NEW USE OF CREATINE

Abstract: Description of a new use of creatine in the preparation of a drug for the treatment of cardiac and/or respiratory insufficiency.

Description: NEW USE OF CREATINE DESCRIPTION This invention refers to a new use of creatme, m particular in the preparation of a drug for the treatment of cardiac and/or respiratory insufficiency. Creatme is a substance that plays an essential role m the metabolism of energy in humans and animals. A certain quantity of this vital compound is produced autonomously by our body, whereas a variable quantity is introduced through diet, basically through meat-based foods (J.B. Walker et al., in Adv. Enzymol. 1979, 50, 177-242). It is well known that the assumption of exogenous creatme can improve the capacity to make brief and intense efforts (maximum exercise) both m normal subjects and in athletes (P.L. Greenhaff, in Clinical Science (1993), 84, 565-571; P.D. Balsom et al., m Scand. J. Med. Sci . Sports 1993, 3: 143- 149) . Effects on the capacity to achieve maximum efforts have also been obtained using relatively high doses However, doses of this kind produce considerable collateral effects, such as gastrointestinal disorders, weight ga and water retention, representing a drawback to the prolonged use of creatme which is therefore not administered to improve the capacity of carrying out prolonged exercises (endurance) (P.D. Balsom et al . , in Acta Physiol. Scand. 1993, 149, 521-523). Moreover, the aforesaid doses, which are required to improve the capacity to perform maximum efforts, must be subdivided into several daily doses given that the administration of a single dose of more than 4-5 grams exceeds the so-called "renal threshold" and any excess substance is eliminated directly through urine without having performed any useful function at a systemic level. The oral administration of creatme has been studied in patients suffering from cardiac msuffiency m whom it has shown a marked capacity to increase maximum effort. Again m this case, however, the action of the substance was obtained at very high doses (15 g/die) (A. Gordon et al . , in Cardiovascular Research 30 (1995) 413-418). Owing to the aforesaid reasons, doses of this type cannot be used outside a closely contolled clinical trial performed for short periods. It is clear that the collateral effects described earlier, which are evident normal subjects, entail particularly high levels of risk for patients whose cardiovascular system is already damaged and/or fatigued by disease, thus representing a genuine obstacle to the administration of creatme. Furthermore, compared to healthy subjects, the muscular energy metabolism of patients with heart and/or respiratory disorders is further damaged (B.M. Massie et al. m Circulation - vol.78, no. 2, 1988, 320-326; B.M. Massie et al . , The American Journal of Cardiology, 1987, 60, 309-315) and treatment must not only take account of the general conditions, which are already critical owing to the underlying pathology, but also weigh up the negative effects of a reduced availability of energy. Although the results of experiments m healthy subjects show that creatme doses of under 10-15 g/die are not efficacious, much lower doses (1-4 g/die) have been used as a food supplement in the diet of elderly, debilitated and/or vegetarian subjects with a marked antiasthenic effect. Moreover, doses of this type have been much better tolerated for prolonged periods. Surprisingly, it has now been found that creatine, administered at low doses (1-4 g/die), enables an improved efficiency of energy metabolism at a muscular level and also results in a general improvement in the exercise capacity of patients suffering from cardiac and/or respiratory insufficiency. The subject of this invention is therefore the use of creatine in the preparation of a drug for the treatment of cardiac and/or respiratory insufficiency in which creatine is included at a dose ranging between 1 and 4 g/die. In particular, it was surprisingly found that the use of creatine at the aforesaid doses was extremely beneficial for the preparation of a drug for the treatment of obstructive bronchopathies at an advanced stage. The oral administration of the drug was found to be particularly well tolerated. The drug prepared according to the method described by this invention can be realised using common pharmaceutical techniques and may include, in addition to a vehicle and/or pharmaceutically acceptable diluent, also one or more active ingredients, for example: amino acids, like arginine, valine, leucine and isoleucine, complex sugars and/or antioxidants . The following example illustrates the invention but is in no way restrictive. EXAMPLE A trial was performed with seven patients suffering from advanced obstructive bronchopathy, 5 males and 2 females, mean age 67 years old; the patients were asked to perform the "walking test" in basal conditions. The test consisted in walking along a flat surface for 6 minutes. For safety reasons, and also because of the need to collect data in real-time, heart rate and oxygen desaturation in venous blood were kept under constant control. After 6 minutes, the distance walked, the final heart rate and oxygen desaturation were recorded for each patient. At the end of each test, dyspnea, or in other words the breathing difficulties experienced by each patient, were evaluated using a special 12-point scale (known as "Borg' s scale). Patients were then administered a drug including 1 gram of creatine 3 times a day, at regular intervals, and the "walking test" was then repeated after 10 days' treatment. After treatment all patients showed a marked increase in the distance covered. This improvement, approximately 32% on average compared to basal levels, was highly significant (Fig. 1 shows, in histogram form, the distances walked by the seven patients and the relative mean: p = 0.01) also following statistical analysis using Student's t- test for paired data. The administration of low doses of creatine was therefore shown to be capable of improving these patients' resistance to prolonged effort. It was also unexpectedly found that all patients had completed the exercise protocol with a lower heart rate than that measured prior to creatine treatment with the sole exception of patient 1 - excluded from the analysis of heart rate - who was only .able to walk alone for 2 minutes in the preliminary test and 3 minutes in the final test. The mean reduction (which was also significant in the statistical tests performed using Student's t- test) was around 12 beats per minute (see Fig. 2 which shows, in histogram form, the heart rates of the seven patients and the relative mean) . The lesser involvement of the cardiovascular apparatus was also confirmed by the subjective reactions of patients. Almost all of them showed a value on the Borg scale which was more than two points lower; no changes hematic desaturation were reported. The ascertainment of the lower involvement of the cardiovascular apparatus and the finding of a lower subjective perception of fatigue surprisingly showed that the administration of low doses of creatine substantially improves the efficiency of the energy metabolism at a muscular level. This result is undoubtedly of considerable importance from a clinical point of view given that the administration of low doses of creatine to patients suffering from cardiac and/or respiratory insufficiency allows them to acquire greater autonomy of mobility, increased independence and a better quality of life.

Claims: CLAIMS 1. Use of creatine in the preparation of a drug for the treatment of cardiac and/or respiratory insufficiency in which creatine ranges between 1 and 4 g/die. 2. Use in accordance with claim 1 for the treatment of advanced obstructive bronchopathies. 3. Use in accordance with claims 1 or 2, in which the drug is adminstered orally.

Inventors: ANELLI MARCO, STRUMIA ETTORE, ANELLI, MARCO, STRUMIA, ETTORE
Applicants: ANELLI MARCO, MONSANTO IT SPA, STRUMIA ETTORE, ANELLI, MARCO, MONSANTO ITALIANA S.P.A., STRUMIA, ETTORE
Application year: 1997
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P11