MXPA00001267A - Peritoneal dialysis fluid - Google Patents
Peritoneal dialysis fluidInfo
- Publication number
- MXPA00001267A MXPA00001267A MXPA/A/2000/001267A MXPA00001267A MXPA00001267A MX PA00001267 A MXPA00001267 A MX PA00001267A MX PA00001267 A MXPA00001267 A MX PA00001267A MX PA00001267 A MXPA00001267 A MX PA00001267A
- Authority
- MX
- Mexico
- Prior art keywords
- peritoneal dialysis
- dialysis fluid
- fluid according
- hydrogenated
- sugar
- Prior art date
Links
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Abstract
The present invention relates to novel peritoneal dialysis fluids and to the use thereof for performing peritoneal dialysis. The peritoneal dialysis fluid comprises a physiologically acceptable aqueous solution containing physiological acceptable inorganic anions and cations and as an osmotic agent, at least onesugar derivative, said physiological acceptable inorganic anions and cations and said at least one sugar derivative being present in concentrations sufficient for the removal of water and solutes from a patient by peritoneal dialysis, characterised in that the sugar derivative is a compound of formula (I) wherein the or each SG, which may be the same or different, represents a residue of a physiologically acceptable metabolizable sugar, SA represents a residue of aphysiologically acceptable metabolizable sugar alcohol, n is from 1 to 4 and (ag) represents a glycoside linkage that is capable of being cleaved by an a-glycosidase enzyme.
Description
ITONEAL PE DIALYSIS FLUID
FIELD OF THE INVENTION The present invention relates to novel fluids for peritoneal dialysis and to the use thereof for performing peritoneal dialysis.
BACKGROUND OF THE INVENTION In the human body, the transfer of solutes and toxins from one body fluid compartment to another occurs through a variety of chemical and physical processes that include diffusion, osmosis and active transport. In this regard, toxins, excess water and solutes are transferred from the tissues to the bloodstream and then through the arteries to the kidneys. In the kidneys, the substances that are going to be eliminated can be metabolized and eliminated in the urine. In kidney disease, the function of the kidney is not sufficient to maintain an adequate degree of elimination, in this way the accumulation of water and uraemic toxins occurs in the body. Currently, the medical treatments available for patients suffering from kidney dysfunction are kidney transplantation, extracorporeal hemodialysis or intracorporeal peritoneal dialysis, alternatively. Treatment by transplant of
P1096 / 00MX kidney continues to be the preferred therapy since patients can lead an almost normal life. Hemodialysis (an extracorporeal procedure) and peritoneal dialysis (an intracorporeal procedure) are alternative therapies to treat patients with end-stage renal disease (ESRD). Peritoneal dialysis is a well established intracorporeal procedure that is currently used as an alternative for extracorporeal hemodialysis. In fact, in many cases, peritoneal dialysis is preferred over extracorporeal therapy. However, in some medical centers, hemodialysis technology is not available and the cost of peritoneal dialysis, in general, may be lower when other complementary medical care procedures are excluded. For some patients, the surgery required to prepare permanent blood access has not been successful.
Finally, some nephrologists prefer peritoneal dialysis as a hemodialysis procedure, because it uses a natural membrane and the function of the residual kidney (what remains) can be maintained for a prolonged period after starting therapy. In dialysis peritoneal a dialysis fluid is introduced with the help of a catheter into the peritoneal cavity in the abdomen of the patient.
P1096 / 00 X This catheter is implanted permanently by surgery through the abdominal wall. The peritoneal cavity is flooded with the dialysis fluid, left for an appropriate period of time and then drained. Peritoneal dialysis is based on the physiological activity of the peritoneum. The peritoneum is a layer of mesothelial cells that contain large amounts of capillaries and blood vessels. These facilitate the use of the peritoneal cavity as a semipermeable membrane. The peritoneal dialysis procedure comprises the introduction of a fluid into the peritoneal cavity for a suitable period of residence. This allows an exchange of solutes between the dialysate and the blood during the residence time of the dialysate in the peritoneum. This residence time (also called residence time) varies from patient to patient and can be approximately five hours. Consequently, the frequency with which the dialysate has to be changed is, on average, four to five times per day. The removal of uraemic toxins takes place through the peritoneal membrane by diffusion and the excess water in the body is removed by means of osmotic pressure induced by an osmotic agent such as glucose. Glucose is currently the standard osmotic agent and is used in general, in a
P1096 / 00MX concentration in the dialysis fluid (% weight by volume) from 1.36 to 4.25. As indicated, glucose is currently included in the dialysis fluid to impart the necessary osmotic gradient, that is, it is the standard osmotic agent for dialysis solutions. However, because it is introduced into the peritoneal cavity, it will find its way into the bloodstream during therapy. In fact, glucose crosses the peritoneum so rapidly that the magnitude of the osmotic gradient falls within 2 to 3 hours after the dialysate injection. This results in the unwanted result of water being reabsorbed from the dialysate towards the end of the dialysis period, i.e., before the dialysis fluid is replaced with fresh fluid. In addition, the amount of glucose that is absorbed represents a large portion of the patient's energy uptake, possibly as high as 15 to 40%. The clinical consequences are hyperglycemia and obesity. In addition, sugar has undesirable long-term effects, especially for diabetic patients, for whom there is an additional requirement to increase the injection of the insulin dose or to introduce additional insulin into the dialysis fluid. An additional negative effect when using glucose is the advanced glycosylation formation of
P1096 / O0MX proteins in diabetic and uraemic patients, due to a high concentration of glucose, which is not rapidly metabolized. This disadvantage may be the cause of damage to the peritoneal membrane during therapy and may also be responsible for sclerosis in the membrane, which decreases the elimination of salt. The reduction of advanced glycated end-product uremia (AGE) in the peritoneal membrane is today a considerable new factor in assessing the performance of dialysis therapy1. The glycosylation of the membrane protein matrix of the peritoneum in CAPD patients has been shown to be followed by continuous ambulatory peritoneal dialysis (CAPD - continuous ambulatory peritoneal dialysis). The local biological effects of AGE on peritoneal cells have been demonstrated in vi tro and include the activation of mesothelial cells and the pathological change of the peritoneal cell matrix that can cause sclerosis. One of the most important and difficult aspects of peritoneal dialysis is finding an adequate osmotic agent for dialysate preparation, by means of which the required osmotic pressure can be achieved without the secondary problems mentioned above. An appropriate osmotic agent must have the following properties: it must meet the needs of dialysis
P1096 / 00MX peritoneal; it must be a non-toxic substance; the accumulation of unacceptable metabolites or derivatives in the peritoneum or circulation should be avoided; it must not rapidly cross the peritoneal membrane into the blood and in this respect it must allow maintenance of the required ultrafiltration; it must not react with the peritoneum or with proteins that lead to secondary reactions that include pathology of the peritoneal membrane or of peritoneal cells or of cells coming from the circulation; it must not alter the cellular function which can reduce the natural local phagocytosis and the capacity of the immune system to kill the bacteria. To date, various osmotic agents have been proposed, such as: dextran2, fructose3, xylitol4, sorbitol6, polyglucose7, 8, amino acids9, glycerol10, peptides11 and plasma substitutes12, but most of these have not completely met medical needs. In Dolkart R.E. WO 82/03987 has suggested the use of a monosaccharide sugar alcohol as glycerol, as an alternative osmotic agent to overcome glucose overload, mainly in diabetic patients. In addition, xylitol and sorbitol have also been proposed in the 1970s. However, when they are provided in their pure form and in sufficient quantity to exert ultrafiltration
P1096 / 00MX transperitoneal, all these sugar alcohols have a high transperitoneal absorption and lead to their accumulation in the blood at a speed above the speed of their metabolic elimination, thus causing several adverse reactions. In U.S. Patent No. 3,911,915 to Seifter et al., A disaccharide in the maltose form has been proposed for intraperitoneal use. Although maltose has been shown to have beneficial effects after intravenous administration14 with regard to the need for insulin and glucose overload when compared to glucose, this substance was not provided as an adequate osmotic agent in peritoneal dialysis. The use of high molecular weight polyglucose has been proposed by Milner in U.S. Patent No. 3,928,135 for use as ingredients for oral or intravenous administration, and by Alexander in No. WO 83/00087 for special use as an osmotic agent. in peritoneal dialysis. This proposal by Alexander is based on the concept that an iso-osmotic solution containing polyglucose exerts transperitoneal ultrafiltration. Although glucose polymers appear to be well tolerated by patients, plasma oligosaccharide concentrations increased dramatically and chronically. The long-term effects of these
P1096 / 00MX levels are not yet known. In this regard, the long-term effects that result in storage diseases with blockage problems of the reticulo-endothelial system that are known to have high molecular weight plasma substitutes13 are speculated. On the other hand, the effects of the accumulation and circulation of high molecular weight oligosaccharides can increase the levels of Maillard and Amadori complex products. These include glucosed end products. A particular undesirable effect is that Agaric products formed from polyglucose (the early and reversible stage of glycosylation) have a strong inhibitory effect on the activity of the a-glucosidase enzyme which is responsible for the metabolism of the oligosaccharide.
