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WO1997038686A1 - Utilisation d'un osmolyte pour traiter les effets d'une infection, d'une inflammation ou d'une dysfonction du systeme immunitaire - Google Patents

Utilisation d'un osmolyte pour traiter les effets d'une infection, d'une inflammation ou d'une dysfonction du systeme immunitaire Download PDF

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Publication number
WO1997038686A1
WO1997038686A1 PCT/EP1997/001862 EP9701862W WO9738686A1 WO 1997038686 A1 WO1997038686 A1 WO 1997038686A1 EP 9701862 W EP9701862 W EP 9701862W WO 9738686 A1 WO9738686 A1 WO 9738686A1
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Prior art keywords
osmolyte
betaine
cells
amino acids
taurine
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PCT/EP1997/001862
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English (en)
Inventor
Dieter Häussinger
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Haeussinger Dieter
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Priority to JP9536746A priority Critical patent/JP2000508331A/ja
Priority to AU26971/97A priority patent/AU2697197A/en
Priority to EP97920677A priority patent/EP0910361A1/fr
Publication of WO1997038686A1 publication Critical patent/WO1997038686A1/fr
Priority to NO984760A priority patent/NO984760L/no

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/047—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates having two or more hydroxy groups, e.g. sorbitol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents

Definitions

  • the present invention relates to the use of osmolytes in the manufacture of therapeutic agent for treating the effects of an infection, inflammation or for treating an immune dysfunction.
  • Liver macrophages or Kupffer cells belong to the mononuclear phagocyte system and play an important role in the body's defense machinery, see e.g. Eur J Biochem, 1990, Vol. 192, pag. 245-261 ; K Decker.
  • the Kupffer cells are the major producer of eicosanoids, such as prostaglandin E2 , D2 and thromboxane A2 in the liver.
  • the eicosanoid production by the Kupffer cells plays a major role in the pathogenesis of septic shock and may contribute to liver cell damages under these conditions.
  • eicosanoids The formation of eicosanoids is dependent on enzymatic conversion of arachidonic acid by cyclooxygenase (Cox) which appears in two iso-forms.
  • Cox-1 One form is constitutively expressed, whereas one form (Cox-2) is induced in macrophages upon the response to proinflammatory stimuli.
  • osmolytes In mammals, osmolytes have been identified in astrocytes, renal medulla cells and lens epithelia. The need for osmolytes in renal medulla cells is obvious, because ambient medullary osmolarity can increase up to 3800 mosmol/1 during antidiuresis and decrease to 170 mosmol/1 during diuresis. In the antidiuretic state (high extracellular osmolarity), intracellular osmolarity increase in renal medullary cells as the result of the intracellular accumulation of inositol and betaine, which are taken up via Na+-dependent transporters. These Na+-dependent transporters are induced upon hyperosmotic exposure in renal cells and astrocytes. Recent studies with Madine-Darby canine kidney (MDCK) cells have identified a hypertonic stress-responsive element in the 5 '-flanking region of the mammalian BGT-1 gene (betaine transporter).
  • MDCK Madine-Darby can
  • betaine is identified as an osmolyte in mouse macrophages.
  • the betaine uptake in mouse macrophages was significantly stimulated when the cells were exposed to a hyperosmotic (450 mosm/1) medium. From the results of this study it was concluded that betaine availability could be a potential site for the regulation of macrophage cell function.
  • Certain organic osmolytes have previously been suggested in the
  • the present invention it has been surprisingly found that certain organic osmolytes, such as betaine, have a powerful capacity, besides restoring the intracellular osmolality to ambient levels, to affect cellular functions which are parts of the mechanisms of inflammation, infection and immune dysfunction.
  • the present invention shows a suppression of the levels of cyclooxygenase-2 and thereby also the production of eicosanoids, such as prostaglandin E2, produced following endotoxin challenge.
  • eicosanoids such as prostaglandin E2
  • compositions which enable the treatment or prevention of an infection, an inflammation or an immune dysfunction, for example by a therapeutically effective supplementation of at least one osmolyte to a parenteral nutrient which is modified to facilitate cellular osmolyte uptake.
