WO2003084528A1 - A method for reversing permeability modifications caused by acute peritonitis - Google Patents
A method for reversing permeability modifications caused by acute peritonitis Download PDFInfo
- Publication number
- WO2003084528A1 WO2003084528A1 PCT/EP2002/004033 EP0204033W WO03084528A1 WO 2003084528 A1 WO2003084528 A1 WO 2003084528A1 EP 0204033 W EP0204033 W EP 0204033W WO 03084528 A1 WO03084528 A1 WO 03084528A1
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- WO
- WIPO (PCT)
- Prior art keywords
- permeability
- peritonitis
- nos inhibitor
- modification consists
- nos
- Prior art date
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- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives
Definitions
- This invention relates to a method and a pharmaceutical composition for reversing at least one of the permeability modifications caused by acute peritonitis during peritoneal dialysis.
- Peritoneal dialysis comprises the periodical infusion of a sterile aqueous solution into the peritoneal cavity. Diffusion exchange takes place between the solution and the bloodstream across the natural body peritoneal membrane. The diffusion removes the waste products that the kidneys normally excrete. The waste products typically consist of solutes like sodium and chloride ions, and the other compounds normally excreted through the kidneys like urea, creatinine, and water. Acute peritonitis remains the most frequent and serious complication of peritoneal dialysis (Pastan and Bailey, 1998, N Engl J Med 338: 1428-1437). Acute peritonitis is defined as an acute or chronic inflammation of the peritoneum, i.e.
- the cause of dialysis-associated peritonitis may be the introduction of bacteria into the peritoneal cavity by the dialysis procedure, for instance through peritoneal dialysis catheters. Inflammation occurs within the peritoneal cavity, which can result in bowel distention, infection of the bloodstream, systemic illness and renal failure. Careful technique when performing peritoneal dialysis may reduce the risk of inadvertently introducing bacteria during the procedure. However, some cases are not preventable.
- the permeability modifications caused by acute peritonitis during peritoneal dialysis include a major increase in permeability for small solutes and glucose, leading to a faster than normal dissipation of the osmotic gradient, a faster glucose absorption from the dialysate, a decrease of free-water permeability and a loss of ultrafiltration (UF). All these permeability modifications are deleterious for the patient and potentially decrease the quality of dialysis. In addition, peritonitis may lead to loss of mesothelial cells and the excessive growth of fibrous connective tissue in the peritoneum membrane, called fibrosis.
- Peritonitis also leads to an increased protein loss in the dialysate, with the patient usually not able to eat to replace this loss (Fried and Piraino, 2000 In: textbook of Peritoneal Dialysis, Gokal et al. R (eds.) Kluwer Academic Publishers, Dordrecht, 2000/ 545-564). Furthermore, severe peritonitis may lead to septic shock, i.e. uncontrolled systemic infection, which is associated with low blood pressure and multiple organ failure (Parillo, 1993, N Engl J Med 328: 1471-1477). The primary treatment of acute peritonitis remains the administration of antibiotics, either intraveinously or intra-peritoneally.
- dialysates containing low glucose concentration should be used.
- ultrafiltration can be maintained by using an icodextrin solution during the exchange.
- Icodextrins are large molecular weight glucose polymers, capable of serving as osmotic agents instead of glucose in peritoneal dialysis solutions.
- the dialysis solutions may include mixtures of nutritionally essential amino acids, like methionine, tryptophan, and isoleucine, and nutritionally non-essential amino acids, like glycine and alanine, to enhance the patient's anabolic state and replace protein loss in the dialysate experienced during peritonitis.
- Another additive is chondroitin sulfate that changes the permeability of the peritoneal membrane during subsequent dialysis using solutions free of chondroitin sulfate.
- Other additives are degradation products of hyaluronic acid, which enhance the regeneration of the peritoneal mesothelium without fibrosis. The additives protect against peritonitis-associated inflammatory reactions, fibrosis and loss of ultrafiltration performance.
- dialysis solutions may provide possibilities to treat some pathological effects caused by acute peritonitis, their administration will not reverse the permeability modifications which may comprise an increased permeability for small solutes and glucose, faster glucose absorption from the dialysate, decreased free- water permeability, loss of mesothelial cells, fibrosis, or increased protein loss in the dialysate. Furthermore, the mentioned dialysis solutions have no influence on hypotension caused by peritonitis-induced septic shock.
- Nitric oxide has been shown to play an important role in inflammatory responses. NO levels may increase in subjects undergoing an inflammatory disease. Consequently, in order to treat subjects afflicted by an inflammatory disease lowering of the NO levels was proposed. Therefore, compounds inhibiting NO synthesis and acting on the enzymes catalyzing nitric oxide production may be used. NO is produced from L-arginine by a family of NO synthase (NOS) isoforms that are expressed in a large variety of tissues and cells (Bredt et al. 1994, Annu Rev Biochem 63:175-195; Kone, 1997, Am J Kidney Dis 30: 311-333).
- NOS NO synthase
- NOS inhibitors such as for example amino-substituted guanidines, to treat subjects afflicted with an inflammatory disease is described in the patent applications WO-A1 -9612483 and WO-A1 -9735566.
- the present invention provides a method for reversing the increase in permeability for small solutes and glucose, the faster glucose absorption from the dialysate, the decrease of free-water permeability, the loss of ultrafiltration (UF), and/or the increase in protein loss in the dialysate.
- the present invention relates to a method of reversing at least one of the permeability modifications caused by acute peritonitis by adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution.
- Present invention provides a rapid, effective and accurate method to reverse the permeability modifications caused by acute peritonitis.
- the invention concerns a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for reversing at least one of the permeability modifications caused by acute peritonitis.
- the present invention relates to the use of a NOS inhibitor in the preparation of a medicament for reversing at least one of the permeability modifications caused by acute peritonitis.
- the present invention relates to a method of reversing at least one of the permeability modifications caused by acute peritonitis by adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution.
- permeability modifications are defined as detrimental effects resulting from the peritoneal dialysis process.
- permeability modifications refers to:
- the method of the present invention provides the possibility to reverse several permeability modifications associated with acute peritonitis.
- dialysis is defined as a method of separating crystalloids and colloids in solution by differences in their rates of diffusion through a semi-permeable membrane.
