WO1999052517A2

WO1999052517A2 - Composition comprising ketanserin and l-carnitine or an alkanoyl l-carnitine for the treatment of crps

Info

Publication number: WO1999052517A2
Application number: PCT/IT1999/000084
Authority: WO
Inventors: Claudio Cavazza; Menotti Calvani
Original assignee: Sigma Tau Industrie Farmaceutiche Riunite SpA
Current assignee: Sigma Tau Industrie Farmaceutiche Riunite SpA
Priority date: 1998-04-10
Filing date: 1999-04-08
Publication date: 1999-10-21
Anticipated expiration: 2000-10-10
Also published as: DK0994703T3; NZ501416A; AU3442699A; DE69909395T2; KR20010013685A; HK1026608A1; US6214884B1; DE69909395D1; ATE244566T1; IL133141A; KR100573010B1; US20040209906A1; CA2292638C; IL133141A0; EP0994703B1; CA2292638A1; ITMI980774A1; IT1299069B1; JP4482163B2; ES2203115T3

Abstract

The use of ketanserin in combination with L-carnitine, some alkanoyl L-carnitines and the pharmacologically acceptable salts thereof is disclosed for the treatment of CRPS.

Description

Composition comprising ketanserin and L-carnitine or an alkanoyl L-carnitine for the treatment of 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°. l , 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 1 1^th

Ed., pag. 834), having formula

and is a specific S2-receptor antagonist with hypotensive properties,

first described in EP application n° 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 Patent 4,255,449 and US Patent 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 mitochondria! 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.

V- 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.

TAB. 1

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

°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 °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

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.

Fig. 1 shows the inventorisation at starting time; special

attention was given to the symptom allodinia, which is pointed on the

first line.

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 °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.

Claims

1. A combination consisting of ketanserin and L-carnitine or an

alkanoyl L-carnitine or one pharmacologically acceptable salts

thereof.

2. Pharmaceutical composition comprising as active ingredients

ketanserin and L-carnitine or an alkanoyl L-carnitine wherein the

linear or branched- chain alkanoyl group has 2-6 carbon atoms or

one pharmacologically acceptable salts thereof, in admixture with

pharmacologically acceptable vehicle and/ or excipient.

3. The composition according to claim 2, for oral, parenteral or

intravenous infusion administration.

4. The composition according to claim 2, wherein the alkanoyl L-

carnitine is selected from the group consisting of acetyl L-

carnitine, propionyl L-carnitine, butyryl L-carnitine, valeryl L-

carnitine and isovaleryl L-carnitine.

5. The composition according to claim 2, wherein the

pharmacologically acceptable salt of L-carnitine or of the alkanoyl

L-carnitine is selected from the group consisting of 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.

6. The composition according to claim 2, in unit dosage form,

comprising 5- 100 mg of Ketanserin and 100-3000 mg of L-

carnitine or of an alkanoyl L-carnitine.

7. The composition according to claim 6, suitable for oral

administration.

8. The composition according to any of the preceding claims for the

therapeutic treatment of CRPS.

9. Co-ordinated use of ketanserin and L-carnitine or of an alkanoyl

L-carnitine or one of their pharmacologically acceptable salts for

the treatment of CRPS.

10. A kit comprising in the same package 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 wherein the

linear or branched- chain alkanoyl group has 2-6 carbon atoms or

one pharmacologically acceptable salts thereof, in admixture with

pharmacologically acceptable vehicle and/ or excipient.

1 1. A kit according to claim 10, further comprising in the same

package a composition of claim 7.

^ΓÇó / ^ΓÇó

12. A kit according to claim 10 , further comprising in the same

package a first orally administrable pharmaceutical composition

comprising 5- 100 mg of Ketanserin and a second orally

administrable pharmaceutical composition comprising 100-3000

mg of L-carnitine or of an alkanoyl L-carnitine.

13. Use of ketanserin and L-carnitine or of an alkanoyl L-carnitine

wherein the linear or branched- chain alkanoyl group has 2-6

carbon atoms or one of their pharmacologically acceptable salts

for the preparation of a medicament for the treatment of CRPS.

14. Use according to claim 13, wherein the alkanoyl L-carnitine is

selected from the group consisting of acetyl L-carnitine, propionyl

L-carnitine, butyryl L-carnitine, valeryl L-carnitine and isovaleryl

L-carnitine.

15. Use according to claim 13, wherein the pharmacologically

acceptable salt of L-carnitine or of the alkanoyl L-carnitine is

selected from the group consisting of 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.

16. Use according to claim 13, wherein said medicament comprises,

5- 100 mg of Ketanserin and 100-3000 mg of L-carnitine or of an

alkanoyl L-carnitine, in a single unit dosage form.

17. Use according to claim 13, wherein said medicament comprises,

5- 100 mg of Ketanserin in a first unit dosage form and 100-3000

mg of L-carnitine or of an alkanoyl L-carnitine in a second unit

dosage form, said first and second unit dosage forms being

physically separated between them.