  • the osmolytes being used according to the present invention are particularly aimed to affect cells which have an active part in producing mediators of said complications or have an active part in the immune system.
  • Such cells typically include, but are not limited to, immune competent cells, endothelial cells and hepatocytes and are examplified below by macrophages, Kupffer cells, and liver sinusoidal endothelial cells.
  • the effects originating from infection, inflammation and immune dysfunction which are treatable by the utility of the present invention include, but are not limited to, an increase in the cellular cyclooxygenase activity, an increase in the cellular inducible nitric oxide synthase levels, raised TNF-levels as typically triggered by bacterial endotoxins, cytokines, microorganisms or their fragments or products, other inflammatory mediators appearing as a result of inflammatory conditions, the transition to neoplastic cells, other dysfunctions of the immune system, or from tissue injuries.
  • These effects can be followed by cell death in vital organs, such as programmed cell death (apoptosis) or necrosis which consequently also can be treated by inventive osmolyte therapy.
  • the mentioned effects can also be accompanied by cellular volume changes induced by plasma hyperosmolarity, for example in severe infectious diarrhea where extensive fluid losses are elicited and in other fluid imbalance conditions where a fluid therapy is mandatory.
  • osmolytes are defined as agents that can be used by the cells for regulation of the cell hydration by a specific transport mechanism through the cellular membranes. Such agents have traditionally not been considered to intervene to alter the cellular metabolism, except for their function as substrates in metabolic pathways.
  • the osmolytes used according to the present invention are preferably selected from a group of organic osmolytes consisting of polyols, amino acids and methylamines that will not interfere with the cellular protein function, although being present at high intracellular concentrations.
  • Preferred osmolytes are polyols, such as myo- inositol and sorbitol, methylamines, such as betaine and alpha-glycerolphosphorylcholine and certain amino acids, such as taurine.
  • salts and precursors of such osmolytes are conceivable to use in the present invention, such as alkyl esters of suitable osmolytes and oligopeptide derivatives
  • chemical modifications of osmolytes are conceivable in order to obtain osmolytic derivatives with facilitated transmembrane transport and thereby increase their intracellular uptake.
  • Other objectives for chemical modifications can be to introduce conjugates of osmolytes with improved target seeking and capacity, to obtain a desired solubility, polarity or physical stability.
  • inositols amino acids and methylamines.
  • taurine, betaine and myo-inositol their salts and precursors such as functional derivatives of betaine or taurine or releasing conjugates, for example alkyl esters of betaine.
  • biological precursors of such compounds are considered as part of the present invention.
  • choline is desirable to select considering its capacity to be conversed to betaine in certain cell types, such as hepatocytes, for transportation to betaine deficient cells without such capacity, such as Kupffer cells.
  • mixtures of the mentioned osmolytes can be a part of the present invention, for example mixtures of amino acids and methylamines with osmolytic capacity.
  • a preferred combination of osmolytes is taurine and betaine in effective amounts.
  • the present invention provides for a new use of osmolytes in therapy and provides new compositions together with selected nutrients. It is obvious that the present invention is applicable in the treatment of reducing the effects of infection, inflammation and immune dysfunction in any pathological condition which involves osmotic stress on cells or tissues or in conditions were osmolyte supply or synthesis is inadequate.
  • Such conditions involving osmotic stress can result from fluid losses, for example from diarrhea, burns and sepsis, or be the result of increased levels of circulating metabolites, for example urea and glucose.
  • Increased urea levels can appear as a consequence of increased protein catabolism, e.g. post trauma, or from impaired nitrogen metabolism including the state of uremia.