- peritoneal dialysis the membrane comprises the peritoneum and tissues, which separate it from the circulating blood.
- Ultrafiltration is defined as the diffusion of water across the peritoneal membrane during dialysis.
- peritoneal dialysis solutions which are administered according to the method of present invention, may be specially formulated for patients for use during and immediately after episodes of peritonitis. The solutions promote the reversion of the permeability modifications of peritonitis upon the dialysis regime of the patient.
- the solutions that embody the features of the invention may include (1) physiological salts such as sodium chloride, calcium chloride and sodium acetate in appropriate concentrations to maintain a normal electrolyte profile. Typical concentrations are from 116 to 140 mEq/liter of sodium; 0 to 6 mEq/liter of calcium, and 100 to 144 mEq/liter of chloride.
- lactate or bicarbonate in appropriate concentrations to maintain a physiologically tolerable pH of between about 5 to about 7.4. Typical concentrations are from 30 to 45 mEq/liter of lactate;
- the present invention relates to a method wherein said nitric oxide inhibitory compound is a NOS inhibitor. More particularly, the present invention relates to a method wherein said NOS inhibitor is an iNOS inhibitor and/or eNOS inhibitor. NO is considered as a key mediator of peritoneal permeability.
- peritoneal permeability An increase in peritoneal permeability can be observed when administering the NO donor nitroprusside in animal models (Nolph et al. 1977, ASAIO Trans 23:210-218) and stable peritoneal dialysis patients (Douma et al. 1997, Kidney Int. 51 :1885-1892). Furthermore, permeability modifications observed in acute peritonitis may be the consequence of increased NO production mediated by the upregulation of NOS isoforms in the peritoneum. Acute peritonitis induces a major increase in NOS activity and upregulates both eNOS and iNOS in the peritoneum (Devuyst et al. 2001 , Nephrol. Dial. Transplant 16:675-678).
- iNOS induction of iNOS is variable in intensity and related to the severity of the peritonitis (Combet et al. 2000, Kidney Int. 57: 332-338).
- the local generation of NO secondary to the upregulation of NOS isoforms, induces major, detrimental changes in peritoneal permeability. Therefore, acute inhibition of the iNOS and/or eNOS isoforms can result in an accurate lowering of the NO levels in the peritoneum and can reverse the permeability modifications caused by the peritoneal inflammation.
- present invention relates to a method wherein the NOS inhibitor is an L-arginine analogue.
- analogues may be selected from a group comprising NG-nitro-L-arginine methyl ester (L-NAME), NG-monoethyl-L-arginine (L-MMA), N-iminoethyl-L-arnithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), L-NG-methyl- arginine (L-NMA), Nw-nitro-L-arginine (L-NA), and mixtures thereof.
- Analogues of L-arginine can inhibit the production of NO by NOS isoforms.
- L-NAME has proven to be one of the most useful NOS inhibitors due to its low cost, commercial availability, chemical stability, solubility in water, and effectiveness in the millimolar range both for tissue studies and in vivo investigations (Breborowicz et al. 1998, Peril Dial. Internal 18:188-192; Griffith and Kilbourn 1996, Methods Enzymol 268: 375-392; Hobbs et al. 1999, Annu. Rev. Pharmacol. Toxicol. 39: 191-220). Addition of L-NAME to a dialysis solution does not induce clinical or biological side-effects, and does not alter the morphology of the peritoneum.
- NOS inhibitors proposed are non- selective in that they inhibit both the constitutive (eNOS) and the inducible NO synthase (iNOS).
- eNOS constitutive
- iNOS inducible NO synthase
- Use of such non-selective NO synthase inhibitors requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO- synthase including hypertension and possible thrombosis and tissue damage.
- NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive NO synthase are preferred as they would be of even greater therapeutic benefit and easier to use (Hobbs et al. 1999, Annu. Rev. Pharmacol. Toxicol. 39: 191-220).
- present invention relates to a method wherein the nitric oxide inhibitory compound is added to said peritoneal dialysis solution in a suitable concentration. This suitable concentration may depend on the body weight of a subject in need of said solution.
- present invention relates to a method wherein said nitric oxide inhibitory compound is in a pharmaceutically acceptable formulation.
- a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for reversing at least one of the above-described permeability modifications caused by acute peritonitis. Consequently, in a further embodiment, present invention relates to the use of a NOS inhibitor in the preparation of a medicament for reversing at least one of the permeability modifications caused by acute peritonitis.
- the permeability modifications may comprise an ultrafiltration loss, a protein loss in the dialysate, an increased peritoneal permeability for small solutes, a decreased free-water permeability or a fast glucose absorption from the dialysate.
- the method of the invention provides a solution for treating hypotension caused by peritonitis-induced septic shock.
- the present invention also relates to a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for treating hypotension caused by a peritonitis-induced septic shock.
- the present invention further concerns the use of a NOS inhibitor in the preparation of a medicament for treating hypotension caused by a peritonitis-induced septic shock.
- the method according to the invention allows minimising the induction of tissue damage of the peritoneal membrane.
- tissue damage of the peritoneal membrane During sequential dialysis operations, the risk of developing peritonitis exists. Peritonitis is believed to induce the production of NO, which can have direct as well chronic effects on the peritoneal membrane. Therefore, sequential dialysis operations accompanied by the sequential induction of peritonitis associated with NO production, may cause serious tissue and cell damage to the peritoneal membrane.
- NOS inhibitors By administering NOS inhibitors to the dialysis solution according to the present invention, the damage to the peritoneal membrane, secondary to the induction of NO during peritonitis, may therefore be minimised.
- the invention relates to a pharmaceutical composition, comprising a NOS inhibitor and a suitable excipient, for minimising the induction of tissue damage of the peritoneal membrane.
- the present invention also relates to the use of a NOS inhibitor in the preparation of a medicament for minimising the induction of tissue damage of the peritoneal membrane.
- the following non-limiting examples and associated drawings illustrate the benefits of using a NOS inhibitor in a dialysis solution.
- Example 1 provides an overview of permeability modifications, which may be associated with peritonitis in a rat model, while example 2 provides evidence for increased NOS expression and increased NOS enzymatic activities in the peritoneum during acute peritonitis in the rat model.
- Example 3 describes the effects of NOS-inhibitor L-NAME on the peritoneal permeability during acute peritonitis in a rat model.