SUMMARY OF THE INVENTION In accordance with one aspect of the present invention, a dialysis fluid is provided, the fluid comprises a physiologically acceptable aqueous solution containing physiologically acceptable anions and inorganic cations and, as the osmotic agent, at least one sugar derivative; the physiologically acceptable anions and inorganic cations and at least one sugar derivative are present in concentrations sufficient for the removal of water and solutes from a patient by means of dialysis
P1096 / 00MX peritoneal, characterized in that the sugar derivative is a compound of the formula:
[SG] n. { ag) [SA] wherein the SG or each SG, which may be the same or different, represents a residue of a physiologically acceptable metabolizable sugar, SA represents a residue of a physiologically acceptable metabolizable sugar alcohol, n is 1 to
4 and represents a glycoside linkage that is capable of being cleaved by an α-glucosidase enzyme. Preferably, n is 1 or 2. However, as indicated, n may also be 3 or 4. Preferably, the adduct of the formula [SG] n, ag [SA] is a hydrogenated oligosaccharide
(especially a hydrogenated a-D-oligosaccharide). Preferred in a special way are the compounds wherein the or each SG represents a glucose residue. When the term "hydrogenated oligosaccharide" is used herein to refer to a compound of the formula [SG] n rag [SA], such use does not necessarily mean that the substance in question has been prepared or manufactured by hydrogenation of a starting material of oligosaccharide, although such a method of preparation is possible. In this way, the adducts of the formula [SG] n ^) [SA] can be prepared by chemical or enzymatic methods where the residues of the
P1096 / 00MX formulas [SG] and [SA] are linked together, or different residues [SG] and [SA] are exchanged with each other. When hydrogenation processes are used, a compound of the formula: [SG] n (ag) [SG] can be hydrogenated to form a compound of the formula: [SG] n (flg) [SA] Similarly, the term "Sugar alcohol" as used herein, is used interchangeably with the term "polyol" to refer to residues obtainable by hydrogenation of sugar residues. As far as the inventor of this invention is aware, hydrogenated oligosaccharides have not been suggested to date for intravenous or intraperitoneal perfusion. The specific hydrogenated oligosaccharides have, however, been studied as oral ingredients with respect to their digestion and absorption in the intestinal tract and are believed to be non-toxic and safe to use. In this way, the degree to which oligosaccharides can be modified to create a more suitable substance than glucose has been studied to date only with the aim of reducing caries, reducing the need for insulin in diabetic patients and to reduce the expense of energy, and as sweeteners for oral ingestion.
P1096 / 00MX The methods applied to make these compounds include transglucosidation, to form the glucosyl bond (1-6) and (1-4) and the desirable chemical reduction of a carbonyl group in the corresponding polyol entity. A) Yes, the so-called Palatinit *, an equimolar mixture of alpha-D-glucopyranoside-1,6-sorbitol and alpha-D-glucopyranoside-1,6-mannitol has been prepared by microbial transglucosidation, followed by chemical reduction. The terms "oligosaccharide alcohol" or "hydrogenated oligosaccharide" have been proposed by Grupp et al. by describing the Palatinit as a hydrogenated palatinose15. The known oligosaccharides having polyol entities have also been synthesized by Ducan et al18, Sawai &; Hehre19, Lindberg20, Fischer and Seyferth21. The invention in its more specific aspects relates to the application of hydrogenated aD-oligosaccharides as new osmotic agents in peritoneal dialysate, specifically, compounds having an aD-glucosyl arrangement with glucosyl bonds (1-> 6) or ( 1-> 4) wherein the non-reducing sugar at the end of the glucosyl array has been hydrogenated. The hydrogenated alpha-D-oligosaccharides used in accordance with the invention include, but are not limited to, those that can be isolated as a naturally occurring entity, or can be derived in synthetic form by known chemical or enzymatic reactions
P1096 / 00MX from available natural carbohydrate substrates. The oligosaccharides used in this invention desirably result from the modification of natural carbohydrates by transglucosidation, for example, by replacement of constituent monosaccharide (s) by blocks of different construction (saccharide units), and chemical reduction of carbonyl groups in a corresponding polyol entity. The preferred resulting hydrogenated alpha-D-oligosaccharides can be used in homogeneous form or as mixtures and may contain, desirably, between one or two glucosyl units plus a terminal polyol (i.e., a unit at the end of the glucosyl chain). ). In this way, the invention, in its preferred aspects, relates to the use of modified oligosaccharides, more particularly to hydrogenated alpha-D-oligosaccharides with glucosyl bonds (1-6) or a (1-> 4) specifically (also called oligosaccharide alcohols) to replace the glucose monohydrate or the glucose polymers in peritoneal dialysis. The hydrogenated alpha-D-oligosaccharides can be designed to be well tolerated and metabolized in uraemic patients. The use of hydrogenated alf-D-oligosaccharides in formulations may result in low levels of transperitoneal absorption, biocompatibility in
P1O96 / 00MX terms cellular function and effect on the peritoneal matrix, an effective osmotic effect of longer duration (time of permanence), and the reduction of the insulin requirement in diabetic patients. Preferred aspects of the invention are based on specific selections of the glycosyl arrangement of the oligosaccharide alcohol, the number of glucosyl groups, the identities of the terminal polyols (sugar alcohols), and the proportion in the mixture of different polyols. In carrying out the invention, the manufacture of the hydrogenated alpha-D-oligosaccharide can be based on (i) transglucosidation to form glycoside bonds (1-> 6) and (1-> 4) and the replacement of constituent monosaccharides by blocks of different construction, or (ii) chemical reduction of the last sugar of a disaccharide and / or trisaccharide. In accordance with preferred aspects of this invention, hydrogenated oligosaccharides with glycosyl linkages specifically (1-> 6) or (1- »4) are used to make dialysis solutions. More preferably, the dialysis solutions are aqueous solutions with a pH between 5.4 and 7.4, and preferably in the physiological pH range of from 7.0 to 7.4. The solutions of this invention can usually contain inorganic physiological salts which are commonly used in dialysate solution
P1096 / 00MX peritoneal, for example, sources of Na +, K +, Ca + and Cl ions. "Regulators to be used in the solution to achieve correction of metabolic acidosis may include lactate, bicarbonate, pyruvate or a combination of pyruvate and bicarbonate The proportion of the hydrogenated oligosaccharide can vary, but would normally be in the range of about 1 to 60% by weight of the dialysate solution.The hydrogenated oligosaccharide can thus be added to a solution of water that normally contains from 116 to 140 mEq / liter of sodium, from 0 to 5 mEq / liter of calcium, from 100 to 144 mEq / liter of chloride and from 5 to 40 mEq / liter of bicarbonate and / or pyruvate and / or lactate.The hydrogenated alpha-D-oligosaccharides of the invention are those which possess one and / or two glucosyl units plus a non-reducing terminal sugar alcohol or a polyol unit.These sugar polyols or alcohols are preferably those which are easily metabolized in humans. They include glucitol (sorbitol), xylitol, ribitol and glycerol. Preferably, the oligosaccharide alcohols with the defined defined terminal sugar polyols or alcohols are mixed in proportions to ensure that the respective terminal metabolites remain below the metabolic capacity of the patients (usually
P1096 / 00MX uraemic) that are treated. The oligosaccharide alcohol used in the invention includes those which can be isolated as naturally existing entities, or those which can be synthetically derived using known chemical or enzymatic reactions from available natural carbohydrate substrates. In accordance with a further preferred aspect of this invention, hydrogenated disaccharides with a molecular weight of from 254 to 368 PM can be used as a complete substitute or as a partial glucose substitute. However, a mixture of hydrogenated alpha-D-oligosaccharide obtained by chemical reduction of a carbonyl group in different polyol entities is preferred. The use of hydrogenated disaccharide is preferred, which at the same time represents the most economical and realistic way to produce hydrogenated disaccharide that is metabolized through the action of alpha-glucosidase, without risk to patients. The most suitable hydrogenated alpha-D-oligosaccharides that can be applied in peritoneal dialysis are 0-alpha-D-glucopyranoside-1, 6-sorbitol (GPSorbitol), 0-alpha-D-flucopyranoside-1, 4-D-Xylitol (GPXilitol),
0-alpha-D-glucopyranoside-1,6,6, ribitol (GPRibitol), 0- alpha-D-glucopyranoside-1,6, glycerol (GPGlycerol).
