MXPA97008873A - Method for modular microcirculac - Google Patents

Abstract

The present invention relates to inter alia, the use of L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, of (i) a nitric oxide donor, and / or (ii) a substrate of the nitric oxide synthetase, and / or (iii) a precursor of this substrate, in the preparation of an enteric drug of a nutritional formulation to alleviate microcirculatory hypoperfusion, and / or for the treatment or prophylaxis of reperfusion injury hypoperfusion, in patients who have undergone elective surgery, characterized in that the drug or the nutritional formulation is administered preoperatively to the patient

Description

METHOD FOR MODULAR MICROCIRCULATION The present invention relates to a method for modulating the microcirculation, particularly in patients who have suffered or who must undergo elective surgery. The alteration of the icrovasculature is a key factor in the mechanisms of, among other things, hepatic, mesenteric and cardiac-reperfusion injury. Recent in vitro studies using a reflux, blood-free, low-flow perfusion liver model have shown that reperfusion injury can be reduced by improving microcirculation. For example, the perfused livers of rats previously treated with a diet of fish oil, showed a marked improvement in microcirculation, and a significant reduction in liver damage. In addition, it is also known that adenosine, a known dilator vessel and an essential component in the Caroline rinse solution, improves survival immediately after liver transplantation. The present invention provides, among other things, a drug, whose preoperative administration to patients who must undergo elective surgery, has a prophylactic effect vis-à-vis reperfusion-hypoperfusion injury in numerous microcirculatory systems. In accordance with the present invention, there is provided the use of L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, in the preparation of a medicament or nutritional formulation to alleviate microcirculatory hypoperfusion and / or for the treatment or prophylaxis of reperfusion-hypoperfusion injury in patients who have undergone elective surgery, characterized in that the medication or the nutritional formulation is administered preoperatively to the patient. Preferred precursors of L-arginine are ornithine or glutamine, and ornithine is particularly preferred. The present invention also provides a method for reducing microcirculatory hypoperfusion, and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that L-arginine, a precursor of L-arginine, is administered. arginine and / or physiologically acceptable salts thereof, preoperatively to the patient. L-arginine is the substrate for nitric oxide synthetase (NOS), the enzyme responsible for the production of nitric oxide, a highly unstable molecule that, among other things, mediates the relaxation of smooth muscle in vascular tissue. It is known that there are two forms of this enzyme present in vivo, a constitutive form sensitive to Calcium-dependent Calcium / NADPH located in the essentially endothelial cell, and an essentially independent form of calcium, whose production / activity is induced in response to , for example, metabolic tension mediated by endotoxin / cytokinin. The inducible form of nitric oxide synthetase is localized in macrophages and similar cells, such as Kupffer cells and microglial cells in the liver and nervous system, respectively. The production of endogenous nitric oxide can also increase blood flow, by reducing the number of blood elements that adhere to the lumen of the vessel. In high doses, nitric oxide can be cytotoxic and can cause oxidation injury. In accordance with the present invention, there is also provided the use of: (i) a nitric oxide donor, and / or (ii) a nitric oxide synthetase substrate, and / or (iii) a precursor of this substrate, in the preparation of a medicament or nutritional formulation for minimizing microcirculatory hypoperfusion and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that the medication or the nutritional formulation is administered preoperatively to the patient. In addition, a method is provided for reducing microcirculatory hypoperfusion, and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that: (i) a nitric oxide donor, and / or (ii) a substrate of the nitric oxide synthetase, and / or (iii) a precursor of this substrate, is administered preoperatively to the patient.