- Figure 1 relates to the effects of acute peritonitis on NOS expression in the peritoneum.
- This figure represents immunoblot analysis for eNOS and iNOS in peritoneum extracts prepared from control rats and rats with acute peritonitis (40 ⁇ g protein/lane, 6 samples in each group). Extracts from bovine aortic endothelial cells (eNOS) and mouse macrophages (iNOS) were used as positive controls (lane C).
- eNOS bovine aortic endothelial cells
- iNOS mouse macrophages
- Figure 2 relates to the effects of acute peritonitis on NOS enzymatic activity in the peritoneum.
- NOS enzymatic activities in the peritoneum of control rats (C) and rats with acute peritonitis (P) are shown.
- Black bars represent total NOS activity (in pmol citrulline/mg protein/min)
- hatched bars represent Ca 2+ -dependent NOS activities
- open bars represent Ca 2+ -independent NOS activities.
- Figure 3 shows the effect of L-NAME on functional parameters of peritoneal dialysis in control and peritonitis rats.
- the dialysate-to-plasma (D/P) ratio of urea (A) and sodium (C), and the progressive removal of glucose from the dilaysate (D/D 0 , B) are represented in control rats (open symbols), and rats with peritonitis (black symbols), during a 2 h-exchange with 15 mL of 7% glucose supplemented (triangles) or not (squares) with 5 mmol/L L-NAME. All parameters were obtained for 6 rats in each group. Acute peritonitis induces a significant increase in permeability for urea and glucose, and a loss of sodium sieving ( * p ⁇ 0.05 vs. C). These modifications are significantly reduced when L-NAME is added to the dialysate (#p ⁇ 0.05 vs. P).
- Figure 4 shows the effects of acute peritonitis and addition of L-NAME in the dialysate on ultrafiltration, protein loss in the dialysate, and urea permeability during peritoneal dialysis in rats.
- EXAMPLE 1 Clinical and biological parameters associated with acute peritonitis in a rat model Following example provides an overview of permeability modifications, associated with peritonitis in a rat model.
- rats with acute peritonitis were characterized by (i) decreased UF (7.6 ⁇ 0.5 vs. 1 ⁇ 1 mL, p ⁇ 0.001),
- NOS The expression of NOS and the enzymatic activities of the NOS in the peritoneum during acute peritonitis in a rat model were assessed.
- the rats described in example 1 were sacrificed by exsanguination at the end of the dwell and similar samples from the parietal and visceral peritoneum were processed for protein extraction. All experiments were conducted in accord with local prescriptions and the NIH Guide for the Care and Use of Laboratory Animals. SDS-PAGE and immunoblotting were performed as according to method known in the art. Efficiency of transfer to nitrocellulose was routinely tested by Ponceau red (Sigma) staining and beta-actin immunoreactivity (Sigma).
- the membranes were blocked for 30 min at room temperature, followed by incubation with monoclonal antibodies raised against eNOS and iNOS at 4°C for 16-18 h. After washing, the membranes were incubated for 1 h at room temperature with peroxidase-labeled secondary antibodies (Dako), before visualization with enhanced chemiluminescence (Amersham, Little Chalfont, UK). Negative controls included incubation with non-immune mouse IgG (Dako). NOS enzymatic activities were measured using the L-citrulline assay according to methods known in the art.
- Total NOS activity was assayed by the conversion of L-[ 3 H]-arginine to L- [ 3 H]-citrulline in the visceral peritoneum. Assays were performed with or without Ca 2+ to measure total vs. Ca 2+ -independent NOS activities, and calculate Ca 2+ -dependent NOS activity.
- tissue extract 350 ⁇ g of total protein
- 20 mM CHAPS 20 mM CHAPS were added to 200 ⁇ L of Tris buffer (50 mM, pH 7.4) containing 10 mM DTT, 10 ⁇ g/ml calmodulin, 1 mM NADPH, 4 ⁇ M FAD, 4 ⁇ M FMN, 2 ⁇ M L-arginine, and 10 "3 mCi/mL L-[ 3 H]- arginine.
- Assays were performed for 30 min at 37°C and stopped with 2 mL of ice-cold stop buffer (20 mM CH3COONa, pH 5.5, containing 2 mM EDTA, 0.2 mM EGTA, and 1 mM L- citrulline).
- L-[ 3 H]-citrulline was separated by cation-exchange chromatography and quantified by liquid scintillation.
- the NOS activity pmol citrulline/mg protein/min
- Determinations were performed in duplicate on 3 randomly selected samples in each group.
- this example provides evidence for increased NOS expression and increased enzymatic NOS activities in the peritoneum during acute peritonitis in a rat model.
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Abstract
The present invention relates to a method for reversing at least one of the permeability modifications caused by acute peritonitis during peritoneal dialysis by adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution. The invention also relates to a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for reversing at least one of the permeability modifications caused by acute peritonitis. In addition, the invention relates to the use of a NOS inhibitor in the preparation of a medicament for reversing at least one of the permeability modifications caused by acute peritonitis.
Description
A METHOD FOR REVERSING PERMEABILITY MODIFICATIONS CAUSED BY ACUTE
PERITONITIS
FIELD OF THE INVENTION This invention relates to a method and a pharmaceutical composition for reversing at least one of the permeability modifications caused by acute peritonitis during peritoneal dialysis.
