INTRAVENOUS CARNITINE FOR THE TREATMENT OF CHRONIC URAEMIC PATIENTS UNDERGOING PERIODICAL DIALYSIS

Abstract: The method for the treatment of chronic uraemic patients undergoing periodical dialysis is useful for preventing and/or treating carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. The method according to the present invention comprises administering an effective dose of carnitine intravenously into the venous return line after each dialysis session.

Description: INTRAVENOUS CARNITINE FOR THE TREATMENT OF CHRONIC URAEMIC PATIENTS UNDERGOING PERIODICAL DIALYSIS The present invention relates to an improved therapeutic method for the treatment of chronic uraemic patients undergoing periodical dialysis. Background of the invention It is known that patients affected by chronic uraemia, undergoing periodical dialysis, frequently develop a clinical picture characterized by marked muscular asthenia and a sensation of torpor, particularly evident immediately following dialysis and which may often last even for several hours, so making difficult, if not impossible, a full resumption of working activity. The clinical experts recognise this problem as "post-dialytic syndrome". A method for treating the post-dialytic syndrome is disclosed in US 4,272,549, issued on June 9, 1981 , herein enclosed for reference in its entirety, together with the references cited therein. US 4,272,549 teaches to treat the "post-dialytic syndrome" by compensating the loss of carnitine occurring during dialytic session. US 4,272,549 claims a method for alleviating asthenia and muscle weakness in a chronic uraemic patient under regular dialysis treatment, which comprises submitting said patient with a polysaline dialytic solution which contains a quantity of carnitine (intended as L-carnitine throughout the present application), or a pharmaceutically acceptable salt thereof, sufficient to render the molar concentration of carnitine in said solution at least equal to the molar concentration of the plasma carnitine of the patient under dialytic treatment. Preferred embodiments of the invention provides that the concentration of carnitine in the dialytic solution is substantially equimolar to the concentration of carnitine in the patient's plasma, but a certain excess of carnitine is also provided, for example between 50 and 100 μmole per liter of solution. An embodiment of the invention provides the administration of from 3 to 6 grams of carnitine or an equivalent amount of a pharmaceutically acceptable salt thereof. The preferred embodiment of the invention provides the oral administration of carnitine, in particular on days between haemodialysis of from 3 to 6 grams of carnitine per day. The oral treatment is coupled with a rather complex treatment with carnitine during the dialytic session, which comprises the administration of carnitine by slow infusion. On the days of haemodialytic session, carnitine may also be administered partly by the oral route and partly by slow infusion. In this case, the overall quantity of carnitine administered shall not exceed approximately 10 g. "Slow infusion" stands for an infusion in which the solution containing carnitine, or any of its pharmaceutically acceptable salts, is administered at the rate of 20 to 40 drops per minute. Particularly favourable therapeutic results were achieved by a method in which carnitine is administered by the oral route to the patient under haemodialytic treatment only on those days during which the patient is not submitted to a dialytic session, while during the actual dialytic session, a dialysing liquid containing carnitine is used. Such preferred therapeutic method for the treatment of chronic uraemic patients undergoing haemodialysis, included more particularly the following steps: 1) on the days between one haemodialytic session and the next, administration by the oral route to these patients of 3 to 6 g per day of carnitine or any of its pharmaceutically acceptable salts; 2) on the days of haemodialytic session, submission of these patients to dialysis using, as dialysing liquid, a solution containing a quantity of carnitine or of any of its pharmaceutically acceptable salts, sufficient to make a molar concentration of carnitine in the said solution at least equal to the molar concentration of the plasma carnitine of the patient under dialytic treatment. By operating in such a manner, it is possible to avoid the loss of plasma carnitine which otherwise takes place during a haemodialytic session; the concentration of plasma carnitine remaining practically unchanged during the dialytic session. In this manner, it is possible to avoid the tissue carnitine depletion, which is the long-term consequence of repeated losses of carnitine the patienl undergoes during the successive dialytic sessions he is submitted to over a prolonged period of time. Although for this purpose it is shown to be sufficient that the solution for the haemodialysis be equimolar in carnitine with respect to the blood of the patient under dialytic treatment, it is preferred to operate with a slightly more concentrated solution. In practice, the haemodialysis solution contains 50 to 100, preferably 60 - 80 μmoles/ litre of carnitine or of any of its pharmaceutically acceptable salts. On the days of haemodialytic session, carnitine may also be administered partly by the oral route and partly by slow infusion. In this case, the overall quantity of carnitine administered shall not exceed approximately 10 g. The therapeutic method disclosed in US 4,272,549 is effective in treating "post-dialysis syndrome", but presents a cumbersome schedule of treatment. This fact makes some problems to occur. The compliance of the patients, whose quality of life is already heavily affected, about the necessity of taking care by themselves of the oral self administration of a prescribed dosage of carnitine between the dialytic sessions. There is also the problem of carnitine bioavailability through the oral route, which is subject to saturation mechanism and to some restrictions as to the absorption sites (Harper at al. Eur. J. Clin. Pharmacol. 