It is preferred that the treatment be started at least one day before surgery, and that the drug or formulation be administered at least during a period of one day before surgery in the event that it is to be administered parenterally. In the case of oral or enteral administration, it is preferred that the drug or formulation be administered for a period of 3 to 10 days before surgery, whereby treatment begins between 3 and 10 days (inclusive) before of surgery. As indicated above, the medicament or formulation can be administered in a form suitable for parenteral or enteral administration. The enteral route of administration is preferred; Oral administration, nasal administration and / or tube feeding are particularly contemplated. The drug or formulation is conveniently administered in the form of an aqueous liquid. The medicament or formulation in a form suitable for enteral application, according to the foregoing, is preferably aqueous or is in powder form, whereby, the powder is conveniently added to water before use. For use in tube feeding, the amount of water that will be added will depend, among other things, on the fluid requirements and the patient's condition. The beneficial effect of the use of the medicament or of the formulation of the present invention for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, is due to the improvement of the microcirculation in the respective organs. The greatest improvements in the icrocirculations are associated with the accumulation of the mesenteric, intestinal, hepatic and cardiac circulation, by the use of the medicament or of the formulation according to the invention. The amount of medication or formulation that is to be administered depends, to a large degree, on the specific requirements of the patient. In the event that the medicament or formulation comprises L-arginine (or a pharmaceutically acceptable salt thereof) or a precursor of L-arginine, such as ornithine, the patient should be administered sufficient to increase the total plasma concentration of L-arginine from the basal levels of about 70 to 85 μM to about 100 to 200 μM, preferably up to about 120 to 150 μM. The total plasma concentration of L-arginine should preferably not rise to above about 200 μM, as a consequence of the use according to the invention. The medicament or formulation can be formulated in such a way as to deliver to the patient from about 1 to about 30 grams, preferably from 5 to 18 grams of nitric oxide synthetase substrate or L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, for 24 hours, or from about 0.1 to about 20 grams of nitric oxide donor for 24 hours. However, it will be appreciated that, in particular, where the drug or formulation comprises nitric oxide donors by themselves, the patient should not be given either medication or formulation so that the (cyto) toxic effects of the drug become apparent. Nitric oxide. It is particularly preferred that the substrate of the nitric oxide synthetase be L-arginine or a physiologically acceptable salt thereof. In an individual with endotoxin / cytokinin tension, one should expect the substrate to be used by the calcium-dependent and NADPH-dependent constitutive nitric oxide synthetase synthetase, and according to the above, the invention contemplates this form of the synthetase as the goal for the L-arginine contained within the drug or formulation, or the L-arginine that results from the precursor (such as orinitin or glutamine contained within the drug or formulation), that metabolically converts to L-arginine on Ingestion / digestion by the patient. The nitric oxide donor present in the medicament or formulation can be selected from the group consisting of glycerol trinitrate, isosorbide dinitrate, nitroprusside, 3,5 '- 8-bromoguanosine monophosphate, spermine-NO, spermidine-NO, and SIN1. Angiotensin II is a powerful splanchnic vasoconstrictor, and is released in increased amounts during surgery, which is associated with a high inability of mucosal hypoperfusion of the intestine. Moreover, non-steroidal anti-inflammatory drugs and free radical scavengers could modulate the degree of mucosal hypoperfusion of the intestine, and / or the degree of consequent histological damage on reperfusion. Accordingly, the medicament or formulation conveniently further comprises free radical scavengers (superoxide) (such as vitamins C and E), and / or angiotensin-converting enzyme (ACE) inhibitors, and / or anti-inflammatory drugs. non-steroidal, such as aspirin, or ibuprofen and / or omega-3 polyunsaturated fatty acids (PUFA) that are protected in a pharmacologically acceptable manner against peroxidation. The omega-3 PUFAs can be employed in free acid form, in a form suitable for the physiological supply of omega-3 PUFA, for example, in the form of triglyceride, or in the form of pharmacologically acceptable natural sources of omega-3 PUFA . These natural sources include flaxseed oil and fish oils, such as menhaden oil, salmon oil, mackerel oil, tuna oil, cod liver oil and anchovy oil. These natural sources, in particular fish oils, comprise substantial