BACKGROUND
Peritoneal dialysis (PD) comprises the periodical infusion of a sterile aqueous solution into the peritoneal cavity. Diffusion exchange takes place between the solution and the bloodstream across the natural body peritoneal membrane. The diffusion removes the waste products that the kidneys normally excrete. The waste products typically consist of solutes like sodium and chloride ions, and the other compounds normally excreted through the kidneys like urea, creatinine, and water. Acute peritonitis remains the most frequent and serious complication of peritoneal dialysis (Pastan and Bailey, 1998, N Engl J Med 338: 1428-1437). Acute peritonitis is defined as an acute or chronic inflammation of the peritoneum, i.e. the membrane lining the abdominal cavity, and is the most frequent and serious complication of peritoneal dialysis. The cause of dialysis-associated peritonitis may be the introduction of bacteria into the peritoneal cavity by the dialysis procedure, for instance through peritoneal dialysis catheters. Inflammation occurs within the peritoneal cavity, which can result in bowel distention, infection of the bloodstream, systemic illness and renal failure. Careful technique when performing peritoneal dialysis may reduce the risk of inadvertently introducing bacteria during the procedure. However, some cases are not preventable. The permeability modifications caused by acute peritonitis during peritoneal dialysis include a major increase in permeability for small solutes and glucose, leading to a faster than normal dissipation of the osmotic gradient, a faster glucose absorption from the dialysate, a decrease of free-water permeability and a loss of ultrafiltration (UF). All these permeability modifications are deleterious for the patient and potentially decrease the quality of dialysis. In addition, peritonitis may lead to loss of mesothelial cells and the excessive growth of fibrous connective tissue in the peritoneum membrane, called fibrosis. Peritonitis also leads to an increased protein loss in the dialysate, with the patient usually not able to eat to replace this loss (Fried and Piraino, 2000 In: textbook of Peritoneal Dialysis, Gokal et al. R (eds.) Kluwer Academic Publishers, Dordrecht, 2000/ 545-564). Furthermore, severe peritonitis may lead to
septic shock, i.e. uncontrolled systemic infection, which is associated with low blood pressure and multiple organ failure (Parillo, 1993, N Engl J Med 328: 1471-1477). The primary treatment of acute peritonitis remains the administration of antibiotics, either intraveinously or intra-peritoneally. In order to limit the increased reabsorption of glucose, dialysates containing low glucose concentration should be used. In parallel, ultrafiltration can be maintained by using an icodextrin solution during the exchange. Icodextrins are large molecular weight glucose polymers, capable of serving as osmotic agents instead of glucose in peritoneal dialysis solutions. Finally, the dialysis solutions may include mixtures of nutritionally essential amino acids, like methionine, tryptophan, and isoleucine, and nutritionally non-essential amino acids, like glycine and alanine, to enhance the patient's anabolic state and replace protein loss in the dialysate experienced during peritonitis. However, the presence of the amino acids in conventional dialysis solutions may be counterproductive too, because many of these amino acids can inhibit the proliferation of mesothelial cells. Furthermore, other known peritoneal dialysis solutions for use during and immediately after an episode of peritonitis are described in US patent NO 5,955,450. These solutions include one or more additives. One additive is a mixture of amino acids sufficient to maintain a positive nitrogen balance, at least one of the amino acids being present in a dipeptide form. Another additive is a compound that scavenges free radicals generated by peritoneal macrophages activated by the peritonitis. Another additive is chondroitin sulfate that changes the permeability of the peritoneal membrane during subsequent dialysis using solutions free of chondroitin sulfate. Other additives are degradation products of hyaluronic acid, which enhance the regeneration of the peritoneal mesothelium without fibrosis. The additives protect against peritonitis-associated inflammatory reactions, fibrosis and loss of ultrafiltration performance.
However, although administration of the above-mentioned dialysis solutions may provide possibilities to treat some pathological effects caused by acute peritonitis, their administration will not reverse the permeability modifications which may comprise an increased permeability for small solutes and glucose, faster glucose absorption from the dialysate, decreased free- water permeability, loss of mesothelial cells, fibrosis, or increased protein loss in the dialysate. Furthermore, the mentioned dialysis solutions have no influence on hypotension caused by peritonitis-induced septic shock.
Nitric oxide (NO) has been shown to play an important role in inflammatory responses. NO levels may increase in subjects undergoing an inflammatory disease. Consequently, in order
to treat subjects afflicted by an inflammatory disease lowering of the NO levels was proposed. Therefore, compounds inhibiting NO synthesis and acting on the enzymes catalyzing nitric oxide production may be used. NO is produced from L-arginine by a family of NO synthase (NOS) isoforms that are expressed in a large variety of tissues and cells (Bredt et al. 1994, Annu Rev Biochem 63:175-195; Kone, 1997, Am J Kidney Dis 30: 311-333). The neuronal and endothelial NOS, nNOS and eNOS respectively, are constitutive isoforms and their activity depends on the intracellular concentration of Ca2+. The inducible NOS, iNOS, is regulated at transcriptional level and its activity is independent of Ca2+ (Bredt er a/. 1994). The use of NOS inhibitors, such as for example amino-substituted guanidines, to treat subjects afflicted with an inflammatory disease is described in the patent applications WO-A1 -9612483 and WO-A1 -9735566. Several other compounds are known to inhibit NOS and lower the NO production, including L-arginine-derived drugs or various drugs mixtures, as described in document WO-A1 -9511014 or document WO-A1 -9848826. Their use in the treatment of peritonitis has also been described, for example by Breborowicz et al. (1998, Peril Dial. Internal 18:188-192).
However, it is very important to note that none of the above-mentioned documents, wherein NOS-inhibitors are administered to lower NO levels, has reported the possibility to treat or even reverse the permeability modifications caused by acute peritonitis during peritoneal dialysis. There remains a need for a method usable to reverse the permeability modifications that are caused by acute peritonitis during peritoneal dialysis. It is an object of present invention to provide a method that can reverse at least one of the permeability modifications caused by peritonitis during peritoneal dialysis. The present invention provides a method for reversing the increase in permeability for small solutes and glucose, the faster glucose absorption from the dialysate, the decrease of free-water permeability, the loss of ultrafiltration (UF), and/or the increase in protein loss in the dialysate.
SUMMARY
In a first aspect, the present invention relates to a method of reversing at least one of the permeability modifications caused by acute peritonitis by adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution. Present invention provides a rapid, effective and accurate method to reverse the permeability modifications caused by acute peritonitis.
In a second aspect, the invention concerns a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for reversing at least one of the permeability modifications caused by acute peritonitis.
In a third aspect, the present invention relates to the use of a NOS inhibitor in the preparation of a medicament for reversing at least one of the permeability modifications caused by acute peritonitis.
Further scope of the applicability of the present invention will become apparent from the detailed description provided below. It should be understood, however, that the following detailed description and examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from the following detailed description.
DETAILED DESCRIPTION In a first embodiment the present invention relates to a method of reversing at least one of the permeability modifications caused by acute peritonitis by adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution.