  • An increase in circulating levels of glucose is a well recognized complication in diabetes as well as reversible insulin resistance, in the catabolic state following trauma and during the progress of certain cancer forms.
  • osmolytes would also be useful in the treatment of colon cancer involving an increase in cyclooxygenase levels where conventionally non-steroidal antiinflammatoric drugs are administered to suppress the carcinogenity.
  • Conventionally used parenteral nutrition products as required by many patients suffering from the above-mentioned complications, generally are low or even completely deficient in betaine and its precursor choline.
  • the betaine deficiency facilitates an augmented eicosanoid production which is known to precipitate cholestasis, a well recognized inflammatory complication in the bile ducts which might appear during parenteral nutrition.
  • the osmolyte is used together with a parenteral or enteral nutrient solution deficient compounds interfering with the osmolyte uptake in immune competent cells.
  • a parenteral or enteral nutrient solution deficient compounds interfering with the osmolyte uptake in immune competent cells.
  • nut ⁇ ents are fluid sources of amino acids comprising am o acids or conjugates thereof (e g peptides) or amino acid precursors, lipid emulsions comprising certain beneficial long-chain fatty acids and/or medium chain fatty acids as energy suppliers and sugars or carbohydrates.
  • compositions are selected to effectively combine osmolyte therapy with an approp ⁇ ate nut ⁇ tional therapy suitably adapted in its composition to patients suffering from severe infections or inflammatory conditions or impairments of the immune system
  • Such diets are well-known and can be made available for enteral or parenteral administration and the skilled practitioner can readily adapt them to be administered together with an osmolyte by removing certain amino acids (or other compounds) which may interfere with the cellular osmolyte uptake.
  • the osmolytes are selected among ammo acids and methylamines it is preferred that the nut ⁇ ents are deficient in certain amino acids interfe ⁇ ng with the cellular uptake of osmolytes.
  • osmolyte specifically is a betaine (or a salt or precursor thereof) it is preferred that a composition is deficient in alanine and proline, which means that it either lacks these amino acids or that it has a suitably low level of them in order to minimize their interference with the cellular osmolyte uptake.
  • the osmolyte is selected among methylamines and amino acids with osmolytic capacity formulated in an enteral or parenteral composition optionally together with one or several nutrients selected from a fluid amino acid source, a lipid emulsion and carbohydrates
  • This composition can further comp ⁇ se such constituents conventionally used m nut ⁇ tion, such as vitamins, trace elements, electrolytes, as well as drugs suitable to administer to a patient in a specific clinic situation, such as antibiotics and anesthetics
  • the composition comprises such an amount of the osmolytes so a plasma concentration within the approximate range of 0 01 to 10 mM and a preferred range 0 1 to 1-2 mM is obtained after its administration
  • the most preferred osmolytes according to the present invention are betaine and taurine and their salts or conjugates (functional equivalents) which can be used either alone or together
  • the following part aims to exemplify the present invention and shall not be regarded as limiting for the scope
  • Fig 1 shows time-dependent induction of BGT-1 (betaine transport protein) and Cox-2 mRNA levels in Kupffer cells du ⁇ ng hyperosmola ⁇ ty
  • BGT-1 betaine transport protein
  • Cox-2 glyceraldehydephosphate dehydrogenase
  • Fig. 2 demonstrates the induction of BGT-1 mRNA by hyperosmola ⁇ ty in unstimulated Kupffer cells.
  • Rat Kupffer cells were exposed for 12 h in hypoosmotic (205 mosmol/1), hyperosmotic (405 mosmol/1) or normoosmotic media (305 mosmol/1) and the mRNA levels for BGT-1 and GAPDH were determined by Northern blot analysis.
  • Fig. 3 displays the effect of medium osmola ⁇ ty on the mRNA levels for BGT-1, Cox-1, Cox-2 and GAPDH.
  • LPS stimulated rat Kupffer cells were exposed for 12 h to media with the osmolarity indicated. Osmolarity changes were performed by appropriate addition/removal of NaCl
  • the mRNA levels for BGT-1 and GAPDH were determined by Northern blot analysis This experiment is representative of three separate expenments.