amounts of omega-6 fatty acids. Where omega-3 PUFAs are used in the form of a triglyceride, these triglycerides may comprise esters with other pharmacologically acceptable fatty acids. Preferred omega-3 PUFAs include eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the form of free acid, in the form of triglyceride, or in the form of natural sources having a high content of EPA and / or DHA. Although the drug or formulation must be administered before surgery, there is no reason why its administration can not be continued optionally post-operatively. This optional use of the medication will naturally depend on the circumstances of the individual, but it is assumed that the use could be continued conveniently throughout the period in which the patient is hospitalized (up to 20 days), if not more. In a preferred embodiment, the present invention provides the use of L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, together with omega-3 PUFA, which are optionally protected in a pharmacologically acceptable manner against peroxidation, in the preparation of a medicament or a nutritional formulation to reduce microcirculatory hypoperfusion and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that the medicament or the nutritional formulation it is administered preoperatively to the patient. In a further preferred embodiment, the present invention provides the use of: (i) a nitric oxide donor, and / or (ii) a nitric oxide synthetase substrate, and / or (iii) a precursor of this substrate, together with omega-3 PUFA, in the preparation of a medicament or a nutritional formulation to reduce microcirculatory hypoperfusion and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that the The medication or nutritional formulation is administered preoperatively to the patient. It is particularly preferred that the substrate of the nitric oxide synthetase be L-arginine or a pharmaceutically acceptable salt thereof. The medicament or the formulation used according to the invention can (and preferably will do so) still further comprise other nutritionally convenient components, such as vitamins, minerals, trace elements., fibers (preferably soluble fibers), as well as nitrogen sources, carbohydrate sources, and additional fatty acid sources. Examples of suitable nitrogen sources include nutritionally acceptable proteins, such as proteins derived from soybeans or whey, caseinates and / or protein hydrolysates. Suitable carbohydrate sources include sugars, such as maltodextrins. Examples of suitable fatty acid energy supply sources include triglycerides, as well as di- and mono-glycerides. Examples of vitamins suitable for incorporation into the medicament of the invention include Vitamin A, Vitamin D, Vitamin K, folic acid, thiazine, riboflavin, Vitamin B6, Vitamin B12, niacin, biotin and pantothenic acid in a pharmaceutically acceptable form. Examples of mineral elements and trace elements suitable for incorporation into the medicament include sodium, potassium, calcium, phosphorus, magnesium, manganese, copper, zinc, iron, selenium, chromium and molybdenum in a pharmaceutically acceptable form. In particular, the medicament or formulation of preference will comprise beta-carotene (Vitamin A), Vitamin E, Vitamin C, thiamin and choline, in a pharmaceutically acceptable form. The term "soluble fiber", as used herein, refers to fibers that can undergo substantial fermentation in the colon to ultimately produce short-chain fatty acids. Examples of suitable soluble fibers include pectin, guar gum, locust bean gum, xanthan gum which optionally may be hydrolyzed. For adults, the total amount of soluble fiber per day will conveniently be in the range of 3 to 30 grams. The drug or formulation is primarily intended to be used as a dietary supplement. In this case, the amount of energy supplied by him should not be too excessive, in order not to unnecessarily suppress the appetite of patients. The supplement should conveniently include energy sources in an amount that supplies 600 to 1,500 kilocalories / day. The contribution of the nitrogen source, the carbohydrate source and the lipid source to the total daily caloric intake can vary within wide ranges. In the preferred forms of the drug or formulation, the carbohydrate source provides 40 to 70 percent of the total energy supply, and the source of nitrogen and fatty acid, each 15 to 30 percent of the total energy supply of the medication. The medicament or formulation can be formulated in a manner known per se, for example, by simple mixing of the ingredients. The invention will be further understood by reference to the following examples. The reflux, low-flow, liver perfusion model is used to investigate the effects of L-arginine on reperfusion injury in the absence of possible complications of the blood elements. In this model, the pericentral regions of the liver lobe become anoxic by reducing the flow rate during an initial period of perfusion. Subsequently, normal flow rates are restored, resulting in an oxygen-dependent reperfusion injury in the pericentral regions of the liver lobe.