P1096 / 00MX These respectively contain sorbitol, xylitol, ribitol and glycerol terminal residues bound to a single glucose residue. According to the invention, the proportions of the various oligosaccharide components can be adjusted to take into account the fact that part of the oligosaccharide alcohol that enters the bloodstream by transperitoneal absorption must be metabolized to avoid high blood oxygen. For example GPSorbitol, GPXilitol, GPRibitol and GPGlicerol are rapidly metabolized and can be included in a relatively high concentration. On the other hand, the hydrogenated alpha-D-oligosaccharide that includes terminal mannitol, arabitol and dulcitol residues, must be absent in a desirable manner, or included in a very low proportion (preferably less than 1%) because they are metabolized more slowly . Preferably, mixtures of hydrogenated disaccharide alpha-D-oligosaccharide are used. Optimal formulations comprise mixtures of GPSorbitol, GPXilitol, GPGlicerol and GPRibitol. These may be present in approximately equal amounts, i.e. a mixture of 25% each. Alternatively, a mixture of hydrogenated alpha-D-oligosaccharides derived from disaccharides and trisaccharides with a molecular weight of 256 to 524 can be used, as a complete substitute or as
P1096 / 00MX partial glucose substitute. These may be based on the conversion of natural carbohydrate substrates such as standard partial corn starch hydrolysates into hydrogenated oligosaccharides. The proportion in the resulting mixture of hydrogenated oligosaccharides of disaccharides and trisaccharides can vary between 1% and 99%. The most suitable hydrogenated alpha-D-oligosaccharides that can be applied to peritoneal dialysis are similar to those prescribed in the disaccharide form, except that the average number of glucosyl residues is between one and two. Alternatively, a preparation of hydrogenated trisaccharide of homogeneous molecular weight can be used as a complete substitute or as a partial substitute for glucose. According to the invention, the use of hydrogenated trisaccharides of molecular weight 524 may have the advantages that the transperitoneal absorption is lower than that of the hydrogenated oligosaccharide in the disaccharide form, and after the hydrolysis in the circulation there are fewer generated polyols. Therefore, osmolality and metabolic half-life are relatively reduced compared to the disaccharide form. Naturally occurring naturally occurring carbohydrate substrates, which may be included in the preparation of hydrogenated alpha-D-oligosaccharides useful in the present invention, may comprise
P1096 / 00MX products of the standard partial hydrolysis of corn starch. These normally contain 11% maltose and 9.1% trisaccharide. The hydrogenated alpha-D-oligosaccharide prepared in the most convenient manner is alpha-D-glucopyranoside-1,6-sorbitol, which can be obtained by microbial transglucosidation by Pro ajnino-Jbac erio rubrum of sucrose in alpha-glucopyranoside-1, 6 -fructose (palatinose or isomaltulose), followed by chemical reduction of palatinose in the mixture of GPSorbitol and GPMannitol16. The isomeric disaccharide alcohols can be fractionated by fractional crystallization of aqueous solution17. Using the same principles, other hydrogenated alpha-D-oligosaccharides can also be prepared such as, for example: 0-alpha-D-glucopyranoside-1,4-D-xylitol 18 O-alpha-D-glucopyranoside-1,6-glycerol , hydrogenated trisaccharides with glucosyl 20,21 (1? 6) or (1? 4) bonds can also be prepared in the same way. Preferably, up to 60 grams of hydrogenated oligosaccharide in the form of disaccharide or trisaccharide can be present per liter of peritoneal dialysis solution. This range of concentrations can be used for all formulations regardless of the molecular weight of hydrogenated oligosaccharides and independently of the mixtures used. In the formulation of solutions for
P1096 / 00MX dialysis based on hydrogenated disaccharides comprising homogenous or equimolar mixtures of GPSorbitol, GPXilitol, GPRibitol and GPGlicerol with molecular weights in the range of 254-368 and with an average of 353, various concentrations can be used to achieve osmolality and ultrafiltration desired. Preferably, 1 to 60 grams per liter of peritoneal dialysis fluid can be used. Added to a standard solution for peritoneal dialysis containing physiological saline concentrations, this represents an osmolality range of between 280 milliOsmoles / kg and 460 milliOsmoles / Kg. In the formulation of solutions for dialysis based on hydrogenated trisaccharide comprising homogenous or equimolar mixtures of
[GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Ribitol and
[GP] 2Glycerol with the molecular weight in the range of
416-524 and an average of 497, again, various concentrations can be used to achieve desirable osmolality and ultrafiltration. Preferably, 1 to 60 grams per liter of peritoneal dialysis fluid can be used. Added to a solution for standard peritoneal dialysis that contains physiological salt concentrations, this represents a range of osmolality between 280 milliOsmoles / kg and 405 milliOsmoles / Kg. In the dialysis solution formulation
P1096 / 00MX based on an equimolar mixture of disaccharide and trisaccharide hydrogenated with a molecular weight in the range of 254-524 and an average of 425, again several concentrations can be used to achieve desirable osmolality and ultrafiltration. Preferably, 1 to 60 grams per liter of peritoneal dialysis fluid can be used. Added to a standard solution for peritoneal dialysis that contains physiological salt concentrations, this represents a range of osmolality between 280 milliOsmoles / kg and 420 milliOsmoles / Kg. Typically, when compared to a 4.25% glucose peritoneal dialysis solution, a 4% hydrogenated disaccharide-based formulation produced a similar ultrafiltration profile at residence times of 6 to 7 hours, and a higher ultrafiltration profile at residence times between 8 and 12 hours, despite a lower initial osmolality (395 versus 485 milliOsm / Kg). A formulation based on hydrogenated trisaccharide produced a similar ultrafiltration profile at 7-8 hours of residence, and a higher ultrafiltration profile above the residence time of 10 hours. Preferably, a hydrogenated disaccharide formulation for peritoneal dialysis with a short residence period during the day can be used, and a trisaccharide formulation can be used for residence time
P1096 / 00MX prolonged for overnight therapy. The use of hydrogenated oligosaccharide reduces the body's glucose load by approximately 40 to 60%, resulting in a lower energy intake. For example, during peritoneal dialysis with both hydrogenated disaccharide and / or trisaccharide formulations, free circulating fatty acids (a parameter that reflects caloric intake) decrease up to 50% compared to the use of a peritoneal glucose solution. This can reduce elevated triglycerides in patients receiving peritoneal glucose dialysis. In addition, the reduction of high levels of circulating glucose in uraemic patients can also reduce the risk of the generation of advanced glycated end products, an advantage that includes a possible health benefit in the pathology of uremia and in particular, in diabetic nephropathy. Reducing sugars such as glucose, oligosaccharide and polyglucose containing carbonyl groups in the sugar unit react with free amino groups of proteins to form labile Schiff bases which undergo Amadori rearrangement to stable ketoamines. This process is called glycosylation and has been found to increase in diabetes and uremia. Amadori products pass very slowly through a series of rearrangement reactions (Maillard reactions) that result in the
P1096 / 00MX formation of cross-linked glucose and brown fluorescent proteins or advanced glycation end products (AGE advanced glycation end), and they play an important role in the aging process, late uremic and diabetic complications. In this invention, the hydrogenated oligosaccharides having the alpha-D-glucosyl arrangement with glucosyl bonds (1-> 6) or (1-> 4) wherein the non-reducing sugar at the end of the glucosyl array has been hydrogenated, do not contain a terminal carbonyl group (see oligosaccharides or sugar monohydrates). Due to the lack of terminal carbonyl groups, the Maillard reaction does not occur which induces the formation of advanced glucose proteins in the peritoneal cavity. This has the advantage that the matrix of the peritoneum and the peritoneal endothelial and mesothelial cells that form the peritoneal membrane are not altered by the possible action of the glucoseed protein, leading to fibrosis and protein cross-linking that can destroy the natural membrane. Formulations of peritoneal solutions, free of carbohydrates without terminal carbonyl groups, can be lyophilized at physiological pH intervals without the risk of caramelization and the formation of a dark color during industrial processing. Glucose monohydrate and normal oligosaccharides should