  • Fig 4 shows the effects of betaine, taurine and glutamine on BGT- 1 mRNA levels in Kupffer cells
  • Rat Kupffer cells were exposed to hyperosmotic medium (380 mosmol/1) for 12 h
  • This medium contained no further additions (control) or betaine, taurine or glutamine at the concentrations indicated
  • the mRNA levels for BGT- 1 and GAPDH were determined by Northern blot analysis This experiment is representation of 3 different experiments Fig.
  • FIG. 5 shows the effect of betaine on the hyperosmola ⁇ ty-induced induction of Cox-2 protein (A) and mRNA (B) in LPS-stimulated Kupffer cells.
  • A Kupffer cells were exposed to LPS ( 1 ⁇ g/ml) in normoosmotic (305 mosmol 1) or hyperosmotic (405 mosmol/1) media for 24h in the absence or in the presence of betaine as indicated. Then whole cell extracts were used for Western blot analysis as described in Methods.
  • B Kupffer cells were treated to LPS in normoosmotic or hyperosmotic media with the indicated concentrations of betaine for 12 h. The mRNA levels for BGT-1 and GAPDH were determined by Northern blot analysis.
  • Fig. 6 shows the time-dependent induction of BGT- 1 (betaine transporting protein) and TAUT (taurine transporting protein) and SMIT (the myo-inositol transporter) mRNA-levels in rat Kupffer cells.
  • the Kupffer cells were exposed to LPS ( 1 ⁇ g/ml) in normoosmotic (305 mosmol/1) or hyperosmotic (405 mosmol/1) media for the time periods indicated and mRNA levels for BGT- 1, SMIT, TAUT and glyceraldehydephosphate dehydrogenase (GAPDH) as a standard were determined by Northern blot analysis.
  • BGT- 1 betaine transporting protein
  • TAUT taurine transporting protein
  • SMIT the myo-inositol transporter
  • RNA levels of COX-2 and iNOS were determined by Northern blot analysis (7 ⁇ g of total RNA per lane). Glyceraldehyde -3 -phosphatase mRNA was used for standardization.
  • Fig. 8 shows the effect of ambient osmolality on mRNA levels for the betaine transporter (BGT-1), the taurine transporter (TAUT), the myo-inositol transporter (SMIT) and GAPDH in the rat liver endothelial cells. Changes in osmolality were performed by approp ⁇ ate addition/removal of sodium chloride. The mRNA levels were determined by Northern blot analysis.
  • Fig. 9 shows the osmolarity dependent induction of the betaine transporter (BGT-1), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS) and GAPDH (as a reference) in rat Kupffer cells following exposure to LPS ( 1 ⁇ g/ml) in normoosmotic media (305 mosmol/1) or hyperosmotic media (375 mosmol/1) the mRNA levels were determined by Northern blot analysis
  • Fig 10 shows the influence of betaine on the transporters for betaine and taurine (BGT- 1 and TAUT) and on inducible nitric oxide synthase mRNA levels in RAW 264 7 mouse macrophages during hyperosmolarity
  • the macrophages were exposed to LPS (1 ⁇ g/ml) for 6 hours in the presence or absence of 0 1 or 5 mmol/1 betaine
  • the mRNA levels of the transporters and iNOS were determined by Northern blot analysis.
  • Fig 1 1 A shows the modulation of the CD95 ligand mRNA expression (a mediator for apoptosis) in rat Kupffer cells in response to LPS challenge ( 1 ug/ml for 6h)
  • the cells were not incubated with LPS.
  • 5 mmol 1 betaine was added 30 mm before and throughout the whole 6 h measurement period.
  • Total RNA was extracted, reverse transcribed and quantified by using PCR technique. Results are expressed as the ratio of number of CD95 ligand transcripts obtained with the indicated primers to the numbers of rat hypoxanthine-guamne phsopho ⁇ byltransferase (HPRT) transcripts.
  • Fig 1 1 B shows the same experiment as in Fig 1 1 A performed with rat sinusoidal endothelial cells
  • Table 1 shows how the hyperosmolarity induced betaine uptake is affected by the presence of vanous amino acids.
  • Table 2 shows the effect of betaine on the prostaglandin E2 production by lipopolysaccharide stimulated rat Kupffer cells in normosmotic and hyperosmotic medium, respectively
  • Moo Kwon (Division of Nephrology, The John Hopkins University School of Medicine, Baltimore, MD, U.S.A.).
  • the cyclooxygenase (Cox-1 and Cox-2) cDNA probes were from Cayman Chemical Company (Ann Arbor, Michigan) and the 1.0 Kb cDNA fragment for glyceraidehyde-3- phosphate dehydrogenase (GAPDH) was used for standardization was from Clontech (Palo Alto, U.S.A.).
  • FCS heat-inactivated fetal calf serum
  • Kupffer cell supematants were assayed for PGE2 by competitive binding radioimmunoassay (RLA) using [3Hllabeled PGE2 (Amersham, Braunschweig, Germany) and a specific antiserum to PGE2 (Sigma, Deisenhofen, Germany).
