WO2006061341A1

WO2006061341A1 - Use of propionyl l-carnitine for the preparation of a high-dose medicament for the treatment of peripheral arterial disease

Info

Publication number: WO2006061341A1
Application number: PCT/EP2005/056323
Authority: WO
Inventors: Aleardo Koverech; Francesco Violi
Original assignee: Sigma Tau Industrie Farmaceutiche Riunite SpA
Current assignee: Sigma Tau Industrie Farmaceutiche Riunite SpA
Priority date: 2004-12-10
Filing date: 2005-11-29
Publication date: 2006-06-15
Anticipated expiration: 2007-06-10

Abstract

The use of propionyl L-carnitine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a patient suffering from peripheral arterial disease at least at stage II of the Leriche-Fontaine's classification, wherein said medicament is suitably formulated for the administration from about 4 to about 8 g/day, preferably 6 g/day, of propionyl L-carnitine by intravenous route is herein disclosed. A preparation for intravenous infusion suitable for the administration of propionyl L-carnitine is also provided. The present invention provides an improved treatment of the disease and an increase of ABI parameter, namely improving symptoms and making better the patient's quality of life, but especially decreasing the risk of peripheral vascular complications.

Description

Use of high-dose propionyl L-carnitine for the preparation of a medicament for the treatment of peripheral arterial disease

The invention described herein relates to the use of propionyl L- carnitine for the preparation of a medicament for the treatment of peripheral arterial disease.

Background of the invention

Peripheral arterial disease (PAD) is caused by atherosclerosis of the leg arteries and is usually complicated by vascular accidents occurring not only in peripheral circulation but also in cerebral and coronary trees. Approximately one third of patients with PAD suffers from claudication, that usually deteriorates slowly: 25% of patients have worsening claudication and about 5% experience amputation within 5 years.

Ankle/arm pressure ratio is a non invasive test which may help to identify patients at high risk of cardiovascular events. An ankle/brachial index (ABI) <0.8 is predictive of cardiovascular events and significantly increased the risk of peripheral vascular complications including surgical intervention, or angioplasty or local thrombolysis (Violi, F., et al., Atherosclerosis 1996,120:25-35). The risk of peripheral vascular complications is even higher with ankle/arm pressure ratio worsening, as documented by an even more elevated risk of peripheral vascular deterioration in patients with ABI <0.5 (Dormandy, JA; Murray, GD; Eur. J. Vase. Surg., 1991;5:131-3).

Despite several medical approaches for preventing peripheral vascular deterioration have been investigated, including antiplatelet drugs such as ticlopidine, aspirin and prostaglandins, few studies examined the efficacy of a medical treatment in patients with severe claudication.

Patients with claudication have severe limitations in exercise capacity due to reduced blood flow in the peripheral circulation. There is evidence that impairment of carnitine function, likely as a consequence of acylcarnitine accumulation, contributes to metabolic changes that facilitate the occurrence of claudication (Hiatt, WR, et al, J. Clin. Invest,. 1989,-84:1167-73).

Metabolic changes including accumulation of carnitines with eventual impairment of skeletal muscle metabolism has been reported in claudicant patients (Brass, EP; Hiatt, WR; J. Am. Coll. Nutr.; 1998 Jun; 17(3): 207- IS). Also, randomised placebo-controlled clinical trials with levocarnitine and propionyl L-carnitine orally given demonstrated a significant increase of walking distance in patients with claudication (Breυetti, G; et al.; J. Am. Coll. Cardiol; 1995; 26:1411-6; Breυetti, G; et al.; Eur. Heart J.; 1992; 13:251-5; Breυetti, G; et al; Circulation; 1988; 77:767-73; Breυetti, G; et al; J. Am. Coll. Cardiol; 1999; 34:1618-24; Hiatt, WR; et al; Am. J. Med.; 2001; 110:616-22), suggesting for metabolic status in deteriorating claudication. It was demonstrated that propionyl L-carnitine inhibits arachidonic acid accumulation in the phospholipids of platelet membrane with ensuing reduction of platelet thromboxane A2 and O2 formation (Pignatelli, P; et al; Am. J. Physiol. Heart Circ. Physiol; 2003; 284.Η41-8). A potential relevance of platelet function on the progression of PAD is known (Hiatt, WR.; N. Engl. J. Med.; 2001; 344:1608-1621).