In the context of the present invention "permeability modifications" are defined as detrimental effects resulting from the peritoneal dialysis process. In the present invention the term "permeability modifications" refers to:
- a loss of ultrafiltration,
- an increased protein loss in the dialysate,
- an increased permeability for small solutes such as urea and glucose,
- a loss of free-water permeability, or - a fast glucose absorption from the dialysate.
The method of the present invention provides the possibility to reverse several permeability modifications associated with acute peritonitis.
The term "dialysis" is defined as a method of separating crystalloids and colloids in solution by differences in their rates of diffusion through a semi-permeable membrane. In "peritoneal dialysis", the membrane comprises the peritoneum and tissues, which separate it from the circulating blood. "Ultrafiltration" is defined as the diffusion of water across the peritoneal membrane during dialysis.
For example, the method of treatment of a human subject for reversing at least one of the permeability modifications caused by acute peritonitis according to the invention may comprise the steps of:
- adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution; - introducing into the peritoneal cavity of the human subject said peritoneal dialysis solution; and reversing at least one of the permeability modifications caused by acute peritonitis. The serial application of the described dialysis solution may be applied as part of a treatment for existing dialysis-induced peritonitis. The peritoneal dialysis solutions, which are administered according to the method of present invention, may be specially formulated for patients for use during and immediately after episodes of peritonitis. The solutions promote the reversion of the permeability modifications of peritonitis upon the dialysis regime of the patient. Like conventional peritoneal dialysis solutions, the solutions that embody the features of the invention may include (1) physiological salts such as sodium chloride, calcium chloride and sodium acetate in appropriate concentrations to maintain a normal electrolyte profile. Typical concentrations are from 116 to 140 mEq/liter of sodium; 0 to 6 mEq/liter of calcium, and 100 to 144 mEq/liter of chloride.
(2) lactate or bicarbonate in appropriate concentrations to maintain a physiologically tolerable pH of between about 5 to about 7.4. Typical concentrations are from 30 to 45 mEq/liter of lactate; and
(3) glycerol or glucose polymers, for example icodextrine, at a concentration sufficient to generate the necessary osmotic pressure to remove water from the patient through ultrafiltration. According to the invention, at least one additive compound selected form the group consisting of nitric oxide inhibitory compounds is added to the dialysis solutions. In a further embodiment, the present invention relates to a method wherein said nitric oxide inhibitory compound is a NOS inhibitor. More particularly, the present invention relates to a method wherein said NOS inhibitor is an iNOS inhibitor and/or eNOS inhibitor. NO is considered as a key mediator of peritoneal permeability. An increase in peritoneal permeability can be observed when administering the NO donor nitroprusside in animal models (Nolph et al. 1977, ASAIO Trans 23:210-218) and stable peritoneal dialysis patients (Douma et al. 1997, Kidney Int. 51 :1885-1892).
Furthermore, permeability modifications observed in acute peritonitis may be the consequence of increased NO production mediated by the upregulation of NOS isoforms in the peritoneum. Acute peritonitis induces a major increase in NOS activity and upregulates both eNOS and iNOS in the peritoneum (Devuyst et al. 2001 , Nephrol. Dial. Transplant 16:675-678). The induction of iNOS is variable in intensity and related to the severity of the peritonitis (Combet et al. 2000, Kidney Int. 57: 332-338). In a well-characterized model of acute peritonitis in rats, for example, the local generation of NO, secondary to the upregulation of NOS isoforms, induces major, detrimental changes in peritoneal permeability. Therefore, acute inhibition of the iNOS and/or eNOS isoforms can result in an accurate lowering of the NO levels in the peritoneum and can reverse the permeability modifications caused by the peritoneal inflammation. In addition, as by lowering the NO levels, the cause of the inflammation is anticipated, this peritoneal dialysis solution will provide more accurate and rapid effects than a conventional dialysis fluid. In a more preferred embodiment present invention relates to a method wherein the NOS inhibitor is an L-arginine analogue. These analogues may be selected from a group comprising NG-nitro-L-arginine methyl ester (L-NAME), NG-monoethyl-L-arginine (L-MMA), N-iminoethyl-L-arnithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), L-NG-methyl- arginine (L-NMA), Nw-nitro-L-arginine (L-NA), and mixtures thereof. Analogues of L-arginine can inhibit the production of NO by NOS isoforms. For instance, L-NAME has proven to be one of the most useful NOS inhibitors due to its low cost, commercial availability, chemical stability, solubility in water, and effectiveness in the millimolar range both for tissue studies and in vivo investigations (Breborowicz et al. 1998, Peril Dial. Internal 18:188-192; Griffith and Kilbourn 1996, Methods Enzymol 268: 375-392; Hobbs et al. 1999, Annu. Rev. Pharmacol. Toxicol. 39: 191-220). Addition of L-NAME to a dialysis solution does not induce clinical or biological side-effects, and does not alter the morphology of the peritoneum.
Some of the NOS inhibitors proposed, such as for example L-NAME and L-NMMA, are non- selective in that they inhibit both the constitutive (eNOS) and the inducible NO synthase (iNOS). Use of such non-selective NO synthase inhibitors requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO- synthase including hypertension and possible thrombosis and tissue damage. While non- selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive NO synthase are
preferred as they would be of even greater therapeutic benefit and easier to use (Hobbs et al. 1999, Annu. Rev. Pharmacol. Toxicol. 39: 191-220).