  • RLA radioimmunoassay
  • Kupffer cells were washed with phosphate-buffered saline, and were lysed in 100 mM NaCl containing 10 mM-Tris/HCl (pH 7.3), 2 mM EDTA, 0.5% deoxycholate, 1% Nonidet P40, 10 mM MgC12, 1 mM phenylmethanesulphonyl flouoride, and 10 ⁇ g of aprotinin/ml for 10 min on ice. Lysates containing 30 ⁇ g of protein were mixed with an equal volume of Laemmli sample buffer, and denatured by boiling for 5 min.
  • the nitrocellulose filters were blocked using 3% defatted dried milk in Tris-buffered saline with 0.1 % Tween-20 (TBS-T) for 1 h. Filters were incubated overnight with a specific antibody to Cox-2 (Cayman chemicals, Ann Arbor, MI) used at a dilution of 1 : 1000. After washing in TBS-T, the filters were incubated with horseradish peroxidase-conjugated anti-rabbit antibody, again washed four times in TBS-T and exposed to enhanced chemiluminescence reagents for 1 min. Blots were exposed to Kodax SAR-5 film for 1-5 min.
  • TBS-T Tris-buffered saline with 0.1 % Tween-20
  • RNA from near-confluent culture plates of Kupffer cells was isolated by using guanidinethiocyanate solution.
  • RNA samples were electrophoresed in a 0.8% agarose/3% formaldehyde and then blotted onto Hybond-N nylon membranes with 20X SSC (3 M NaCl, 0.3 M sodium citrate). After brief rinsing with water and UV-crosslinking (Hoefer UV-crosslinker 500), the membranes were inspected under UV illumination to determine RNA integrity and location of the 28S and 18S rRNA bands.
  • Blots were then subjected to a 3 h-prehybridization at 43 jC in 50% deionized formamide, in sodium phosphate buffer (0.25 M, pH 7.2), containing 0.25 M NaCl, 1 mM EDTA, 100 mg/ml salmon sperm DNA and 7% SDS.
  • Hybridization was carried out in the same solution with approx. 106 cpm/ml ( ⁇ -32P)dCTP-labeled random primed BGT1, Cox-1 or Cox-2 and GAPDH cDNA probes.
  • Membranes were washed three times in 2x SSC/0.1 % SDS and twice in sodium phosphate buffer (25 mM, pH 7.2)/EDTA (1 mM)/l % SDS. Blots were then exposed to Kodak AR X-omat film at 70 °C with intensifying screens and analysed with PDI densitometry scanning (Pharmacia, Freiburg, Germany).
  • Fig. 1 hyperosmotic exposure of Kupffer cells led to a strong and time dependent increase in BGT-1 mRNA levels. Maximal BGT-1 mRNA levels were found after 12 h of hyperosmotic exposure (Fig. 1 ). The time course of hyperosmolarity - stimulated expression of BGT1 mRNA roughly paralleled the increase in mRNA levels for cyclooxygenase-2 (Cox-2), when Kupffer cells were simultaneously exposed to lipopolysaccharide (LPS) (Fig. 1 ).
  • Cox-2 cyclooxygenase-2
  • LPS lipopolysaccharide
  • Fig. 7 The findings demonstrated in Fig. 7 indicate that the osmolytes myo-inositol, taurine and betaine are effective in downregulating COX-2 expression also in endothelial cells.
  • Fig. 9 demonstrate that in Kupffer cells, osmolytes are effective in downregulating COX-2 and iNOS expression also at notmoosmolar conditions which implies that osmolytes exert these effects through a mechanism independent of cellular hydration.
  • Fig. 10 show that osmolytes are effective in downregulating inducible nitric oxide synthase (iNOS) in macrophages.
  • iNOS inducible nitric oxide synthase
  • Fig. 11 A and 1 1 B demonstrates the capacity of osmolytes in protection of apoptosis.
  • Table 2 and Fig. 5 also demonstrates that betaine suppresses the hyperosmolarity-induced increase in PGE2 formation and Cox-2 induction, thus indicating that this osmolyte does interfere with the inflammatory response of immune competent cells, such as liver macrophages.
  • An addition of betaine (1 mmol/1) to hyperosmotically exposed Kupffer cells abolished the strong induction of Cox-2 and the increase of prostaglandin E2 formation.
  • the betaine concentrations required for such an effect (Table 2) are well in the range of the physiological plasma concentration, which is reported to be 20-120 ⁇ mol/1.
  • Kupffer cells were exposed for 12 h to hyperosmotic medium (405 mosmol/1); thereafter [ 14C] betaine (10 ⁇ mol/1) uptake was measured in the absence (control) or presence of various effectors, which were added at a concentration of 10 mmol/1, each. Data are give as mean ⁇ SEM and are from four different experiments.
  • Rat Kupffer cells were incubated with LPS (1 ⁇ g/ml) in normoosmotic (305 mosmol/1) or hyperosmotic (380 mosmol/1) medium for 24 h. PGE2 formation was measured by radioimmunoassay. Data are given as mean 1SEM and are from four different experiments.

