WO1989000428A1 - Utilisation d'anticorps du peptide atrial , d'antagonistes de recepteurs et d'inhibiteurs de synthese de peptide atrial afin de reguler la vasodilatation renale et du systeme dans le diabete sucre - Google Patents

Utilisation d'anticorps du peptide atrial , d'antagonistes de recepteurs et d'inhibiteurs de synthese de peptide atrial afin de reguler la vasodilatation renale et du systeme dans le diabete sucre Download PDF

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Publication number
WO1989000428A1
WO1989000428A1 PCT/US1988/002427 US8802427W WO8900428A1 WO 1989000428 A1 WO1989000428 A1 WO 1989000428A1 US 8802427 W US8802427 W US 8802427W WO 8900428 A1 WO8900428 A1 WO 8900428A1
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anp
condition
atrial
rats
atrial peptide
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PCT/US1988/002427
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English (en)
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Barry M. Brenner
Barbara J. Ballermann
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Brigham And Women's Hospital
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Publication of WO1989000428A1 publication Critical patent/WO1989000428A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4702—Regulators; Modulating activity
    • C07K14/4703—Inhibitors; Suppressors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • ATRIAL PEPTIDE ANTIBODIES RECEPTOR ANTAGONISTS
  • ATRIAL PEPTIDE SYNTHESIS INHIBITORS IN CONTROLLING RENAL AND SYSTEMIC VASODILATION IN DIABETES MELLITUS
  • the invention relates to the use of atrial natri- uretic peptide (ANP) antibodies, ANP synthesis inhibi ⁇ tors and ANP receptor antagonists to treat diabetes mellitus and prevent the complications thereof.
  • ANP atrial natri- uretic peptide
  • Diabetes mellitus is a metabolic disorder in which the ability to oxidize carbohydrates is more or less impaired. This is usually due to faulty pancreatic activity, especially with regard to the islets of Langerhans, which consequently results in disturbance of the normal insulin mechanism. This produces hyper- glycemia with resulting glycosuria and polyuria which result in symptoms of thirst, hunger, emaciation and weakness. In addition, imperfect metabolism of fats results in acidosis, sometimes leading to dyspnea, lipemia, ketonuria, and finally coma. Moreover, diabetes mellitus is frequently associated with progressive cornea sive disease of the small vessels (microangiopathy) , which particularly affects the eye (diabetic retino- pathy) and the kidney.
  • GFR glome ⁇ rular filtration
  • RPF renal plasma flow
  • Atrial natriuretic peptide is a hormone released by atrial myocytes in response to acute [Lang, R.E., et al.. Nature (London) 211:264-266 (1985)] and chronic [Tanaka, I., al. , Biochem. Biophvs. Res.
  • Atrial peptides are biologically active peptides isolated from atrial heart tissue.
  • the biological effects of ANP include diuresis, natriureses, vasodila- tion with inhibition of vascular wall contraction by norepinephrine and angiotensin II, inhibition of aldo- sterone secretion from the adrenal, and modulation of arginine vasopressin secretion from the posterior pituitary.
  • ANP levels were found to be elevated in diabetics with cardiac autonomic neuropathy. Kahn et al.. Re ⁇ ul. Peot. 15:323-332 (1986). Kahn et al.. Clin. Res. 3.:427A (1986) .
  • ANP levels are elevated in pathological states which include hyper ⁇ tension and induced iiypervoiemia.
  • RIA radioimmunoassay
  • This invention is based upon the observation by the inventors that many of the renal and systemic vascular responses observed in early diabetics mimic those induced by exogenous atrial peptide infusions into normal animal and human subjects, i.e., renal and systemic vasodilation, glomerular hyperfiltration, reduced plasma renin activity and inhibition of adrenal aldosterone biosynthesis. Since early diabetes is often associated with extracellular fluid volume expansion, the proximate stimulus to atrial peptide secretion, it was hypothesized by the present inventors that the above-described features of the early diabetic state are the consequence of elevated circulating atrial peptide levels.
  • the invention is related to the discovery that infusion of high affinity atrial peptide sheep antibody resulted in an inhibition of atrial peptide action in the diabetic rat and reversed renal hyperfiltration and the natriuretic response.
  • the invention also relates to the use of chimeric antibodies, receptor antagonists and atrial peptide synthesis inhibitors to inhibit atrial peptide action and thereby prevent high glomerular pressures and resulting hyperfiltration and thereby oppose the high risk factors in the causation of diabetic glomerulopathy.