The administration of NOS inhibitors to subjects, in need of a treatment, as additives to a dialysis solution has several advantages. Besides the possibility to reverse at least one of the above-described permeability modifications, use of NOS inhibitors in dialysis solutions results in easier formulation and administration, faster effects, and the possibility to determine more accurate dosages. In addition, by administering the inhibitors as additives in dialysis solutions, acute and severe hypertension, which generally results from systemic infusion of compounds, can be minimised. In another embodiment, present invention relates to a method wherein the nitric oxide inhibitory compound is added to said peritoneal dialysis solution in a suitable concentration. This suitable concentration may depend on the body weight of a subject in need of said solution. In another embodiment, present invention relates to a method wherein said nitric oxide inhibitory compound is in a pharmaceutically acceptable formulation. Another embodiment of the present invention relates to a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for reversing at least one of the above-described permeability modifications caused by acute peritonitis. Consequently, in a further embodiment, present invention relates to the use of a NOS inhibitor in the preparation of a medicament for reversing at least one of the permeability modifications caused by acute peritonitis. As mentioned above, the permeability modifications may comprise an ultrafiltration loss, a protein loss in the dialysate, an increased peritoneal permeability for small solutes, a decreased free-water permeability or a fast glucose absorption from the dialysate. In addition, in another embodiment, the method of the invention provides a solution for treating hypotension caused by peritonitis-induced septic shock. The present invention also relates to a pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for treating hypotension caused by a peritonitis-induced septic shock. The present invention further concerns the use of a NOS inhibitor in the preparation of a medicament for treating hypotension caused by a peritonitis-induced septic shock. Furthermore, the method according to the invention allows minimising the induction of tissue damage of the peritoneal membrane. During sequential dialysis operations, the risk of developing peritonitis exists. Peritonitis is believed to induce the production of NO, which can have direct as well chronic effects on the peritoneal membrane. Therefore, sequential dialysis operations accompanied by the sequential induction of peritonitis associated with NO
production, may cause serious tissue and cell damage to the peritoneal membrane. By administering NOS inhibitors to the dialysis solution according to the present invention, the damage to the peritoneal membrane, secondary to the induction of NO during peritonitis, may therefore be minimised. Therefore, in another embodiment, the invention relates to a pharmaceutical composition, comprising a NOS inhibitor and a suitable excipient, for minimising the induction of tissue damage of the peritoneal membrane. The present invention also relates to the use of a NOS inhibitor in the preparation of a medicament for minimising the induction of tissue damage of the peritoneal membrane. The following non-limiting examples and associated drawings illustrate the benefits of using a NOS inhibitor in a dialysis solution. Example 1 provides an overview of permeability modifications, which may be associated with peritonitis in a rat model, while example 2 provides evidence for increased NOS expression and increased NOS enzymatic activities in the peritoneum during acute peritonitis in the rat model. Example 3 describes the effects of NOS-inhibitor L-NAME on the peritoneal permeability during acute peritonitis in a rat model.
DETAILED DESCRIPTION OF FIGURES
Figure 1 relates to the effects of acute peritonitis on NOS expression in the peritoneum. This figure represents immunoblot analysis for eNOS and iNOS in peritoneum extracts prepared from control rats and rats with acute peritonitis (40 μg protein/lane, 6 samples in each group). Extracts from bovine aortic endothelial cells (eNOS) and mouse macrophages (iNOS) were used as positive controls (lane C).
Figure 2 relates to the effects of acute peritonitis on NOS enzymatic activity in the peritoneum. NOS enzymatic activities in the peritoneum of control rats (C) and rats with acute peritonitis (P) are shown. Black bars represent total NOS activity (in pmol citrulline/mg protein/min), hatched bars represent Ca2+-dependent NOS activities and open bars represent Ca2+-independent NOS activities. * p < 0.05 between peritonitis and control rats. Figure 3 shows the effect of L-NAME on functional parameters of peritoneal dialysis in control and peritonitis rats. The dialysate-to-plasma (D/P) ratio of urea (A) and sodium (C), and the progressive removal of glucose from the dilaysate (D/D0, B) are represented in control rats (open symbols), and rats with peritonitis (black symbols), during a 2 h-exchange with 15 mL of 7% glucose supplemented (triangles) or not (squares) with 5 mmol/L L-NAME. All parameters were obtained for 6 rats in each group. Acute peritonitis induces a significant increase in permeability for urea and glucose, and a loss of sodium sieving (*p < 0.05 vs. C).
These modifications are significantly reduced when L-NAME is added to the dialysate (#p < 0.05 vs. P).
Figure 4 shows the effects of acute peritonitis and addition of L-NAME in the dialysate on ultrafiltration, protein loss in the dialysate, and urea permeability during peritoneal dialysis in rats.
A: Net ultrafiltration (volume in - volume out, in mL);
B. Total protein concentration in the dialysate (in g/L);
C. Cumulative urea permeability during the dwell (area under the curve for the 120 min-dwell, in min) in control rats (C, open bars) and rats with acute peritonitis (P), untreated (black bars) or treated (hatched bars) with different doses of L-NAME (2.5, 5 and 10 mmol/L) in the dialysate. * p < 0.05 vs. C; # p < 0.05 vs. P.
EXAMPLE 1 Clinical and biological parameters associated with acute peritonitis in a rat model Following example provides an overview of permeability modifications, associated with peritonitis in a rat model.
Adult (8 wks) male Sprague-Dawley rats (Iffa Credo, Brussels, Belgium) weighing 279 ± 2 g were randomly assigned to control and peritonitis groups. Peritonitis was induced by non- sterile implantation of a peritoneal catheter under anesthesia with SC Nembutal® (Sanofi, Brussels) (day 1) followed for 6 days by a daily, 2 h-exchange with 15 mL of 1.36% glucose dialysate (DianealR, Baxter, Nivelles, Belgium). Both catheter insertion and PD exchanges were performed without aseptic precautions, in order to reflect manipulation errors and touch contamination from the skin flora in PD patients. Control rats matched for age and weight were left untouched for 6 days. All rats had access to standard chow and tap water ad libitum.
On day 7, control and peritonitis rats were anesthesized to perform a 2 h-exchange PD with 15 mL of a 7% glucose dialysate (Dianeal). Blood and dialysate samples were obtained before (T0), at 30 min (T30), 60 min (T60), and 120 min (T120) of dwell time, glucose, sodium, potassium, total protein, and osmolality, were assayed by standard methods. White blood cells (WBC) in the dialysate (elts/μl) were counted and dialysate cultures were obtained. Rats with positive culture and WBC count in the dialysate > 1500 elts /μl were considered as having peritonitis. They represented 75% of rats that have been infected according to the protocol. In comparison with controls, rats with acute peritonitis were characterized by
(i) decreased UF (7.6 ± 0.5 vs. 1 ± 1 mL, p < 0.001),
(ii) increased protein loss in the dialysate (0.8 ± 0.1 vs. 4.7 ± 0.9 g/L, p < 0.001);
(iii) cloudy dialysate with increased WBC count (9844 ± 3335 vs. 313 ± 35 elts/μl, p =
0.03); and (iv) bacteria-containing dialysate cultures.