1988; 35(5):555-62 and Matsuda Et Al. Biol Pharm. Bull 1998, Jul; 21 (7):752-5). Also, the oral administration of carnitine to a chronic uraemic patient may give rise to the accumulation of toxic metabolites. A recent work by Sloan et al. (Am. J. Kidney Dis. 1998, Aug; 32(2):265-72) demonstrated that oral supplementation of carnitine is effective in improving the quality of life of patients in the early stage of treatment, but the perceived effect was not sustained through long term treatment (six months). Summary of the invention It has now been found in a totally unexpected manner an improved therapeutic method for the treatment of chronic uraemic patients undergoing periodical dialysis. The method for the treatment of chronic uraemic patients undergoing periodical dialysis is useful for preventing and/ or treating carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. The method according to the present invention comprises administering an effective dose of carnitine intravenously into the venous return line after each dialysis session. As dialysis session both haemodialysis and peritoneal dialysis are intended. The method according to the present invention provides the surprising improvement with respect to the method disclosed in US 4,272,549 to eliminate the need of the oral treatment, without affecting the maintenance of the correction of carnitine deficiency obtained by the administration of carnitine through intravenous route. The invention shall be disclosed in detail, with reference to Figures and Examples. Brief description of the figures Figure 1 illustrates the treatment schedule, where the letters A-F denote the heart effluent sampling times for the measurement of metabolites. Figure 2 shows the effect of carnitine (A) and carnitine fumarate (B) on creatine phosphate and ATP. Figure 3 compares lactate (A) with succinate (B) released by the heart, as measured in the effluent. Figure 4 illustrates the release of malate. Figure 5 illustrates the release of LDH. Figure 6 illustrates the production of lactate. Detailed disclosure of the invention The preferred starting dose is 10-20 mg/kg dry body weight as a slow 2-3 minute bolus injection into the venous return line after each dialysis session. Initiation of the therapy may be prompted by through (pre- dialysis) plasma carnitine concentrations that are below normal (40- 50 umol/L). Dose adjustments should be guided by through (pre- dialysis) carnitine concentrations, and downward dose adjustments (for example to 5 mg/kg after dialysis) may be made as early as the third or fourth week of therapy. Carnitine can be administered as inner salt or in any pharmaceutically acceptable salts thereof. In the above mentioned patents US 4272549 and US 4272549, the invention is given in detailed manner as to put it into practice. As far as carnitine is concerned, the active ingredient is mentioned as "carnitine or any of its pharmaceutically acceptable salts" (see for instance US 4272549, column 4, line 16), thus clearly teaching to the skilled person that any of the pharmaceutically acceptable salts will do in the invention therein disclosed. In the present invention we confirm that for the practice of the improved method for the treatment of chronic uraemic patients undergoing periodical dialysis, any of the pharmaceutically acceptable salts of carnitine will do. But, in a particular embodiment of the invention, the skilled person might have to face a problem with some patients. During the dialytic session, some patients are affected by hypervolemic heart, and this can give a severe outcome as heart failure. Moreover, a number of patients undergoing hemodialysis are affected by diabetes. In a particular embodiment of the present invention, it has been found that fumarate of L-carnitine exerts a surprising beneficial effect on heart. Moreover, due to its physiologic role, fumarate may have beneficial effects in diabetic patients. Accordingly, a particular embodiment of the present invention relates to the method above disclosed, wherein fumarate is the pharmaceutically acceptable salt of L-carnitine. Suitable formulations of carnitine, or a pharmaceutically acceptable salt thereof, are in the form of injectable compositions, for example comprising an equivalent amount of carnitine of 200 mg per 1 mL. A 2.5 or a 5 mL single dose ampoule may be convenient. When a pharmaceutically acceptable salt of L-carnitine is used, such as fumarate, the amount of active ingredient shall be calculated as to give an equivalent amount of L-carnitine as above specified. Description of the preferred embodiment Patients showing a pre-dialysis carnitine level equal or lower than 40-50μM were treated with the method according to the present invention with a 10-20 mg/kg dose of carnitine at the end of the 4-hours dialytic session. According to a standard dialytic schedule, the treatment was repeated twice a week every 44 hours, then after 68 hours. This treatment was continued for 3-4 weeks, monitoring pre-dialytic levels of carnitine. As a further embodiment of the present invention, a maintenance method of treatment is provided, giving, as a preferred example, a dose of 5 mg/kg of carnitine. The following table explains the preferred method for a 3 -weeks treatment: Wherein X shows a 4-hours dialytic session and the carnitine intravenous administration according to the present invention at the end of the session. 