P1096 / 00HX should be maintained during lyophilization procedures at acidic pH ranges of 5.2 to 5.6, to avoid caramelization of sugars and to reduce the production of sugar degradation products. The use of peritoneal solution based on glucose-acid has cytotoxic effects on the perifoneal cells that lead to the alteration and inhibition of natural immunological protection such as cytokine production and bacterial killing properties. Hydrogenated oligosaccharides having a molecular weight greater than glucose monohydrate diffuse less rapidly through the peritoneal membrane. For example, transperitoneal absorption of solution of disaccharides or hydrogenated trisaccharides at concentrations of 1% to 4% is reduced between 20% to 40% compared to a 4.25% glucose solution for a residence period of 8 hours. The reasons for low peritoneal absorption of hydrogenated oligosaccharide is probably not only due to its higher molecular weight but also due to the lack of hydrogenated oligosaccharide receptors on endothelial and mesothelial cells that would otherwise accelerate transport. Replacement (or partial replacement) of glucose by alcohol oligosaccharide in peritoneal dialysis may reduce the requirement for insulin
P1096 / 00MX and the body glucose load is significantly reduced. For example, after the venous infusion in rats, of 0.6 grams of a formulation of hydrogenated disaccharides or mixed hydrogenated trisaccharides, the insulin increase was reduced by an average of 50% when compared to the same amount of glucose infusion. The hydrogenated oligosaccharides absorbed transperitoneally are rapidly metabolized predominantly in the liver by the action of cellular lysosome maltase acid which acts during the first hour, cleaving 50% glucose and 50% polyols for the hydrogenated oligosaccharide formulations, or by cleaving 75% glucose and 25% polyols for the hydrogenated trisaccharide formulations. Although a large portion of the metabolites are glucose, it does not require insulin for additional metabolism. For example, the metabolic response to a venous infusion of 0.6 grams of a formulation of hydrogenated trisaccharides or hydrogenated disaccharides mixed in experiments with rats demonstrated a total metabolism of the hydrogenated oligosaccharide and the resulting final metabolites, such as glucose and polyols, after 120 minutes The urinary excretion of all the metabolites represented only a maximum portion of 10%, which shows that under uremic condition there is no risk in the accumulation of
P1O96 / 00MX hydrogenated disaccharides and hydrogenated trisaccharides. It is after these experiments with these animals that the rate of transperitoneal adsorption of hydrogenated alpha-D-oligosaccharide with 100% hydrolysis occurring in the first two hours and inducing the cleavage of glucose and polions can not exceed the metabolic capacity of Polyol of the body even under uraemic conditions. In the case of the formulation of peritoneal solution of trisaccharide and hydrogenated disaccharide at a concentration between 0.1 and 6% provides an osmolality to effect the required ultrafiltration and exchange, the net weight of glucose that is received in the bloodstream after the total metabolism is reduced by 50% to 75%, compared to a corresponding glucose solution. Furthermore, in the case of the formulation of peritoneal solution of trisaccharide and hydrogenated disaccharide at a concentration of between 0.1 and 6%, it provides an osmolality to effect the required ultrafiltration and exchange, the net weight of polyols that are received in the blood circulation after the The metabolism is 25% to 50%, compared to a polyol solution such as a glycerol, sorbitol or xylitol solution. In this way, a mixed formulation containing 2 to 3 types of hydrogenated oligosaccharide, as
P1096 / 00MX proposes in the preferred aspects of this invention, it will significantly reduce the net weight of the polyols that are received in the blood. In the case of a homogeneous formulation containing hydrogenated disaccharides at a concentration of between 0.1 and 6%, the maximum doses of final metabolites of xylitol or sorbitol, or glycerol or ribitol are calculated to be between lOg / day and 60g / day. Respectively, a homogeneous formulation containing hydrogenated trisaccharide, will induce a maximum dose of between 5g / day and 30g / day. In the case of an equimolar mixture containing different hydrogenated disaccharides at a concentration of between 0.1 and 6%, the maximum dose of final metabolites of xylitol and sorbitol, and glycerol and ribitol are calculated to be between 2.5g / day and 15g / day . Similarly, an equimolar mixture containing hydrogenated trisaccharide will induce a maximum dose of between 1.25 g / day and 7.5 g / day. The use of a mixed formulation is preferred and at the same time it reduces the risk of side effects associated with polyols. The use of hydrogenated oligosaccharides as osmotic agents has advantages over their biocompatibility and cytoxicity. Since the hydrogenated oligosaccharides can be provided at a more physiological pH and that the hydrogenated oligosaccharides are not metabolized in the peritoneum
P1096 / 00MX (forming glucose), no alteration in cell function (such as cell inhibition) tends to take place during therapy. The advantage of the use of hydrogenated disaccharides or hydrogenated trisaccharides is that these substances are not glucose and do not inhibit the action of alpha-glucosidase. This has the advantages that long-term peritoneal dialysis with hydrogenated oligosaccharides, as described in this invention, does not induce the so-called storage disease. For example, in an experiment in vi tro, it can be shown that incubation of polyglucose (a situation that occurs in the body) inhibits the action of alpha-glucosidase after six weeks. In contrast, the incubation of hydrogenated oligosaccharide with glucose does not inhibit the action of alpha-glucosidase. The importance of alpha-glucosidase is to cleave the glycosyl bond (1-> 6) and (1-> 4), its inhibition can lead to storage diseases involved in the blockage of the reticulo-endothelial system described by the use of high molecular weight osmotic agents. The specific use of hydrogenated disaccharides and / or hydrogenated trisaccharides as described in this invention has the advantage that the metabolites of glucose and maltose can be metabolized before the Amadori reaction or
P1096 / 00MX Maillard reaction (without enzymatic reaction) can take place to modify these substances in the bloodstream. The use of hydrogenated oligosaccharides with a higher degree of polymerization (for example up to four) is not preferred, because their metabolism is slow and in this way the glycosylation takes place in the circulation. The consequences are that the inhibition of alpha-glucosidase can occur and reduces the cascade metabolism of the oligosaccharide. The amino acid materials, preferably a mixture of essential amino acids with a concentration ranging between 5 and 35 grams per liter, can be replaced by a portion of the hydrogenated oligosaccharide, to increase the osmolality or to provide a desired amount of nutrition to patients and to compensate for the loss of amino acids and peptides in the peritoneum during therapy. The antioxidants of the sulfhydryl type can be added to stabilize the amino acids. By the addition of amino acids, the concentration of hydrogenated oligosaccharide can be reduced to maintain the desired osmotic properties of the peritoneal solution. The hydrogenated oligosaccharides of the invention can, as indicated, be supplied and used as a dialysis fluid. However, a solution for peritoneal dialysis that contains
P1096 / 00MX Hydrogenated oligosaccharides can be prepared in a solid form by lyophilization. Before being used in peritoneal dialysis, the dry material is reconstituted by dissolving in sterile water and without pyrogen. Thus, in accordance with a further aspect of the invention, there are provided compositions for use in the preparation of a peritoneal dialysis fluid as defined herein, by the reconstitution by addition of sterile, pyrogen-free water, the composition comprising the components specified in dry form or in the form of an aqueous concentrate. The invention further provides a method for performing peritoneal dialysis comprising perfusing the peritoneal membrane with a fluid for peritoneal dialysis, as defined herein. Additionally, the invention provides the use of a compound of the Formula: [SG] n (ag) [SA] in the manufacture of a fluid for peritoneal dialysis.