  • the invention relates to a method of treating d iabetes mellitus-induced renal and systemic vasodila- tion, glomerular hyperfiltration, glo erulopathy, and microangiopathy associated with diabetes mellitus comprising administering to an animal or human a composition which comprises at least one compound selected from the group consisting of antibodies directed toward atrial peptides, atrial peptide receptor antagonists, and atrial peptide synthesis inhibitors.
  • the present invention was developed.
  • the objective of . this invention is to treat various patho ⁇ logies associated with diabetes mellitus by ameliorating the effects of ANP by administration of antibodies directed against ANP, ANP antagonists or ANP synthesis inhibitors.
  • the method of treating diabetes-induced systemic vasodilation, glomerular hyperfiltration, may prevent glomerulopathy and other microvascular complica ⁇ tions and therefore comprises administering the composi ⁇ tions of this invention to an animal.
  • FIG. 1 This figure shows plasma immunoreactive
  • FIG. 2 This figure shows the glomerular filtration rate (GFR) in moderately hyperglycemic rats in the baseline period and during infusion of either ANP antiserum (left panel) or non-immune serum (right panel), *p ⁇ 0.001 vs baseline.
  • the shaded band denotes mean value ⁇ 1SD for non-diabetic control rats.
  • the invention is directed toward treatment to prevent certain pathological conditions associated with diabetes mellitus by administration of antibodies directed toward ANP, ANP synthesis inhibitors or antagonists.
  • pathological conditions associated with diabetes mellitus include, but not limited to, diabetes ellitus-induced renal and systemic vasodila- tion, glomerular hyperfiltration, glomerulopathy, and microangiopathy, in addition to chronic volume expansion states which occur in non-diabetic individuals, includ ⁇ ing idiopathic edema, nephrotic syndrome, congestive heart failure, cirrhosis and some forms of hypertension. These latter conditions contribute to microvascular disease such as retinopathy, cardiomyopathy, nephropathy and neuropathy.
  • treating is included the prevention, elimination and attenuation or amelioration of the conditions of pathology included above.
  • antibody refers both to monoclonal antibodies which have a substantially homogeneous population and to polyclonal antibodies which have a heterogeneous population.
  • Polyclonal antibodies are derived from the antisera of animals immunized with ANP.
  • Monoclonal antibodies directed toward ANP may be prepared, for example, by the method described by Naruse, M., et al.. Peptides 2:141-145 (1986).
  • monoclonal antibodies to ANP may be obtained by other methods known to those skilled in the art. See, for example, Kohler and Milstein, Nature 256:495- 497 (1975) . Such antibodies may be of any immunoglobu- in class.
  • antibody is meant as well to include both intact molecules as well as fragments thereof, such as, for example. Fab and F(ab') , which are capable of binding to ANP.
  • Atrial peptide is intended biologically active compounds belonging to a group of peptides, found in atrial heart tissue, called atrial natriuretic factors (ANF) .
  • ANP synthesis inhibitors potential compounds which inhibit the in vivo synthesis of ANP.
  • ANP antagonists compounds which bind to ANP receptors but which do not elicit a biological response characteristic of ANP.
  • animal By the term “animal” is intended all animals in which ANP is manufactured biosynthetically and for which the reduction of ANP levels or blockage thereof has a beneficial effect. Foremost among such animals are humans; however, the invention is not intended to be so limiting, it being within the contemplation of the invention to treat any and all animals which may experience the beneficial effects of the invention.
  • pharmaceutically acceptable salts is intended salts with pharmaceutically acceptable acids or bases, e.g., acids such as sulfuric, hydrochloric, phosphoric acid, etc. , or bases such as alkali or alkaline earth metal hydroxides, ammonium hydroxide, alkyl ammonium hydroxides, etc.
  • compositions within the scope of this invention include all compositions wherein each of the components thereof is contained in an amount effective to achieve its intended purpose.
  • one enbodiment of the invention comprises a composition which contains a monoclonal antibody directed toward ANP in an amount sufficient, upon administration, to bind 50-100% of circulating ANP in vivo.
  • the binding activity of a given lot of antibody directed toward ANP may be determined according to the protocol set forth in Example 2.
  • a second embodiment of the invention comprises a composition which contains one or more ANP synthesis inhibitors in an amount sufficient to result, upon administration, in the inhibition of the synthesis of ANP in vivo.
