6
 All patient had a story of surgery on the affected area of hand, foot, or
 knee.
 In spite of the fact that this group comprised only 12 patients, they
 matched with the general picture of CRPS patients found in greater
 studies, like H. J. M. Veldman et al., The Lancet, 342, 1012-1016 (1993).
 In a group of 829 CRPS patients Veldman had 76% females and 24% males. In
 the group treated according to the present invention, there were 67%
 females and 33% males.
 The mean age of the Valdeman's study showed 42 years, in the study
 according to the example of the present invention, it was 40.7 years.
 Veldman found 59% CRPS of the upper extremity and 41% lower extremity.
 In our group were 42% CRPS of the upper extremity and 58% CRPS of the lower
 extremity.
 The delay time between start of the symptoms and start of the treatment was
 in our case of 33 months.
 This extremely long time interval is the consequence of two patients with a
 delay of 108 and 192 months.
 When we eliminate these two patients, delay time is reduced to 9.5 months,
 and for six patients delay time is six months or less.
 Looking at the phenomenon of a warm or a cold CRPS the objective
 measurement of the skin temperature was used.
 Taking into account that normal skin temperature is about 32.degree. C., 7
 cold extremities and five normal or warm extremities were observed.
 Special attention was given to the symptom of abnormal pain feeling,
 hyperpathia and allodinia.
 This kind of symptom was found in 6 patients.
 Treatment
 All i.v. treatments were performed after at least 15 minutes of
 acclimatisation at constant temperature (20-23.degree. C.).
 The temperature of the affected limb was recorded with Hewlett Packard
 electro-skin probe between digit 4 and 5. In addition continuos
 photoplethysmograpy of the affected hand (digit 2) or foot (digit 1),
 blood pressure and hearth rate were recorded.
 All patients received a bolus of 10 mg of ketanserin i.v. in a running
 saline infusion.
 Ketanserin administration was continued by rate of 4 mg per hour.
 After one hour, a bolus injection of 1000 mg of L-carnitine was given.
 After this infusion start, oral maintenance therapy was started is with
 ketanserin three times daily 20 mg, and L-carnitine three times daily 990
 mg.
 Results
 To compare the clinical manifestation of the CRPS before and after the
 infusion treatment followed by three months oral therapy an evaluation of
 seven symptoms was made.
 The seven symptoms were: pain at rest, pain during exercise, impaired
 mobility, hyperhidrosis, oedema, small veins and allodinia/ hyperpathia.
 A scale with five degree was used. The nurse recorded the degree of the
 symptoms of the patient according to the following scale: absent, mild,
 reasonable, moderate and severe.

This symptom was present in six out of these twelve patients. The results
 after three months are shown in FIG. 2.
 After the intravenous treatment with ketanserin all patients had peripheral
 circulation of the affected limb normalised, as proven in the past by
 Moesker (above cited) and by M. H. Hanna et al. [Pain, 38, 145-150
 (1989)].
 The symptom of small vein disappeared and the skin temperature was
 normalised.
 After three months treatment with the two compounds according to the
 invention, patient "F" which was a severe case with a delay time of 108
 months, had still the worst symptomatology, with pain at rest, pain during
 exercise and impaired mobility.
 Patient "C" was a remarkably case, who had good recovery, but still oedema
 and Hyperhidrosis.
 Patient "B" was fully cured of any complaint of CRPS, despite she had a
 three months old full blow CRPS, with a skin temperature of 29,1.degree.
 C. and seriously debilitating allodinia of the affected foot. Is
 noteworthy that the allodinia symptom disappeared in all patients that
 showed this symptom.
 Impaired mobility and pain during exercise did not disappear completely
 probably because the treatment time with the combination according to the
 present invention was too short.
 Other positive results were obtained changing the therapeutic treatment
 protocol above cited.
 In fact, it is possible to increase or decrease the amount of the two
 compounds either during the initial intravenous infusion or during the
 maintenance therapeutic treatment (os).
 In mild or recent CRPS it is possible to start directly with the above
 cited maintenance therapeutic treatment (os) with ketanserin and
 L-carnitine, three times daily.
 It is an object of the present invention an orally or parenterally
 administrable composition comprising ketanserin and L-carnitine or an
 alkanoyl L-carnitine or one of its pharmacologically acceptable salts.
 Object of the present invention is also the co-ordinated use of the
 above-mentioned compounds 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 composition of the invention can be orally, parenterally or
 intravenously per infusion administered. The composition according to the
 invention can be in the form of tablets, capsules, effervescent sachets,
 suppositories or vials.
 Further object of the present invention is to provide a therapeutical kit
 comprising in the same package:
 a) a first set of vials for intravenous infusion, said first set of vials
 comprising 5-50 mg of ketanserin in admixture with pharmacologically
 acceptable vehicle and/or excipient, a second set of vials for intravenous
 infusion, said second set of vials comprising 500-2000 mg of L-carnitine
 or an equivalent amount of an alkanoyl L-carnitine or one
 pharmacologically acceptable salts pharmaceutical composition comprising
 100-3000 thereof, in admixture with pharmacologically acceptable vehicle
 and/or excipient;
 and further comprising in the same package,
 b) a first orally administrable pharmaceutical composition comprising 5-100
 mg of Ketanserin and a second orally administrable mg of L-carnitine or of
 an alkanoyl L-carnitine or one pharmacologically acceptable salts thereof,
 in admixture with pharmacologically acceptable vehicle and/or excipient.