There was a significant, inverse correlation between the magnitude of UF and the severity of peritonitis as reflected by WBC count in the dialysate (p = 0.03; r2 = 0.31). In conclusion, using the rat model, the induction of several permeability modifications caused by peritonitis is demonstrated.
EXAMPLE 2 NOS expression and enzymatic activities in the peritoneum during acute peritonitis in a rat model
The expression of NOS and the enzymatic activities of the NOS in the peritoneum during acute peritonitis in a rat model were assessed. The rats described in example 1 were sacrificed by exsanguination at the end of the dwell and similar samples from the parietal and visceral peritoneum were processed for protein extraction. All experiments were conducted in accord with local prescriptions and the NIH Guide for the Care and Use of Laboratory Animals. SDS-PAGE and immunoblotting were performed as according to method known in the art. Efficiency of transfer to nitrocellulose was routinely tested by Ponceau red (Sigma) staining and beta-actin immunoreactivity (Sigma). The membranes were blocked for 30 min at room temperature, followed by incubation with monoclonal antibodies raised against eNOS and iNOS at 4°C for 16-18 h. After washing, the membranes were incubated for 1 h at room temperature with peroxidase-labeled secondary antibodies (Dako), before visualization with enhanced chemiluminescence (Amersham, Little Chalfont, UK). Negative controls included incubation with non-immune mouse IgG (Dako). NOS enzymatic activities were measured using the L-citrulline assay according to methods known in the art. Total NOS activity was assayed by the conversion of L-[3H]-arginine to L- [3H]-citrulline in the visceral peritoneum. Assays were performed with or without Ca2+ to measure total vs. Ca2+ -independent NOS activities, and calculate Ca2+-dependent NOS activity. Briefly, 25 μL of tissue extract (350 μg of total protein) containing 20 mM CHAPS were added to 200 μL of Tris buffer (50 mM, pH 7.4) containing 10 mM DTT, 10 μg/ml calmodulin, 1 mM NADPH, 4 μM FAD, 4 μM FMN, 2 μM L-arginine, and 10"3 mCi/mL L-[3H]- arginine. Assays were performed for 30 min at 37°C and stopped with 2 mL of ice-cold stop buffer (20 mM CH3COONa, pH 5.5, containing 2 mM EDTA, 0.2 mM EGTA, and 1 mM L-
citrulline). L-[3H]-citrulline was separated by cation-exchange chromatography and quantified by liquid scintillation. The NOS activity (pmol citrulline/mg protein/min) was determined by subtracting counts obtained with or without 1 mM L-NMMA. Determinations were performed in duplicate on 3 randomly selected samples in each group. Immunoblot analyses (Figure 1) confirmed that acute peritonitis induced a significant upregulation of both the endothelial (140 kDa) and inducible (130 kDa) NOS isoforms in the peritoneum. A consistent upregulation of eNOS (140 kDa) is detected in samples from rats with acute peritonitis. In rats with acute peritonitis, the signal for iNOS, 130 kDa (lower band of the blot), which is never detected in control samples, is upregulated with variable intensity, ranging from weak to very strong as shown in the lower band of the gel on Figure 1. The monoclonal antibody against iNOS cross-react with eNOS (middle band at 140 kDa) and nNOS (upper band at 155 kDa).
The upregulation of NOS isoforms in the peritoneum was reflected by a significant increase in total NOS activity of 0.39 ± 0.04 vs. 0.12 ± 0.06 pmol citrulline/mg protein/min (p < 0.01), due to both Ca2+-dependent and Ca2+-independent NOS isoforms (Figure 2).
In conclusion, this example provides evidence for increased NOS expression and increased enzymatic NOS activities in the peritoneum during acute peritonitis in a rat model.
EXAMPLE 3 Peritoneal permeability during acute peritonitis in a rat model and effects of NOS-inhibitor L-NAME
This example describes the several permeability modifications associated with acute peritonitis in a rat model and the effects of NOS-inhibitor L-NAME thereon. Acute peritonitis induces a major increase in peritoneal permeability for small solutes such as urea (Figure 3A), a faster glucose absorption from the dialysate (Figure 3B), and a reduced free-water permeability, as attested by the loss of sodium sieving (Figure 3C). These changes are reflected by a fall in UF and an increased protein loss in the dialysate (see also example 1; Figure 4A-B), as well as an increased cumulative urea transport during the 2 h-dwell (Figure 4C). Addition of 5 mmol/L L-NAME to the dialysate in control rats did not change peritoneal permeability parameters (Figure 3A-C), and was not reflected by significant changes in UF (- vs. + L-NAME : 7.6 + 0.5 vs. 8.8 ± 0.5 mL) and protein loss in the dialysate (- vs. + L-NAME : 0.8 ± 0.1 vs. 1 ± 0.1 g/L). The lack of functional consequences of NOS inhibition in control rats shows that NO does not influence significantly peritoneal permeability in stable,
uninfected peritoneal dialysis. Thus, the very low levels of bioactive NO generated by the peritoneum during stable, uninfected PD, do not critically affect peritoneal permeability. In contrast, addition of 5 mmol/L L-NAME to the dialysate in rats with acute peritonitis significantly reduced the hyperpermeability to urea and glucose (Figure 3A-B), and significantly improved the dialysate-over-plasma ratio for sodium (Figure 3C). Also, treatment with L-NAME in rats with acute peritonitis induced a significant increase in the dialysate-over- plasma ratio for osmolality at T30, from 2.29 ± 0.02 (P) to 2.34 ± 0.02 (P-LA5) and further to 2.42 + 0.03 (P-LA10). The effect of L-NAME on UF was maximal at 2.5 mmol/L (Figure 4A), whereas the effect on protein loss and permeability for urea was dose-dependent and maximal at 10 mmol/L (Figure 4B-C).
In conclusion, inhibition of NOS in the peritoneum during acute peritonitis significantly improves UF and reduces protein loss in the dialysate.
Claims
1. A method of reversing at least one of the permeability modifications caused by acute peritonitis by adding at least one nitric oxide inhibitory compound to a peritoneal dialysis solution.
2. A method according to claim 1 whereby said permeability modification consists of an ultrafiltration loss.
3. A method according to claim 1 whereby said permeability modification consists of a protein loss in the dialysate.
4. A method according to claim 1 whereby said permeability modification consists of an increased peritoneal permeability for small solutes.