Brevetti et al. studies, see also US patent N° 4,968,719, provide a limited teaching to the oral administration of L-carnitine or propionyl L-carnitine to a daily dose of 2 g. In particular, Brevetti et al. (Circulation, 1988; 77:767-73) demonstrated that in six claudicant patients intravenously treated with 3 g L-carnitine as a bolus followed by infusion of 2 mg/Kg/man for 30 minutes the increase of venous lactate induced by walking test was lowered; but it was not reported if this treatment had some effects on walking distance or ABI.

Corsi, US patent N° 5,811,457, discloses the use of propionyl L- carnitine in a therapeutical method for the treatment of chronic arteriosclerosis obliterans at stage II of Leriche Fontaine's classification in patients with maximal walking distance (MWD) equal to or greater than 100 meters and shorter than 300 meters. This reference, makes a better distinction of the patient population affected by peripheral arterial disease with respect to US 4,968,719. The patent enables for an oral administration of 2 g/day of propionyl L- carnitine and the clinical response began to be significantly apparent between the 4^th and 6^th month of treatment. The whole treatment was for 12 months. The preferred administration route is the oral one and no particular weight is given to other administration modes, given as intended to be equivalent each other.

However, the effect of propionyl L-carnitine in patients with moderate to severe PAD has never been examined.

The state of the art successfully improved the walking distance, a symptomatic parameter, but did not yet really improved the physiopathological state of the patient.

In spite of all the intense search for an effective therapy for peripheral arterial disease, the need for an improved therapeutic treatment still remains, with particular view for patient's improvement of physiopathological parameters, patient's compliance, especially for the treatment period length; safety and efficacy.

Summary of the invention

It has now been found that the intravenous administration of propionyl L-carnitine at the high dose surprisingly provides a favourable relief from peripheral arterial disease and a faster recovery in the short term.

The present invention provides an improvement in the treatment of peripheral arterial disease (PAD) by dramatically shortening the period of treatment. Moreover, in spite of the high dosage used according to the present invention, no serious adverse or side effects were observed, thus further improving patients' compliance.

Of more importance, the present invention improves the ABI parameter, thus giving an indication not only of increased walking distance, namely improving symptoms and making better the patient's quality of life, but especially decreasing the risk of peripheral vascular complications.

Therefore, it is an object of the present invention the use of propionyl L-carnitine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a patient suffering from peripheral arterial disease at least at stage II of the Leriche- Fontaine's classification, wherein said medicament is suitably formulated for the administration of about 4 to about 8 g/day of propionyl L-carnitine by intravenous route.

This and other objects will be disclosed in the foregoing detailed description of the invention, recurring also to examples.

Detailed description of the invention.

Propionyl L-carnitine is a well-known compound, currently available on the market or it can be easily prepared with well-known methods. The preparation of propionyl L-carnitine and its pharmaceutically acceptable salts is disclosed, for example, in the patent literature in the name of the applicant.

Examples of pharmaceutically acceptable salts of propionyl L-carnitine are chloride, bromide, orotate, acid aspartate, acid citrate, magnesium citrate, acid phosphate, fumarate and acid fumarate, magnesium fumarate, lactate, maleate and acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulfate, glucose phosphate, tartrate, acid tartrate, magnesium tartrate, 2 -amino ethansulfonate, magnesium 2- amino ethansulfonate, choline tartrate and trichloroacetate.

The present invention is applied to patients suffering from peripheral arterial disease with a moderate to severe grade. Reference to the grade is made to the Leriche-Fontaine's classification, see the above mentioned US patent 5,811,457.

In some cases, the patient may not suffer rest pain; however, the medicament according to the present invention can be advantageously used, in order to prevent a worsening of the disease.

In most severe cases, the patient is at risk of amputation; in this case the medicament herein disclosed can be used in order to prevent a dramatic outcome of the disease.

Generally, the medicament of the present invention is used in patients having a walking autonomy lower than 200 meters and an ABI lower than 0,6.

Conveniently, said medicament is in the form of a preparation for infusion and said infusion lasts about 8 hours. The person skilled in the art will decide the effective time of administration, depending on the patient's conditions, degree of severity of the disease, response of the patient and any other clinical parameter within the general knowledge of this matter.