DESCRIPTION OF THE DRAWINGS In addition, reference will be made to the accompanying drawings, in which: Figure 1 illustrates the relationship between osmolality and concentration for specific mixtures
P1096 / 00MX of disaccharides and hydrogenated trisaccharides. Figures 2 to 9 illustrate in graphic and diagrammatic form the results of the experiments described in experimental procedures 1-4. Figures 10 to 15 illustrate the structures of representative sugar derivatives suitable for use in accordance with the invention. The invention will now be described, by way of illustration without limitation, in the following experimental examples and procedures in vivo and in vi tro.
Example 1 A solution for peritoneal dialysis having an osmolality of approximately 395 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,925 grams per liter of sodium lactate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of a
[GP] sorbitol (hydrogenated disaccharide). The solution will be sterilized in a conventional manner as described for parenteral solutions.
Example 2 A solution for peritoneal dialysis having an osmolality of approximately 395 milliosmoles per liter of water can be prepared
P1096 / 00MX mixing 5,786 grams of sodium chloride, 2,940 grams per liter of sodium bicarbonate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter of magnesium chloride and 40 grams of a [GP] sorbitol (hydrogenated disaccharide) . The solution will be sterilized in a conventional manner as described for parenteral solutions.
Example 3 A solution for peritoneal dialysis having an osmolality of approximately 395 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,850 grams per liter of sodium pyruvate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of a [GP] sorbitol (hydrogenated disaccharide). The solution will be sterilized in a conventional manner as described for parenteral solutions.
Example 4 A solution for peritoneal dialysis having an osmolality of approximately 395 milliosmoles per liter of water can be prepared by mixing 5,493 grams of sodium chloride, 1,100 grams per liter of sodium pyruvate and 2,520 of sodium bicarbonate, 0.2573 grams per liter of chloride of calcium, 0.1017 grams per liter of chloride
P1096 / 00MX of magnesium and 40 grams of a [GP] sorbitol (hydrogenated disaccharide). The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 5 A solution for peritoneal dialysis having an osmolality of about 400 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,925 grams per liter of sodium lactate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] sorbitol, [GP] xylitol and [GP] glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 6 A solution for peritoneal dialysis having an osmolality of about 400 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 2,940 grams per liter of sodium bicarbonate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] sorbitol, [GP] xylitol and
[GP] glycerol. The solution will be sterilized in
P1096 / 00MX conventional as prescribed for parenteral solutions.
Example 7 A solution for peritoneal dialysis having an osmolality of about 400 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,850 grams per liter of sodium pyruvate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] sorbitol, [GP] xylitol and [GP] glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 8 A solution for peritoneal dialysis that has an osmolality of approximately 400 milliosmoles per liter of water can be prepared by mixing 5,493 grams of sodium chloride, 1,100 grams per liter of sodium pyruvate, 2,520 of sodium bicarbonate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] sorbitol, [GP] xylitol and [GP] glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
P1096 / 00MX Example 9 A solution for peritoneal dialysis having an osmolality of approximately 370 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,925 grams per liter of sodium lactate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter of magnesium chloride and 40 grams of a [GP] 2sorbitol (hydrogenated trisaccharide). The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 10 A solution for peritoneal dialysis having an osmolality of approximately 370 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 2,940 grams per liter of sodium bicarbonate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of a [GP] 2sorbitol, (hydrogenated trisaccharide). The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 11 A solution for peritoneal dialysis having an osmolality of about 370
P1096 / 00MX milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,850 grams per liter of sodium pyruvate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter of magnesium chloride and 40 grams of a [ GP] 2sorbitol, (hydrogenated trisaccharide). The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 12 A solution for peritoneal dialysis having an osmolality of about 370 milliosmoles per liter of water can be prepared by mixing 5,493 grams of sodium chloride, 1,100 grams per liter of sodium pyruvate and 2,520 of sodium bicarbonate, 0.2573 grams per liter of chloride of calcium, 0.1017 grams per liter of magnesium chloride and 40 grams of a [GP] 2sorbitol,
(Hydrogenated trisaccharide). The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 13 A solution for peritoneal dialysis having an osmolality of approximately 375 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,925 grams per liter of sodium lactate, 0.2573 grams
P1096 / 00MX per liter of calcium chloride, 0.1017 grams per liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] 2sorbitol, [GP] .xylitol and [GP] 2glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 14 A solution for peritoneal dialysis having an osmolality of approximately 375 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 2.940 grams per liter of sodium bicarbonate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] 2sorbitol, [GP] 2xylitol and
[GP] 2glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 15 A solution for peritoneal dialysis having an osmolality of about 375 milliosmoles per liter of water can be prepared by mixing 5,786 grams of sodium chloride, 3,850 grams per liter of sodium pyruvate, 0.2573 grams per liter of calcium chloride, 0.1017 grams per liter. liter of magnesium chloride and 40 grams of a
P1096 / 00MX equimolar mixture of [GP] 2sorbitol, [GP] 2xylitol and [GP] 2glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Example 16 A solution for peritoneal dialysis having an osmolality of about 375 milliosmoles per liter of water can be prepared by mixing 5,493 grams of sodium chloride, 1,100 grams per liter of sodium pyruvate and 2,520 of sodium bicarbonate, 0.2573 grams per liter of chloride of calcium, 0.1017 grams per liter of magnesium chloride and 40 grams of an equimolar mixture of [GP] 2sorbitol, [GP] 2xylitol and [GP] 2glycerol. The solution will be sterilized in a conventional manner as prescribed for parenteral solutions.
Experimental procedure 1 The purpose of this experiment was to evaluate the solutions for dialysis with hydrogenated oligosaccharide proposed, in a rat model. Normal male rats weighing between 250 and 400 g were used for all experiments. Briefly, the animals were anesthetized with sodium pentobarbital (35 mg / Kg intraperitoneal), placed on a warming blanket (37 ° C) and kept under anesthesia with 20 injections.