44 hours occur between two subsequent carnitine administrations from Monday to Friday and 68 hours occur between two subsequent carnitine administrations from Friday to Monday. As far as the particular embodiment of L-carnitine fumarate, the following examples further illustrate the invention. EXAMPLE 1 Effect of the administration of L-carnitine fumarate on the perfused heart In this example, the low-pressure or low-flow ischemia model was used, which is a model recognised as valid for cardiac ischemia (Bolukoglu, H. et al. Am. J. Physiol. 1996: 270; H817-26). The treatment schedule is illustrated in Figure 1., in which the letters A-F denote the heart effluent sampling times for the measurement of metabolites. The hearts are removed from the animals and mounted on a Langerdorff appliance. The perfusion medium replacing the blood was a Krebs-Heinsleit standard bicarbonate buffer containing glucose 12 mM as energy source for cardiac metabolism. After 30 minute perfusion at a pressure of 100 cm of water, ischemia was induced by reducing the perfusion pressure of the heart to 25 cm of water, thus reducing coronary flow from approximately 2 ml/min to approximately 0.3 ml/min. Reduction of the perfusion pressure gives rise to ischemia, since the heart will pump the fluid in the low-perfusion area rather than via the coronary bloodstream, supplying the flow to the heart. This control model was compared with hearts perfused with L- carnitine 10 mM or L-carnitine fumarate 10 mM. Cardiac function was tested in three different ways. In the first, the NRM 31 P signal was monitored in real time. This signal provides the best indication of the energy status of the heart. In the second, the haemodynamics of the heart was measured by means of a pressure transducer mounted to measure the perfusion pressure. The haemodynamic measurements include heart rate, relative dP/dt (measurement of the contraction force of the heart) and the cardiac contraction amplitude. Coronary flow was also measured as an indicator of the heart's ability to provide oxygen and energy for its own metabolism. In the third type of test, the metabolites and the enzyme LDH released by the heart were analysed in the effluent. The release of LDH indicates damage to cardiac tissue. The release of metabolites by the heart was tested by means of mass spectrometry coupled with gas chromatography. The results of the experiments show that the hearts treated with carnitine fumarate have reduced release of LDH; the reserves of high-energy phosphai.e after 45 minutes of ischemia are greater in treated hearts, as indicated by the increase in creatine phosphate observed at NMR and the profile of the metabolites released indicates that the treated heart generates less lactate, but more malate. A high lactate level indicates intense anaerobic metabolism and acidosis. The increase in malate indicates that fumarate is metabolised by the heart to yield a system of intermediates of the citric acid cycle favourable to the heart. Haemodynamic function, as indicated by the postischemic cardiac contraction amplitude and by coronary flow, is greater in hearts treated with carnitine fumarate. EXAMPLE 2 The procedures of example 1 were substantially repeated, with the addition of a treatment with carnitine alone as a further control. The results are given in Figures 2-6, where: Figure 2 illustrates the effect of carnitine (A) and carnitine fumarate (B) on creatine phosphate and ATP. The data were evaluated after 40 minutes of ischemia. CP indicates creatine phosphate and α,β and γ denote the phosphate peaks of ATP; as can be seen in part (A) of the figure, the ATP peaks are lacking in the absence of fumarate. Figure 3 shows the comparison between lactate (A) and succinate (B) released by the heart, as measured in the effluent. The lactate reduction indicates the favourable effect of carnitine fumarate. The low amount of succinate as compared to lactate indicates that the generation of ATP as a result of the reduction of fumarate to succinate is not the main source of anaerobic ATP. Figure 4 illustrates the release of malate. The greater malate levels in the treated heart indicate that fumarate enters the cardiac mitochondrion and is metabolised in the TCA cycle. Figure 5 illustrates the release of LDH. The greater LDH levels in controls indicate that carnitine fumarate affords protection against ischemic damage. Figure 6 illustrates lactate production.

Claims: CLAIMS 1. The use of L-carnitine or of a pharmaceutically acceptable salt for the preparation of a medicament to be administered intravenously only useful for the treatment of chronic uraemic patients undergoing periodical dialysis. 2. The use of L-carnitine or of a pharmaceutically acceptable salt for the preparation of a medicament to be administered intravenously only useful for preventing and/ or treating carnitine deficiency in patients with end stage renal disease who are undergoing dialysis. 3. The use according to claim 2, wherein said medicament is administered intravenously into the venous return line after each dialysis session. 4. The use according any one of claim 2-3, wherein the dialysis session is haemodialysis or peritoneal dialysis. 5. The use according any one of claim 2-4, wherein the pharmaceutically acceptable salt is fumarate. 6. The use according to any one of claims 2-5, wherein said medicament is suitably formulated for a starting dose of 10- 20 mg/kg dry body weight as a slow 2-3 minute bolus injection into the venous return line after each dialysis session. 7. The use according to any one of claims 2-6, wherein said medicament is indicated for patients having pre-dialysis plasma carnitine concentrations that are below normal 40- 50 μmol/L. 8. The use according to claim 5, wherein the patient is affected by hypervolemic heart. 9. The use according to claim 5, wherein the patient is affected by diabetes.

Inventors: CAVAZZA CLAUDIO, CAVAZZA, CLAUDIO
Applicants: SIGMA TAU IND FARMACEUTI, SIGMA-TAU INDUSTRIE FARMACEUTICHE RIUNITE S.P.A.
Application year: 2001
Main classification: A61K31
IPC codes: A61K31, A61P7