The high dose of propionyl L-carnitine ranges from about 4 to about 8 g/days, preferably about 6 g/days.

In a preferred embodiment of the present invention, the infusion is suitable for the administration of about 750 mg/hour of propionyl L- carnitine or of an equivalent amount of a pharmaceutically acceptable salt thereof. The treatment normally lasts about 7 days, the length of treatment being decided by the skilled person, as per the duration of the infusion discussed above.

By the term "about" it is intended a range around the indicated values, namely the lower and higher dosage, the infusion administration flow, the length of the treatment and other parameters involved in the present invention. The person skilled in the art, by carrying out the invention, will use the normal, general experience in determining the range implied in the term "about". For example, the dosage can be adjusted around the indicated values depending on the patient's conditions, degree of the disease and any other element evaluated in the normal practice in this field.

Conveniently, the medicament is in the form of a package suitable for 7 days treatment. This can be particularly advantageous for non- hospitalized, home-cared patients.

It is a further object of the present invention a preparation for intravenous infusion suitable for the administration of about 750 mg/hour, in order to administer a total of from about 4 to about 8, preferably 6 g/day of propionyl L-carnitine or of an equivalent amount of a pharmaceutically acceptable salt thereof. This preparation can be obtained with procedures commonly used in the art. A guidance for the preparation of the intravenous infusion can be found in technical literature, see for example Remington's Pharmaceutical Science Handbook, the last edition, or regulatory textbooks, such as European Pharmacopoeia.

The following examples further illustrate the invention. Example 1

Clinical Study

To investigate the effect of propionyl L-carnitine on severe PAD we analysed two groups of 10 patients each; in the first group (GROUP 1) an open label treatment with 6 g/day i.v. propionyl L-carnitine for 7 days was administrated to patients (n=10; 6 males and 4 females; mean age 70.1±5.5); the second group (GROUP 2) included patients (n=10; 9 males and 1 females; mean age 69.6±4.57) who underwent a single-blind study, consisting in treating them with i.v. placebo for 7 days and thereafter with 6 g/day propionyl L-carnitine i.v. for other 7 days. In both studies infusion of propionyl L-carnitine will last about 8 hours/day, corresponding to 750 mg/h.

20 patients, affected by severe or moderate PAD (according to Rutherford and Fontaine classifications), were admitted to the hospital for the study.

The institutional ethic committee of the centres participating in the study approved the trial protocol. In the month preceding the study, after two treadmill tests, written informed consent was obtained from all patients who satisfied inclusion criteria; they were consecutive clinical patients admitted, previously, to the ambulatory or to the day- hospital of the two centres participating in the study. Patients didn't participate before to other clinical study.

All patients underwent a full medical history, physical examination, 12-lead ECG, laboratory test, measurement of ABI and a screening treadmill test whereupon the maximal walking distance (MWD) was recorded. Patients eligible for the study had to have ABI <0.6 and MWD <200 meters after treadmill. Patients should be in stable conditions without abrupt changes of walking distance and ABI in the last month; accordingly, in two consecutive tests performed in the month receding the inclusion in the study, none patients had >20% variability in the MWD and ABI. Patients were excluded from the study if they had PAD at the stage III or TV of the Leriche-Fontaine classification, liver insufficiency, serious renal disorders (serum creatinine 2.8 mg/dl), myocardial infarction or coronary revascularization, peripheral vascular surgery or percutaneous intervention procedure within 6 months, unstable angina within the previous 3 months, stroke or transient ischaemic attack within 6 months, or deep venous thrombosis within the previous 3 months before hospital admission.

Treadmill test was performed using a treadmill speed of 3.5 km/h at 12% grade until maximal claudication pain.

ABI was calculated, as previously described (Hiatt WR., N. Engl. J. Med., 2001; 344:1608-1621), with the patient placed in the supine position, measuring the higher systolic pressure of the anterior tibial or posterior tibial artery in each limb and dividing this pressure with the highest brachial systolic pressure. In patients with diabetes we performed toe pressure determinations. ABI measurement was obtained 5 minutes before the exercise.