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Abstract

La présente invention concerne une thérapie ainsi que des compositions appropriées à celle-ci et impliquant la présence d'une quantité efficace d'un osmolyte capable de traiter les effets d'une infection, d'une inflammation ou d'une dysfonction du système immunitaire.
PCT/EP1997/001862 1996-04-12 1997-04-14 Utilisation d'un osmolyte pour traiter les effets d'une infection, d'une inflammation ou d'une dysfonction du systeme immunitaire WO1997038686A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP9536746A JP2000508331A (ja) 1996-04-12 1997-04-14 感染、炎症または免疫障害の影響を治療するためのオスモライトの使用
AU26971/97A AU2697197A (en) 1996-04-12 1997-04-14 Use of an osmolyte for treating the effects of an infection, an inflammation or an immune dysfunction
EP97920677A EP0910361A1 (fr) 1996-04-12 1997-04-14 Utilisation d'un osmolyte pour traiter les effets d'une infection, d'une inflammation ou d'une dysfonction du systeme immunitaire
NO984760A NO984760L (no) 1996-04-12 1998-10-12 Anvendelse av en osmolytt ved behandling av effekter forÕrsaket av en infeksjon, en inflammasjon eller en immundysfunksjon

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SE9601395-8 1996-04-12
SE9601395A SE9601395D0 (sv) 1996-04-12 1996-04-12 New therapeutic treatment 1

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WO1999004784A1 (fr) * 1997-07-25 1999-02-04 Cultor Corporation Agent prophylactique
WO1998057620A3 (fr) * 1997-06-16 1999-03-18 Cedars Sinai Medical Center Compositions, dispositifs, kits, et procede de modulation de la reponse immunitaire
WO2002013813A1 (fr) * 2000-08-11 2002-02-21 The Lawson Health Research Institute Inhibition du dysfonctionnement des îlots de langerhans et de troubles autoimmunes, et compositions à cet effet
WO2001076572A3 (fr) * 2000-04-12 2002-04-11 Bitop Gmbh Utilisation de solutes compatibles en tant que substances aux proprietes de piegeage de radicaux
EP1139746A4 (fr) * 1998-12-22 2003-09-17 Univ North Carolina Compose et techniques permettant de traiter les maladies des voies respiratoires et de distribuer des medicaments contre lesdites maladies
US6926911B1 (en) 1998-12-22 2005-08-09 The University Of North Carolina At Chapel Hill Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs
WO2006097263A2 (fr) 2005-03-12 2006-09-21 bitop Aktiengesellschaft für biotechnische Optimierung Agents contenant des solutes compatibles destines a un usage par voie orale
WO2006050585A3 (fr) * 2004-11-10 2007-03-22 Jallal Messadek Modulation de synthases d'oxyde nitrique par des betaines
US7608640B2 (en) 1999-03-02 2009-10-27 Jallal Messadek Glycine betaine and its use
US7780990B2 (en) 2005-02-15 2010-08-24 Jallal Messadek Combination therapeutic compositions and method of use
US7786077B2 (en) 2005-04-27 2010-08-31 Jallal Messadek Insulins combinations
US8343947B2 (en) 2003-07-15 2013-01-01 Jallal Messadek Therapeutic treatment