Example 1"Low flow reflux of liver perfusion - animal model" Animals v Diets Male Sprague-Dawley rats weighing between 100 and 160 grams, are individually caged, and powdered diets containing 5 weight percent are given as corn oil, encapsulated fish oil, or fish oil encapsulated with additional L-arginine in a blind design at pleasure for 12 hours. at 19 days, or a powder diet containing 5 weight percent L-arginine for three days (Table 1). The diets are kept under nitrogen at 4 ° C, and fresh diets are provided daily. The assimilation of food is assessed by weighing the remaining diet every day. The rats are fasted for 24 hours before the perfusion of the liver.

Perfusion The rats are anesthetized with sodium pentobarbital (1 microliter / gram) before surgery, and the livers are surgically removed and perfused by means of a cannula inserted into the portal vein with a pH regulator of bicarbonate Krebs-Henseleit ( pH 7.4, 37 ° C) saturated with a mixture of oxygen-carbon dioxide (95: 5) in a non-recirculating system, as is known in the art. After surgery, the livers are perfused at flow rates of approximately 1 milliliter / gram / minute for 75 minutes (low flow). Under these conditions, the periportal areas are normoxic, while the adjacent pericentral regions are anoxic. Subsequently, the livers are perfused at normal flow rates (4 milliliters / gram / minute) for 40 minutes (reflux). The oxygen concentration in the effluent perfusate is continuously monitored with a Teflon-protected Clark-type oxygen electrode. The recovery of oxygen is calculated from the difference in concentration of the influencer minus the effluent, the flow rate and the wet weight of the liver. A three-way plug is inserted into the tubing just before the cannula enters the portal vein. A polyethylene tube (PE 240) is placed in the three-way plug perpendicular to the cannula entering the portal vein. Portal pressure is monitored for changes in the height of a column of hard water before perfusion. The common bile duct is cannulated with polyethylene tubing (PE-10); Clay Adams), and aliquots of bile are collected in vials at 15 minute intervals in the low flow period, and at 10 minute intervals during the reflux periods. The bile production indices are calculated from the weight of the bile, the intervals of time, and the wet weight of the liver.

Assays The activity of lactate dehydrogenase (LDH) in the perfusate is determined, using conventional enzymatic techniques, and malonic dialdehyde (MDA) is evaluated using thiobarbituric acid according to known methods. Briefly, three milliliters of perfusate are mixed thoroughly with a reagent containing 15 percent prechloroacetic acid, 0.375 percent thiobarbituric acid, and 0.25 N hydrochloric acid, and heated for 15 minutes in a boiling water bath. After cooling, the absorbance at 535 nanometers of the supernatant is determined. The concentration of MDA in the perfusate is calculated by comparison with the MDA standards. LDH and MDA release rates are expressed per gram in wet weight of the liver per hour. To evaluate the microcirculation in the liver, triphane blue is infused into the liver at the end of all experiments, at a concentration of 0.2 mM. The time for the liver surface to become uniformly dark blue is recorded - which is an indication of the state of the microcirculation of the livers. The results are subjected to statistical analysis where appropriate. Student's T Test or ANOVA is used, considering the significant differences in a level of P < 0.05.

Effects of Arqinine Treatment on Hepatocellular Damage in a Baio Flow Reflux Model Rat livers are perfused at flow rates of about 1 milliliter / gram / minute for 75 minutes., followed by reperfusion for 40 minutes, at flow rates of about 4 milliliters / gram / minute. Lactate dehydrogenase release rates of biliary production, malonic dialdehyde release rates, and portal pressure are determined during periods of both low flow and reflux. During the period of low flow, LDH release is minimal (about 3 international units / gram / hour in 60 minutes) in livers of rats treated with corn oil and encapsulated fish oil, and in rats fed a diet of fish oil supplemented with L-arginine. When the flow rate was increased to 4 milliliters / gram / minute, however, LDH release increased gradually, reaching a new steady state value in approximately 30 minutes. The maximum release of LDH during the reperfusion period was around 50 international units / gram / hour in the livers of the control rats, but the values were significantly reduced by treatment with encapsulated fish oil, the treatment with L-arginine, or by a combined treatment of L-arginine and encapsulated fish oil, up to around 20 international units / gram / hour. Bile production rates were around 12 microliters / gram / hour at the end of the low flow period in the corn oil controls, and were not significantly different in the group treated with encapsulated fish oil (optionally supplemented with arginine ). The maximum production of bile was increased to approximately 23 microliters / gram / hour during the reflux period in the controls, but the value reached 36 microliters / gram / hour in the livers of rats treated with encapsulated fish oil. Oxygen recovery during reperfusion was 111, 119 and 93 micromoles / gram / hour in the livers of the control rats, of the rats treated with encapsulated fish oil, and of the rats fed encapsulated fish oils supplemented with L-arginine, respectively (p >; 0.05, Student's T Test). Taken together, the reperfusion injury is minimized, which occurs when oxygen is re-introduced into the previously anoxic liver, previously feeding the rats with a diet supplemented with fish oil and arginine.