Group 1

Ten patients in stable conditions were immediately enrolled to assume 6 g/day of propionyl L-carnitine i.v.. Every infusion was carried out over an eight hour period. All patients have been hospitalised during the period of the study (8 days).

ABI measurement and treadmill exercise were performed at baseline and at day 8, 12 hours after the final infusion of propionyl-1-carnitine.

Group 2

Patients who satisfied the entry criteria underwent one week infusion with placebo, followed by another week infusion with propionyl L- carnitine (6 g/day). Every infusion was carried out over an eight hour period. All patients have been hospitalised during the period of the study (15 days). ABI and treadmill were measured at baseline, at day 8 and at the day 15, 12 hours after the final infusion of placebo and propionyl-1-carnitine.

NO2/NO3 plasma levels.

NO levels were evaluated through the measurement of metabolic end products (Calbiochem nitrite/nitrate assay), i.e. nitrite and nitrate, using enzymatic catalysis coupled with Griess reaction as reported by Verdon (Anal. Biochem., 1995; 224:502-508).

Statistical analysis was carried out with the SPSS software package, version 11.0. Categorical variables are reported as counts (percentage) and continuous variables as means ± SD. The efficacy parameters (ABI and MWD) were analysed using Wilcoxon test, paired samples T test, ANOVA for repeated measures with post-hoc Bonferroni and Tukey A. P value <0.05 was considered statistically significant.

Clinical characteristics of patients are the following: 95% of the patients were hypertensive, 50% had dyslipidemia, 50% were diabetics and 40% smokers (no current users but ex-users of cigarettes). Forty and 25% of patients had had a clinical history of coronary heart disease (CHD) and cerebrovascular disease respectively. Concomitant treatments included: anticoagulants (10%), anti-platelets agents (95%), anti-hypertensive treatment (ACE-inhibitors 55%, Calcium antagonists 45%, doxazosin 10%, diuretics 55%), metformin 30%, insulin 20%, statins 45%. Diabetes mellitus was defined according to the American Diabetic Association new criteria and as the use of insulin or oral hypoglicemic drugs (Diabetes Care, 1997; 20:1183-1197).

Hypertension was defined according to the criteria of the Sixth Joint National Committee Report on the Detection, Evaluation and Treatment of Hypertension or in subjects who were currently taking antihypertensive medication {Arch. Intern. Med.; 1997; 157:2413- 2444). Dyslipidemia was defined according to the criteria of the Third Report of the National Cholesterol Education Program or in subjects who were currently taking lipid lowering drugs {JAMA; 2001; 285: 2486-2497). Ischaemic heart disease was defined on the basis of history and medical records. Current smokers were defined as patients smoking at least five cigarettes a day.

In patients who underwent immediately propionyl L-carnitine treatment (Group 1) baseline MWD and ABI were 43.8±40.56 meters and 0.49±0.05 respectively; after 7 days of propionyl L-carnitine treatment MWD and ABI increased to 90.6±49.78 meters and to 0.61±0.05 respectively; the increases of MWD (p<0.02) and ABI (p<0.02) were statistically significant.

In the group of patients who underwent a single-blind study (Group 2) baseline values of MWD and ABI were 65.7±36.12 meters and 0.47±0.13 respectively and did not differ from the baseline values of Group 1 patients. After treatment with placebo MWD and ABI were 69.3±39.1 meters and 0.47±0.11 respectively and did not significantly differ from baseline values. After treatment with propionyl L-carnitine MWD and ABI significantly increased to 117.6±66.0 meters (p<0.05, compared to baseline and placebo, using ANOVA for repeated measures with post-hoc Bonferroni and Tukey A) and to 0.60±0.11 (p<0.05, compared to baseline and placebo, using ANOVA for repeated measures with post-hoc Bonferroni and Tukey A) respectively; the increases of MWD and ABI were seen in all but one patient. Finally we examined the effect of propionyl L-carnitine taking into account all the patients (n=20) who participate in either study. Baseline values of MWD and ABI were 54.75±39.03 meters and 0.48±0.09 respectively; after seven days of treatment MWD and ABI significantly increased to 104.1±58.58 meters (p<0.001) and to 0.6±0.089 (p<0.001) respectively at paired samples T test; these figures corresponded to 90% increase of MWD and to 25% increase of ABI. The clinical efficacy was equally distributed among diabetic and non- diabetic patients.