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EA200701434A1 (ru) * 2005-01-05 2008-10-30 Магд Ахмед Котб Абдалла Тауриновый синтез, производство и применение в качестве лекарственного средства

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WO1998057620A3 (fr) * 1997-06-16 1999-03-18 Cedars Sinai Medical Center Compositions, dispositifs, kits, et procede de modulation de la reponse immunitaire
WO1999004784A1 (fr) * 1997-07-25 1999-02-04 Cultor Corporation Agent prophylactique
EP2258183A1 (fr) * 1998-12-22 2010-12-08 The University of North Carolina at Chapel Hill Compose et usages permettant de traiter les maladies des voies respiratoires et de distribuer des medicaments contre lesdites maladies
EP1139746A4 (fr) * 1998-12-22 2003-09-17 Univ North Carolina Compose et techniques permettant de traiter les maladies des voies respiratoires et de distribuer des medicaments contre lesdites maladies
US6926911B1 (en) 1998-12-22 2005-08-09 The University Of North Carolina At Chapel Hill Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs
US7666395B2 (en) 1998-12-22 2010-02-23 The University Of North Carolina At Chapel Hill Compounds and methods for the treatment of airway diseases and for the delivery of airway drugs
US7608640B2 (en) 1999-03-02 2009-10-27 Jallal Messadek Glycine betaine and its use
WO2001076572A3 (fr) * 2000-04-12 2002-04-11 Bitop Gmbh Utilisation de solutes compatibles en tant que substances aux proprietes de piegeage de radicaux
WO2002013814A1 (fr) * 2000-08-11 2002-02-21 The Lawson Health Research Institute Compositions enrayant un dysfonctionnement des ilots de langerhans ainsi que des maladies auto-immune et methodes afferentes
WO2002013813A1 (fr) * 2000-08-11 2002-02-21 The Lawson Health Research Institute Inhibition du dysfonctionnement des îlots de langerhans et de troubles autoimmunes, et compositions à cet effet
US8343947B2 (en) 2003-07-15 2013-01-01 Jallal Messadek Therapeutic treatment
WO2006050585A3 (fr) * 2004-11-10 2007-03-22 Jallal Messadek Modulation de synthases d'oxyde nitrique par des betaines
US8318805B2 (en) 2004-11-10 2012-11-27 Jallal Messadek Modulation of nitric oxide synthases by betaines
US7780990B2 (en) 2005-02-15 2010-08-24 Jallal Messadek Combination therapeutic compositions and method of use
WO2006097263A3 (fr) * 2005-03-12 2007-02-22 Bitop Ag Agents contenant des solutes compatibles destines a un usage par voie orale
WO2006097263A2 (fr) 2005-03-12 2006-09-21 bitop Aktiengesellschaft für biotechnische Optimierung Agents contenant des solutes compatibles destines a un usage par voie orale
US9089568B2 (en) 2005-03-12 2015-07-28 Bitop Ag Method of using compatible solutes containing ectoine and/or hydroxyectoine
US7786077B2 (en) 2005-04-27 2010-08-31 Jallal Messadek Insulins combinations

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NO984760L (no) 1998-10-12
JP2000508331A (ja) 2000-07-04
EP0910361A1 (fr) 1999-04-28

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