Effect of Previous Feeding with Ring: Inina On the Production of Malonic Dialdehyde MDA, a final product of lipid peroxidation, is released into the effusive perfusate at speeds around 15 nanomoles / gram / hour for 75 minutes of flow perfusion low in the livers of rats fed corn oil, fed encapsulated fish oil, fed L-arginine, and fed encapsulated fish oil and arginine. When the flow rates were restored to normal, the MDA production increased rapidly to the standard values in approximately 15 minutes, and then decreased slightly. The maximum production of MDA during the reperfusion period was around 90 nanomoles / gram / hour in the control rats, of 80 nanomoles / gram / hour in the rats treated with encapsulated fish oil, of 45 nanomoles / gram / hour in the rats treated with L-arginine, and 67 nanomoles / gram / hour in the rats previously fed with encapsulated fish oil supplemented with arginine, respectively, the differences between the different groups being not statistically significant.

Effect of Previous Feeding with Arginine on the Distribution Time of Trifan Blue The distribution time of triphane blue is an indicator of the hepatic microcirculation. It takes 10.7 minutes for the tripano blue to be uniformly distributed in the livers of rats treated with corn oil, 6.0 minutes in the case of rats previously fed with encapsulated fish oils, 3.8 minutes in the case of rats previously fed with L -arginine, and 2.8 minutes for rats previously fed with encapsulated fish oils supplemented with arginine. These results are extremely significant (p < 0.05, Student's T Test). The above description (the results of which are summarized in Table 2) clearly indicates that the previous diet with a diet rich in arginine, provides an improved microcirculation in organs that are likely to be subject to reperfusion injury-hypoperfusion, and that this protective effect of arginine is apparent, even when the diet is reduced before surgery. One of the consequences of elective surgery (as well as surgery by accident for this matter), is a partial deactivation of the microcirculations associated with the liver and heart, but particularly the mesentery / intestine. This "deactivation" facilitates the metabolic changes associated with these microcirculations, which is provided for the damage of free radicals, particularly by superoxide anions, on their subsequent reperfusion. This damage of free radicals can cause the microcirculation of the intestine to escape towards the products of digestion, in particular the components of bacterial cells. These components can enter the general circulation, and subsequently initiate toxic (endo) shock syndromes, which manifest themselves post-operatively, and whose consequences can be fatal. In the previous example, the rats were fasted for 24 hours before the perfusion of the liver. This "fasting" mimics that which is experienced by patients before elective surgery. Therefore, it is clear that prior feeding of humans with a medicament or nutritional formulation comprising L-arginine, can be expected to have a prophylactic effect vis-à-vis reperfusion-hypoperfusion injury that is otherwise experienced post -operatively. The practical significance of this prophylaxis, especially in the case of mesenteric / bowel microcirculation, can not be overestimated.