The effect of propionyl L-carnitine was also analysed in accordance to the Rutherford classification. At baseline, 17 were in II class and 3 in III class; after treatment 10 were in II class and 10 in III class. In patients of group 2 NO plasma levels were measured at baseline and 12 hours after the final infusion of propionyl L-carnitine; compared to baseline values a significant increase of NO was found after propionyl L-carnitine treatment (19.95±4.9 μmol/L vs 28.29±5.7 μmol/L; pO.001).

All patients were discharged with 2 grams of propionyl L-carnitine orally given; after three months from propionyl L-carnitine infusion 5 patients of Group 2 accepted to be further investigated; they sustained the drug effect with minimal but not significant reduction of ABI (O.β±O.l vs 0.59±0.1) and MWD (141.8±80.7 vs 132±72.9) compared to values obtained after the infusion treatment.

Side effects were essentially characterised by superficial thrombophlebitis, that occurred in 4 patients of Group 2 during propionyl L-carnitine treatment at site of venipuncture. No changes of systemic blood pressure were observed during and after propionyl L- carnitine infusion.

After propionyl L-carnitine infusion, according to the present invention, there was a lesser number of patients who had severe claudication (85% at baseline vs 50% after treatment).

Furthermore, and more interestingly, we found that, compared to the placebo, propionyl L-carnitine significantly increased ABI, indicating that this treatment could enhance blood flow in the peripheral circulation. We can reasonably exclude that the increase of ABI was due to an artefact because no changes in systemic blood pressure was detected. Although the inventors do not wish to be bound by any theory, a possible explanation of the result of the present invention is that intravenous infusion of propionyl L-carnitine increases peripheral blood flow via a vasodilating property, that however, has never been reported in human.

As far as the industrial applicability of the present invention is concerned, the preparation for intravenous infusion is obtained by any conventional method generally known in the art, for example as provided in the European Pharmacopoeia or United States Pharmacopoeia.

For example, the active ingredient can be formulated in an injectable composition, to be diluted into saline at the suitable concentration.

An example of injectable formulation can be an injectable solution of the active ingredient or a lyophilized form of the same.

An example of injectable solution is the following:

Lyophilized powder

Propionyl L-carnitine 300 mg

Mannitol

Solvent

Water for injectable

Sodium phosphate bibasic dihydrated

Trometamine

Claims

1. Use of propionyl L-carnitine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a patient suffering from peripheral arterial disease at least at stage II of the Leriche-Fontaine's classification, wherein said medicament is suitably formulated for the administration from about 4 to about 8 g/day, preferably 6 g/day, of propionyl L-carnitine by intravenous route.

2. Use according to claim 1, wherein said salt of propionyl L- carnitine is selected from the group consisting of chloride, bromide, orotate, acid aspartate, acid citrate, magnesium citrate, acid phosphate, fumarate, acid fumarate, magnesium fumarate, lactate, maleate, acid maleate, mucate, acid oxalate, pamoate, acid pamoate, acid sulfate, glucose phosphate, tartrate, acid tartrate, magnesium tartrate, 2-amino ethansulfonate, magnesium 2-amino ethansulfonate, choline tartrate and trichloroacetate.

3. Use according to claim 1 or 2, wherein said patient does not suffer rest pain.

4. Use according to claim 1 or 2, wherein said patient is at risk of amputation.

5. Use according to any one of claims 1-3, wherein said patient has a walking autonomy lower than 200 meters and an ABI lower than 0.6.

6. Use according to any one of the preceding claims, wherein said medicament is in the form of a preparation for infusion and said infusion lasts about 8 hours.

7. Use according to claim 6, wherein said infusion is suitable for the administration of about 750 mg/hour of propionyl L-carnitine or of an equivalent amount of a pharmaceutically acceptable salt thereof.

8. Use according to any one of the preceding claims, wherein said medicament is in the form of a package suitable for 7 days treatment.

9. A preparation for intravenous infusion suitable for the administration of about 750 mg/hour, or from about 4 to about 8 g/day, preferably 6 g/day, of propionyl L-carnitine or of an equivalent amount of a pharmaceutically acceptable salt thereof.