P1096 / 00MX mg / kg in the neck region. A 16-gauge catheter was introduced into the peritoneal cavity and a volume of 15 ml of dialysate was injected at a temperature of 37 ° C. After 1,2,3,4,5,6,8,10 and 12 hours, the animals were weighed and blood samples taken for analysis. For each of the time points, 3 animals were investigated. The fluid in the peritoneum was taken using a syringe and opening the abdomen, then the animals were sacrificed and bled. The dialysate solutions were: A: a lactated Ringer's hypo-osmolar control solution with an osmolality of 255 mOsm / Kg; B: a solution for peritoneal dialysis at 4.25% glucose, hyper-osmolar standard (Fresenius Medical Care) with an osmolality of 504 mOsm / Kg; C: a peritoneal dialysate of hydrogenated disaccharides formulated in Example 5; D: a peritoneal dialysate of 4% hydrogenated trisaccharide as formulated in Example 13. Substances [GP] sorbitol,
[GP] xylitol, [GP] glycerol, [GP] 2sorbitol, [GP] 2xylitol
Y [GP] 2glycerol were prepared as described17-21.
The Osmolality of solution C at 4% was 395 mOsm / Kg and respectively the osmolality of solution D was 370 mOsm / Kg was measured by the freezing point method. For example, Figure 1 shows the osmolality function of both C and D formulations and varying the concentration of
P1096 / 00MX hydrogenated oligosaccharide. Figure 2 shows the volumes of peritoneal dialysate as a function of residence time. It was shown that solutions D, C and D induced a transperitoneal ultrafiltration demonstrated by an increase in peritoneal volume profiles. No ultrafiltration occurred with the hypo-osmolar control solution A. When compared with solution B) of glucose at 4.25%, solution C produced a similar ultrafiltration profile after a residence time of 6 hours, despite a lower initial ultrafiltration during the first 4 hours of residence time . On the other hand, solution D produced ultrafiltration similar to that of solution B, after residence times of 10 hours did not decrease during the residence time period of 12 hours. Both solutions C and D have the advantages of their ultrafiltration profiles. In contrast, the ultrafiltration profile of glucose solution of 4.25% decreased after the residence time of 6 to 8 hours suggesting the onset of a negative ultrafiltration rate. The results of Figure 3 show the serum osmolalities during the study time, with a marker for metabolisms related to time and absorption of osmotic agents. The increase in serum osmolality for
P1096 / 00 X 4.25% glucose solution occurred after the 2 hour residence time. For solutions C and D, the serum osmolality increased after 6 hours. For both solutions C and D, the maximum increase in serum osmolality relative to the values before the intraperitoneal injection was between 5 and 6%. However, these increases in serum osmolality were lower than those observed (9.4%) induced by 4.25% glucose dialysis (Solution B). The results of Figure 4 show the blood hematocrit, which shows only minor changes for all solutions. Conclusion: Both the trisaccharides and the hydrogenated disaccharides showed an ultrafiltration profile that is quantitatively comparable to that obtained by a 4.25% hyperosmolar glucose dialysate. However, the ultrafiltration rates throughout the residence time of 8 to 12 hours, both for trisaccharides and hydrogenated disaccharides, were higher than those obtained by the glucose solution.
Experimental procedure 2. The purpose of this experiment described the metabolic response to intravenous administration of hydrogenated disaccharides (Example 5) and hydrogenated trisaccharides (Example 13). The
P1O96 / 00MX hydrogenated oligosaccharides were prepared as described 17"" 21. The experiments were designed to analyze the metabolic response during the period of 120 min. The injection doses were the total amount contained in 15 ml of dialysate, which represents the average of 1.85 g / kg of body weight. Male Wistar rats weighing between 250 and 400 g were used for all experiments. The animals were anesthetized with sodium pentobarbital (35 mg / Kg intraperitoneal). An intravenous dose of 0.6 g in 3 ml volume of the investigated substances was administered in the femoral inguinal vein during the 10 minute period. The femoral artery was cannulated for the sampling of blood taken in a period of 15 minutes of time. Measurements of [GP] sorbitol, [GP] xylitol, [GP] glycerol,
[GP] 2sorbitol, [GP] 2xylitol and [GP] 2glycerol, sorbitol, xylitol and glycerol were made by gas chromatography using the acetyl derivative. The blood plasma samples were analyzed to determine free fatty acids (FFA), glucose by glucose oxidase method, insulin by analysis of immunoassay by activated carbon. The urine was collected for 2 hours after the venous infusion. The results of Figures 5 and 6 show metabolic responses to the intravenous loading of 0.6 g of glucose (B), of an equimolar mixture of
P1096 / 00MX [GP] sorbitol, [GP] xylitol, [GP] glycerol (C), [GP] 2sorbitol, [GP] 2xylitol and [GP] 2glycerol (D). The control solution was 0.6 g of the lactated Ringer's solution salts. The results showed that after injection of C and D, there was no significant increase in serum glucose during the total interval of 120 min. The blood glucose concentrations increased to 30% over the initial values. In contrast, after glucose injections, blood glucose increased to 160%. As demonstrated, disaccharides and hydrogenated trisaccharides were probably well used due to alpha-glucosidase activity. During the entire 120 min time interval, the total doses of hydrogenated oligosaccharide of 1.85 g / kG were metabolized. The serum insulin concentration increased from 2.8 to 3.1 times more. Subsequent concentrations of serum insulin were similar for hydrogenated oligosaccharides. Following the infusion of substances C and D. After the infusion of glucose, there was a 5-fold increase in serum insulin. A drop in plasma FFA after the infusion of B, C and D was noted. However, the drop initiated by glucose was significantly (p <0.01) stronger than the drops induced by hydrogenated oligosaccharides, suggesting that the Caloric absorption was lower than absorption by
P1096 / 00MX glucose. Figure 7 shows the metabolic response in serum polyol levels and the urinary excretion of all the metabolites of [GP] sorbitol, [GP] xylitol and [GP] glycerol, [GP] 2sorbitol, [GP] 2xylitol and [GP] 2glycerol. The results showed that all the polyols were completely metabolized during the whole time of 120 min. The urinary excretion of all possible metabolites of the disaccharides and hydrogenated trisaccharides was below 9% of the injected doses, suggesting that the metabolism occurred mainly in the body. Conclusion: The ability of rats to metabolize disaccharides and circulating hydrogenated trisaccharides suggests that these substances can be used as osmotic agents in peritoneal dialysis. In addition, the results showed that these substances need less insulin.
Experimental procedure 3 The purpose of the study described the cytotoxic effects of hydrogenated oligosaccharide in a monocyte model. This in vitro model allows to evaluate the inhibition of cellular function after exposure with possible toxic substances. The experiments have been carried out in accordance with the previously published protocol22.
P1096 / 00MX Briefly, peripheral blood mononuclear cells (PBMC) from healthy human donors were separated by density centrifugation (Ficoll-Hypaque). The phase containing PBMC was collected, washed with saline, counted and resuspended in RPMI (Rooswelt Memorial Park Medium - Middle Memorial Park Rooswelt) at the desired concentration. The cytotoxic effects after exposure of PBMC with the dialysate were analyzed as follows: 1) For the determination of anion (02 ~) superoxide, the PBMC were incubated for 15 minutes with the test solutions, in this way the cells were washed and they were incubated with opsonized zymosan. The formation of O2 radical "that can be inhibited by superoxide dismutase was determined by the reduction of Cytochrome C at 546 n; 2) for cytokine tests, cells were exposed to sterile solutions for 15 mins and resuspended in sterile RPMI, stimulated with endotoxin (lng / ml), and incubated at 37 ° C in an atmosphere of 5% C02 for 24 hours.The cells were lysed and analyzed to detrimentally interleukin-l.The test solutions were the hydrogenated disaccharide solution of the Example 6 and Example 8. The control solution was glucose solutions at 4.25% The results of Figure 8 demonstrated
P1096 / 00MX that both glucose-free solutions (Examples 6 and 8) have no effect on PBMC function as determined by the production of cytokine and oxygen free radicals. In contrast, glucose solutions inhibited PBMC by a reduction of 80 to 90% on cellular activities. Conclusion: Glucose-free hydrogenated oligosaccharide solutions have no effect on cellular functions and represent an advantage with respect to the biocompatibility of solutions for peritoneal dialysis.