TABLE 1 Diet composition (based on corn oil) control and encapsulation of fish oil, optionally containing arginine The encapsulated fish oil is in a triglyceride form, with an EPA: DHA ratio of 18:12. The content of fatty acid is as follows: omega-3 fatty acids 35% which include: • EPA 18% fish oil • DHA 12% fish oil • Docosapentaenoic acid (DPA) 2% fish oil. • Other 3% fish oil Polyunsaturated fatty acids other than omega-3. eleven% Monounsaturated fatty acids 28% Saturated fatty acids 26% (% is by weight) The mineral mixture includes: Mineral Calcium% weight / weight of diet 0.50 Chlorine% weight / weight of diet 0.05 Magnesium% weight / weight of diet 0.04 Phosphorus% weight / weight of diet 0.40 Potassium% weight / weight of diet 0.36 Sodium% weight / weight of diet 0.05 Sulfur% weight / weight of diet 0.03 Chromium mg / kg of diet 0.30 Copper mg / kg of diet 3.00 Fluorine mg / kg diet 1.00 Iodine mg / kg diet 0.15 Iron mg / kg of diet 35.00 Manganese mg / kg diet 50.00 Selenium mg / kg diet 0.10 Zinc mg / kg of diet 12.00 The mixture of vitamins includes, per kilogram of diet; A (D 4,000.00 U D (2) 1,000.00 U E < 3 > 30.00 U Kl 50.00 μg Hill 1,000.00 mg Folic acid 1.00 mg Niacin 20.00 mg Pantothenate (calcium) 8.00 mg Riboflavin 3.00 g Thiamine 4.00 mg Vitamin B6 6.00 mg Vitamin B12 50.00 μg (1) Vitamin A: 1 International Unit = 0.500 μg retinol. (2) Vitamin D: 1 International Unit = 0.025 μg of ergocalciferol. (3) Vitamin E: 1 International Unit = 1 mg of DL-α-tocopheryl acetate.

TABLE 2 Effects of the diet containing fish oil, and containing fish oil and arginine, on the microcirculation of perfused rat livers fifteen p < 0.05 against the diet of corn oil and fish oil p < 0.05 against the corn oil diet Example 2"Patient Study" To assess whether preoperative administration of a supplemented enteral formula (see Table 3) results in improved microcirculation in patients undergoing major elective abdominal surgeries, intraoperative mesenteric blood flow (with Doppler) was measured at laparotomy and at end of surgery, and intraoperative mucosal pHi and oxygenation (tonometry) in laparotomy and at the end of surgery. The monitoring of gastrointestinal mucosal perfusion by tonometry during major surgery and soon after trauma appears to be a very sensitive method to predict the development of organ failure and poor outcomes. It has repeatedly been shown that patients with low pHi after injury have a high risk of morbidity and mortality. The study included 40 patients who underwent radical surgery for gastric, pancreatic and colorectal cancer. Patients were randomized into two groups: Group A - who received preoperative enteral supplemented formula by oral route for 7 days before surgery, plus post-operative nutrition from the end of the operation for 7 days, and Group B - who received a pre-operative enteral control diet through the oral route for 7 days before surgery, plus post-operative nutrition from the end of the operation for 7 days. The composition of the diets is reported in Table 3.

Patients drank one liter of supplemented enteral formula or daily control formula (for 7 days before surgery), corresponding to 1,000 kilocalories / day, and were allowed to eat a standard diet in a contemporary manner. Postoperatively, the two groups received the same energy (25 kilocalories / kilogram / day) ingestion of nitrogen (0.25 grams of N / kilogram / day). Plasma arginine levels one day before surgery were approximately 65 + 20 micromoles / liter for Group B, and approximately 105 + 46 micromoles / liter for Group A.

TABLE 3 Composition of diets (per 100 milliliters) The measurement of intraoperative intestinal icroperfusion measured by Doppler Laser is given in the following Table 4: TABLE 4 Laser-Doppler measurement of blood flow in perfusion units (UP) * vs. Standard + vs. Final The jejunal mucosal pH and postoperative tonometry are given in the following Table 5: TABLE 5 Postoperative tonometry, measurement of the pHi of the intestinal mucosal oxygen metabolism * p < 0.05 vs. Control Although an adequate blood flow is not a guarantee of good tension, delivery and utilization of oxygen in the tissue, the data given above show that a higher intestinal microperfusion, measured directly by the Doppler Laser flowmetry technique, is parallel to a better oxidative metabolism of the intestinal mucosa.