5. A method according to claim 1 whereby said permeability modification consists of a decreased free-water permeability.
6. A method according to claim 1 whereby said permeability modification consists of a fast glucose absorption from a dialysate.
7. A method according to claim 1 for treating hypotension caused by a peritonitis-induced septic shock.
8. A method according to claim 1 , for minimising the induction of tissue damage of the peritoneal membrane.
9. A method according to any of claims 1-8, wherein said nitric oxide inhibitory compound is a NOS inhibitor.
10. A method according to claim 9, wherein said NOS inhibitor is an iNOS inhibitor and/or eNOS inhibitor.
11. A method according to claim 10 wherein said NOS inhibitor is an L-arginine analogue.
12. A method according to any of claims 9-11 wherein said NOS inhibitor is chosen from the group comprising NG-nitro-L-arginine methyl ester (L-NAME), NG-monoethyl-L-arginine (L-MMA), N-iminoethyl-L-arnithine (L-NIO), NG-monomethyl-L-arginine (L-NMMA), L-NG- methyl-arginine (L-NMA), Nw-nitro-L-arginine (L-NA), and mixtures thereof.
13. A method according to any of the claims 9-12 wherein said NOS inhibitor is L-NAME.
14. A method according to any of the claims 1-13 wherein said one nitric oxide inhibitory compound is added to said peritoneal dialysis solution in a suitable concentration depending on the body weight of a subject in need of said solution.
15. A method according to any of the claims 1-14 wherein said nitric oxide inhibitory compound is in a pharmaceutically acceptable formulation.
16. A pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for reversing at least one of the permeability modifications caused by acute peritonitis.
17. A pharmaceutical composition according to claim 16 whereby said permeability modification consists of an ultrafiltration loss.
18. A pharmaceutical composition according to claim 16 whereby said permeability modification consists of a protein loss in the dialysate.
19. A pharmaceutical composition according to claim 16 whereby said permeability modification consists of an increased peritoneal permeability for small solutes.
20. A pharmaceutical composition according to claim 16 whereby said permeability modification consists of a decreased free-water permeability.
21. A pharmaceutical composition according to claim 16 whereby said permeability modification consists of a fast glucose absorption from the dialysate.
22. A pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for treating hypotension caused by a peritonitis-induced septic shock.
23. A pharmaceutical composition comprising a NOS inhibitor and a suitable excipient for minimising the induction of tissue damage of the peritoneal membrane.
24. Use of a NOS inhibitor in the preparation of a medicament for reversing at least one of the permeability modifications caused by acute peritonitis.
25. Use of a NOS inhibitor according to claim 24 whereby said permeability modification consists of an ultrafiltration loss.
26. Use of a NOS inhibitor according to claim 24 whereby said permeability modification consists of a protein loss in the dialysate.
27. Use of a NOS inhibitor according to claim 24 whereby said permeability modification consists of an increased peritoneal permeability for small solutes.
28. Use of a NOS inhibitor according to claim 24 whereby said permeability modification consists of a decreased free-water permeability.
29. Use of a NOS inhibitor according to claim 24 whereby said permeability modification consists of a fast glucose absorption from the dialysate.
30. Use of a NOS inhibitor in the preparation of a medicament for treating hypotension caused by a peritonitis-induced septic shock.
31. Use of a NOS inhibitor in the preparation of a medicament for minimising the induction of tissue damage of the peritoneal membrane.
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| PCT/EP2002/004033 WO2003084528A1 (en) | 2002-04-11 | 2002-04-11 | A method for reversing permeability modifications caused by acute peritonitis |
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| US9254279B2 (en) | 2004-05-12 | 2016-02-09 | Baxter International Inc. | Nitric oxide scavengers |
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Non-Patent Citations (7)
| Title |
|---|
| BREBOROWICZ A; WIECZOROWSKA-TOBIS K; KORYBALSKA K; ET AL: "The effect of a nitric oxide inhibitor (L-NAME) on peritoneal transport during dialysis in rats", PERITONEAL DIALYSIS INTERNATIONAL, vol. 18, pages 188 - 192, XP009003812 * |
| FERRIER M-L; COMBET S; LANDSCHOOT M V; ET AL: "Inhibition of nitric oxide synthase reverses changes in peritoneal permeability in a rat model of acute peritonitis", KIDNEY INTERNATIONAL, vol. 60, 2001, pages 2343 - 2350, XP002228577 * |
| KILBOURN R G; JUBRAN A; GROSS S S; ET AL: "Reversal of endotoxin-mediated shock by NG-methyl-L-arginine, in inhibitor of nitric oxide synthesis", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 172, no. 3, 15 November 1990 (1990-11-15), pages 1132 - 1138, XP009004377 * |
| LIN M-C; EBIHARA S; DWAIRI Q E; ET AL: "Diaphragm Sarcolemmal injury is induced by sepsis and alleviated by nitric oxide synthase inhibition", AM J RESPIR CRIT CARE MED, vol. 158, pages 1656 - 1663, XP002228578 * |
| NARAYANAN K; SPACK L; MCMILLAN K; KILBOURN R G; ET AL: "S-Alkyl-L-thiocitrullines", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 19, May 1995 (1995-05-01), pages 11103 - 11110, XP002090570 * |
| PETROS A ET AL: "EFFECT OF NITRIC OXIDE SYNTHASE INHIBITORS ON HYPOTENSION IN PATIENTS WITH SEPTIC SHOCK", LANCET THE, LANCET LIMITED. LONDON, GB, vol. 338, no. 8782-8783, 21 December 1991 (1991-12-21), pages 1557 - 1558, XP000979414, ISSN: 0140-6736 * |
| SCHILLING J; CAKMAKCI M; BÄTTIG U; GEROULANOS S: "A new approach in the treatment of hypotension in human septic shock by NG-monomethyl-L-arginine, an inhibitor of the nitric oxide synthestase", INTENSIVE CARE MED, vol. 19, 1993, pages 227 - 231, XP000981558 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US9254279B2 (en) | 2004-05-12 | 2016-02-09 | Baxter International Inc. | Nitric oxide scavengers |
| US9511053B2 (en) | 2004-05-12 | 2016-12-06 | Baxter International Inc. | Nitric oxide scavengers |
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