Experimental procedure 4 The purpose of the study was to describe the influence of Amadori and Maillard products on alpha-glucosidase. The in vitro model evaluated the generation of Maillard products by incubation of 4% hydrogenated disaccharides (Example 8) and 4% hydrogenated trisaccharides. The control experiments were the solutions containing 4.25% glucose and 7% polyglucose (icodextrin-Baxter). 50 mg / ml albumin was incubated for 6 weeks with test dialysate solution to generate glucosed end products (AGE). The AGEs were measured after each week of incubation. After the incubations, the samples were further incubated for 2 hours
P1096 / 00MX at 37 ° C with alpha-glucosidase (from Saccharomyces cerevisae) and maltose labeled C14 and pentasaccharides. The alpha-glucosidase activity was evaluated by the incision of the labeled oligosaccharide using high resolution chromatography (HPLC). Figure 9 showed that Maillard products generated by dialyzed solution containing both glucose and polyglucose. However, the polyglucose induced, based on weight, fewer Maillard products than the solutions containing glucose. In contrast, in the hydrogenated oligosaccharide for which the carbonyl groups were reduced, generation of AGE did not occur. Alpha-glucosidases are inhibited by the Maillard (and Amadori) compounds induced by Icodextrin but not by glucose.
References 1 Mahiout A, Ehlerding G, Brunkhorst R. Nephrol Dial Transplant, 5.2-6, 1996. 2 Twardowsky ZJ, Moore HL, McGary TJ, Poskuta M, Stathkis C, Hirszel P. Perit Dial Bull 4 (3): 125; 1984. 3 Raja RS, Kramer MS, Manchanda R. Lazaro N. Rosenbaum JL. Ann Intern Med 79: 511; 1973. 4 Bazzato G, Coli U, Landini S et al. Perit Dial Bull 2: 161; 1982. 5 Yatuc W, Ward G. Shiepetar G, Tenckoff H. Trans Am
P1096 / 00MX Soc Artif Intern Organs 13: 168; 1967. Higgins JT, Cross ML, Somani P. Perit Dial Bull 4: 131; 1984. Winchester JF, Stegink LD, Ahmad S et al. In frontiers In Peritoneal Dialysis, edited by Maher
JF, Winchester JF, New York, Field, Rich and Associates Inc, 1986, p 231. 8 Mistry CD, Mallick NP, Gokal R. Lancet ii: 178-182; 1982. 9 Gjessing J. Lancet ii 82, 1968. 10 De Paepe M, Matthijis E, Peluso F et al. In
Prevention and Treatment of Diabetic Nephropathy, edited by Keen H, Legrain M. Boston, MTP Press
Ltd, 1983, p 299. 11 Klein E, Ward RA, Williams TE, Feldhoff PW. Trans
Am Soc Artif Intern Organs 32; 550, 1986. 12 Twardowski ZJ, Hain H, McGary TJ, Moore HL, Keller RS. In Frontiers in Peritoneal Dialysis, edited by Mahler JF, Winchester JF, New York, Fields, Rich and Associates Inc, 1986, p. 249. 13 Schildt B, Bouveng R, Sollenberg M. Acta Chir Scand 141: 7, 1975. 14 Johns MY, Weser WJ Clin. Invest. 50: 986; 1971
Grupp U, Siebert G. Res. Exp. Med 173: 261-278; 1978. 16 Wolfrom M.L. Thomson A., O'Neil A.N., Galkowski T.T .: J.Amer. Chem. Soc, 74, 1062-1064, 1952. 17 Garu W., Kurz J., Fischer E., Steinle G., grupp
P1096 / 00MX U., Siebert G.Z. Lebensm. Unters Forsch 168, 125-130; 1979. 8 Ducan, Manners, and Thomson, Biochem J., 73, 295; 1959. 19 Sawai and Hehre. J. Biol. Chem, 237: 2047, 1962.
Lindberg, Acta, Sean, 7: 1119; 1953. 21 Fischer and Seyferth, Hoppe-Seyler 's. Z. Physiolo. Chem, 349: 1662; 1968. 22 Mahiout A, Matata BM, Brunkhorst R. Kidney International 51: 860-867; 1997
LEGENDS OF THE FIGURES Figure 1 Osmolality of C: hydrogenated disaccharide mixture 4% (equimolar mixture of GPSorbitol,
GPXylitol, GPGlicerol); D: hydrogenated trisaccharides
4% (equimolar mixture [GP] 2Sorbitol, [GP] 2Xilitol;
[GP] 2Glycerol).
Figure 2 Volume of peritoneal dialysate as a function of residence time in animals (rats) injected with 15ml of: A: a lactated Ringer's solution; B: a 4.25% glucose solution; C: 4% hydrogenated disaccharide mixture (equimolar mixture of GPSorbitol, GPXylitol, GPGlycerol); D: 4% hydrogenated trisaccharides (equimolar mixture of [GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Glycerol). For
P1096 / 00MX each group (A, B, C, D) were injected 3x9 rats with 15 ml of peritoneal dialysis solution. For each hour of the residence time the dialysate was removed and its volume was measured.
Figure 3 Serum osmolality (mOsm / Kg) as a function of residence time in animals (rats) injected with 15 ml of: A: a lactated Ringer's solution; B: a 4.25% glucose solution; C: 4% hydrogenated disaccharide mixture (equimolar mixture of GPSorbitol, GPXylitol, GPGlycerol); D: 4% hydrogenated trisaccharides (equimolar mixture of
[GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Glycerol). For each group (A, B, C, D) 3x9 rats were injected with 15 ml of peritoneal dialysis solution. For each hour of the residence time the dialysate was removed and its volume was measured.
Figure 4 Blood hematocrit as a function of residence time in animals (rats) injected with 15ml of: A: a lactated Ringer's solution; B: a 4.25% glucose solution; C: 4% hydrogenated disaccharide mixture (equimolar mixture of GPSorbitol, GPXylitol, GPGlycerol); D: 4% hydrogenated trisaccharides (equimolar mixture of [GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Glycerol). For each group (A, B,
P1096 / 00MX C, D) were injected with nine rats with 15 ml of peritoneal dialysis solution. For each hour of the residence time the dialysate was removed and its volume was measured.
Figure 5 (A) and 5 (B) Metabolic response to intravenous administration of hydrogenated oligosaccharides in rats: A: 0.6gr of a lactated Ringer's solution; B: 0.6gr of glucose; C: 0.6gr of hydrogenated disaccharide mixture (equimolar mixture of GPSorbitol, GPXilitol, GPGlycerol); D: 0.6g of hydrogenated trisaccharides (equimolar mixture of [GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Glycerol).
Figure 6 (A) and 6 (B) Metabolic response to intravenous administration of hydrogenated oligosaccharides in rats: A: 0.6gr of a lactated Ringer's solution; B: 0.6gr of glucose; C: 0.6gr of hydrogenated disaccharide mixture (equimolar mixture of GPSorbitol, GPXilitol, GPGlycerol); D: 0.6g of hydrogenated trisaccharides (equimolar mixture of [GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Glycerol).