Although the invention has been particularly described with respect to the specific examples above, the skilled person will understand that the invention is not limited to this, but includes all logical developments. For example, the invention further provides the use of L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, or of a nitric oxide donor, and / or of a nitric oxide synthetase substrate, and / or a precursor of said substrate in the preparation of a medicament or a nutritional formulation for the prevention and / or reduction of the activation or adherence of neutrophils, or for the prevention and / or reduction of free radical damage mediated by the superoxide anion, in patients who have undergone elective surgery, characterized in that the drug or the formulation is administered preoperatively to the patient.

Claims (13)

NOVELTY OF THE INVENTION Having described the foregoing invention, it is considered as a novelty and, therefore, the content of the following is claimed as property: CLAIMS

1. The use of L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, in the preparation of a medicament or a nutritional formulation to ameliorate microcirculatory hypoperfusion, and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that the medication or the nutritional formulation is administered preoperatively to the patient.

2. The use of (i) a nitric oxide donor, and / or (ii) a nitric oxide synthetase substrate, and / or (iii) a precursor of this substrate, in the preparation of a medicament or a nutritional formulation to reduce microcirculatory hypoperfusion, and / or for the treatment or prophylaxis of reperfusion injury-hypoperfusion, in patients who have undergone elective surgery, characterized in that the medication or the nutritional formulation is administered preoperatively to the patient.

3. The use according to claim 1 or claim 2, wherein the administration is initiated at least one day before surgery.

4. The use according to claim 1 or claim 2, wherein the administration is initiated between 3 and 10 days (inclusive) before surgery.

5. The use according to any of claims 1 or 3, wherein the medicament or formulation is administered enterally, orally and / or parenterally.

6. The use according to any of the preceding claims, wherein the medicament or formulation is formulated in such a way as to deliver to the patient approximately 1 to 30 grams of nitric oxide substrate or L-arginine, a precursor of L- arginine and / or physiologically acceptable salts thereof, for 24 hours, or approximately 0.1 to 20 grams of donor for 24 hours. The use according to any of the preceding claims, wherein the medicament or formulation is administered to the patient in an amount such that the total concentration of nitric oxide substrate or L-arginine, a precursor of L-arginine, and / or physiologically acceptable salts thereof, in the plasma of the patient, is from about 100 to about 200 μM. 8. The use according to any of the preceding claims, wherein the nitric oxide substrate is L-arginine or a physiologically acceptable salt thereof. 9. The use according to any of the preceding claims, wherein the precursor is ornithine or glutamine, which, upon ingestion / digestion by the patient, is etabolized into L-arginine. The use according to any of the preceding claims, wherein the donor is selected from the group consisting of glycerol trinitrate, isosorbide dinitrate, nitroprusside, 3,5'-8-bromoguanosine monophosphate, spermine-NO , spermidine-NO, and SIN1. The use according to any of the preceding claims, characterized in that the medicament or formulation further comprises at least one compound selected from the group consisting of superoxide free radical scavengers, angiotensin-converting enzyme inhibitors (ACE) ), non-steroidal anti-inflammatory compounds, omega-3 polyunsaturated fatty acids that are produced in a pharmacologically acceptable manner against peroxidation, vitamins, mineral elements, soluble fiber, caseinates or protein hydrolysates, and omega-6 polyunsaturated fatty acids. 12. The use of L-arginine, a precursor of L-arginine and / or physiologically acceptable salts thereof, a nitric oxide donor, and / or a nitric oxide synthetase substrate, and / or a precursor thereof substrate, in the preparation of a drug for the prevention or reduction of activation and / or adherence of neutrophils, or for the prevention or reduction of free radical damage mediated by superoxide anion, in patients who have undergone elective surgery, characterized in that the drug or formulation is administered preoperatively to the patient. The use according to any of the preceding claims, characterized in that the medicament or formulation further comprises omega-3 polyunsaturated fatty acids, which are optionally protected in a pharmacologically acceptable manner against peroxidation.