Figure 7 (A) and 7 (B) Metabolic response and urinary excretion to intravenous administration of oligosaccharides
P1096 / 00MX hydrogenated in rats: C: 0.6gr of hydrogenated disaccharide mixture (equimolar mixture of
GPSorbitol, GPXilitol, GPGlicerol); D: 0.6g of hydrogenated trisaccharides (equimolar mixture of [GP] 2Sorbitol, [GP] 2Xilitol, [GP] 2Glycerol).
Figure 8 Mean (± SD) production of 02- stimulated with Zymosan and IL-1β stimulated with endotoxin in PBMC after exposure for 15 min. to different CAPD solutions.
Figures 9 (A) and 9 (B) AGE formation after incubation of 50 mg / ml of Albumin with different CAPD solutions and the resulting effect on alpha-glucosidase activity.
Figure 10 Sorbitol 0, a, D Glucopyranoside- (1-> 6).
Figure 11 Xylitol 0, a, D Glucopyranoside- (1- > 4)
Figure 12 Glycerol 0,, D Glucopyranoside- (1-1;
Figure 13
P1096 / 00MX Sorbitol 0, a, D Glucopyranoside- (1- »6) 0, a, D Glucopyranoside- (1-» 6).
Figure 14 Xylitol 0, a, D Glucopyranoside- (1? 6) 0, a, D
Glucopyranoside- (1- »6).
Figure 15 Glycerol 0, a, D Glucopyranoside- (1? 6) 0, a, D Glucopyranoside- (1- > 1).
P1096 / 00MX
Claims (29)
- NOVELTY OF INVENTION Having described present invention, it is considered as a novelty and, efore, content of following CLAIMS is claimed as property: 1. A fluid of peritoneal dialysis, fluid comprises a physiologically acceptable aqueous solution containing physiologically acceptable anions and inorganic cations and, as an osmotic agent, at least one sugar derivative; physiologically acceptable anions and inorganic cations and at least one sugar derivative are present in concentrations sufficient for removal of water and solutes from a patient by means of peritoneal dialysis, characterized in that sugar derivative is a compound of formula: [SG] n. { ag) [SA] wherein SG or each SG, which may be same or different, represents a residue of a physiologically acceptable metabolizable sugar, SA represents a residue of a physiologically acceptable metabolizable sugar alcohol, n is 1 to 4 and (ag) represents a glycoside linkage that is capable of being cleaved by an α-glucosidase enzyme.
- 2. A peritoneal dialysis fluid according to claim 1, wherein adduct of formula [SG] n, ag ^ [SA] is a hydrogenated oligosaccharide.
- 3. A peritoneal dialysis fluid according to P1096 / 00MX claim 1 or 2, wherein n is 1.
- 4. A peritoneal dialysis fluid according to claim 3, wherein n is 2.
- 5. A peritoneal dialysis fluid according to any preceding claim, wherein SG or each SG represents a glucose residue.
- 6. A peritoneal dialysis fluid according to any preceding claim, wherein SA represents a residue of a sugar alcohol selected from sorbitol, xylitol, ribitol and glycerol.
- 7. A peritoneal dialysis fluid suitable for use in peritoneal dialysis, comprising an aqueous solution of substantially physiological pH and comprising physiological salts and a sugar derivative as an osmotic agent, fluid is characterized in that sugar derivative is a disaccharide or hydrogenated trisaccharide, concentrations of components of fluid are suitable for effecting removal of water and solutes from a patient by means of peritoneal dialysis.
- 8. A peritoneal dialysis fluid according to any of preceding claims having a pH in range of 5.4 to 7.4, preferably 7.0 to 7.4.
- 9. A peritoneal dialysis fluid according to any of preceding claims that P1O96 / 0OHX contains following concentrations of specific inorganic ions: Na + 116-140 mEq / 1 Ca + 0-5 mEq / 1 Cl "100-144 mEq / 1 10.
- A peritoneal dialysis fluid according to any of preceding claims which contains a total of 5 to 40mEq / L of regulation counterions selected from bicarbonate, pyruvate and lactate ions 11.
- A peritoneal dialysis fluid according to any of preceding claims containing from 1 to 60 g / 1 of sugar derivative.
- A peritoneal dialysis fluid according to claim 11 containing from 10 to 50 g / 1, preferably from 35 to 45 g / 1 of sugar derivative
- 13. A peritoneal dialysis fluid according to any of preceding claims having an osmolality from 250 to 550 milliOsmoles / 1, preferably from 300 to 500 milliOsmoles / 1.
- 14. A peritoneal dialysis fluid according to any of preceding claims comprising sugar residues linked by glycoside bonds (1? 6) or (1? 4)
- 15. A peritoneal dialysis fluid according to any of preceding claims comprising a sugar residue bound to a sugar alcohol residue by a glycoside linkage (1- > 6) or P1096 / 00MX (1? 4).
- 16. A peritoneal dialysis fluid according to any preceding claim, wherein sugar derivative can be obtained by chemical modification of an oligosaccharide containing 2 glucosyl units.
- 17. A peritoneal dialysis fluid according to claim 16, wherein the chemical modification comprises the transglucosidation of the oligosaccharide.
- 18. A peritoneal dialysis fluid according to claim 16, wherein the chemical modification comprises reducing a terminal glycoside residue of a disaccharide or trisaccharide.
- 19. A peritoneal dialysis fluid according to any of claims 16 to 18, wherein the sugar derivative can be obtained by chemical modification of an oligosaccharide containing 3 glucoside units.
- 20. A peritoneal dialysis fluid according to any of claims 16 to 19, wherein a mixture of sugar derivatives is obtained by chemical modification of a mixture of one or more disaccharides and trisaccharides.
- 21. A peritoneal dialysis solution according to claim 16, wherein the sugar derivative can be obtained by chemical modification of an oligosaccharide containing between 4 and 9 units P1096 / 00MX glucosyl.
- 22. A peritoneal dialysis fluid according to any preceding claim comprising an aqueous solution containing a mixture of hydrogenated oligosaccharides, the hydrogenated oligosaccharides have sugar terminal sugar residues selected from sorbitol, xylitol, ribitol and glycerol.
- 23. A peritoneal dialysis fluid according to any of claims 1 to 13 containing Isomalt (Palatinit) as an osmotic agent, Isomalt (Palatinit) is a substantially equimolar mixture of alpha-D-glucopyranoside-1,6-sorbitol and alpha- D-glucopyranoside-1,6-mannitol.
- 24. A peritoneal dialysis fluid according to any preceding claim containing from 125 to 140 m.Eq / 1 sodium, from 90 to 125 mEq / 1 chloride, from 1 to 5 mEq / 1 calcium, from 0.2 to 5 mEq / 1 of magnesium, and of 25 to 40 mEq / 1 of a regulation anion selected from lactate, pyruvate and bicarbonate.
- 25. A peritoneal dialysis fluid according to any preceding claim having an osmolality of 280 to 455 milliosmoles per liter.
- 26. A peritoneal dialysis fluid according to any preceding claim comprising essential amino acids to increase the osmolality of the solution and / or to compensate for the loss of P1096 / 00MX amino acids and / or to provide the patient with protein nutrition.
- 27. A composition for use in the preparation of a peritoneal dialysis fluid according to any preceding claim, by reconstitution by the addition of sterile, pyrogen-free water, the composition comprises the specified components in dry form or in the form of an aqueous concentrate. .
- 28. A method for performing peritoneal dialysis comprising perfusing the peritoneal membrane of a patient with a peritoneal dialysis fluid, as defined herein.
- 29. The use of a compound of the formula [SG] n, ag-) [SA] wherein [SG], n and < ag), as defined in any preceding claim, in the manufacture of a peritoneal dialysis fluid. P1096 / 00MX
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9714218.6 | 1997-07-04 |
Publications (1)
Publication Number | Publication Date |
---|---|
MXPA00001267A true MXPA00001267A (en) | 2001-06-26 |
Family
ID=
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