  • a third embodiment of the invention comprises compositions which include ANP antagonists in an amount sufficient to result, upon administration, in the blockage of ANP binding at the receptor sites.
  • the compositions of the present invention also include combinations of ANP antibodies, ANP synthesis inhibitors and antagonists.
  • compositions comprising the present invention may be administered by any manner known to the art.
  • Typical modes of administration include oral, enteral, parenteral (i.e., subcutaneous, intramuscular, intra- orbital, intracapsular, intraspinal, intravenous, etc.), intranasal and rectal administration.
  • parenteral i.e., subcutaneous, intramuscular, intra- orbital, intracapsular, intraspinal, intravenous, etc.
  • intranasal and rectal administration As understood by those skilled in the art, the dosage of active ingredient administered will be dependent upon the age, health and weight cf the recipient, kind of concurrent treatment, if any, frequency of the treatment, and the nature of the effect desired.
  • the new pharmaceutical preparations may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • Suitable formulations for parenteral administration of the compositions of the present invention include aqueous solutions of the active compounds in water- soluble form, for example, water-soluble salts.
  • suspensions of the active compounds as appropriate oily injection suspensions may be adminis ⁇ tered.
  • Suitable lipophilic solvents or vehicles include fatty oils, for example, sesame oil, or synthetic fatty acid esters, for example, ethyl oleate or triglycerides.
  • Aqueous injection suspensions may contain substances which increase the viscosity of the suspension includ ⁇ ing, for example, sodium carboxymethyl cellulose, sorbitol, and/or dextran.
  • the suspension may also contain stabilizers.
  • the preparations particularly those preparations which can be administered orally and which can be used for the preferred type of administration, such as tablets, dragees, and capsules, and also preparations which can be administered rectally, such as suppositories, as well as suitable solutions for administration by injection or orally, contain from about 0.1 to 99 percent, preferably from about 25-85 percent of active compound(s) , together with the excipient.
  • compositions of the present invention are manufactured in a manner which is itself known, for example, by means of conventional mixing, granulating, dragee-making, dissolving, or lyophilizing processes.
  • pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipients, optionally grinding a resulting mixture and processing the mixture of granules, after adding suitable auxilliaries, if desired or necessary, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch, paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropylmethylcellulose, sodium carboxy- methylcellulose, and/or polyvinyl pyrrolidone.
  • fillers such as sugars, for example lactose or sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, as well as binders such as starch, paste, using, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose
  • disintegrating agents may be added such as the above-mentioned starches and also carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, or algenic acid or a salt thereof, such as sodium alginate.
  • Auxiliaries are, above all, flow-regulating agents and lubricants, for example, silica, talc, steric acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol.
  • Dragee cores are provided with suitable coatings which, if desired, are resistant to gastric juices.
  • concen ⁇ trated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures.
  • suitable cellulose prepara ⁇ tions such as acetylcellulose phthalate or hydroxy- propylmethyl-cellulose phthalate, are used.
  • Dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize different combinations of active compound doses.
  • Other pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid poly ⁇ ethylene glycols.
  • stabilizers may be added.
  • Possible pharmaceutical preparations which can be used rectally include, for example, suppositories, which consist of a combination of the active compounds with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which consist of a combination of the active compounds with a base.
  • Possible base materials include, for example, liquid triglycerides, polyethylene glycols, or paraffin hydrocarbons.
  • EXAMPLE 1 This Example demonstrates that moderate hyper- glycemia in the diabetic rat stimulates cardiac ANP release and that elevated circulating levels of ANP serve to augment GFR, thereby contributing to glomerular hyperfiltration commonly observed in the diabetic state.
  • mice in group IB received a daily subcutaneous injection of 1.0 U Ultralente Novo insulin (Novo Industrie, Copenhagen, Denmark) , an amount designed to maintain the blood glucose concentration between 300 and 400 mg/dl (moderate hyperglyce ia) .
  • Rats in group 1C received 3.2 U of insulin daily to maintain the blood glucose concentration below 100 mg/dl (normoglycemia) .
  • Rats with blood glucose concen ⁇ trations between 100 and 300 mg/dl were excluded from the study.
  • Plasma ANP levels The rats were sacrificed by decapitation on day 15 and trunk blood collected in iced tubes containing 15 mg EDTA, aprotonin (1500 kallikrein- inactivator units) , and 10 N- -benzoyl-L-arginine ethyl ester units of soybean trypsin inhibitor (Sigma Chemical Co., St. Louis, MO) for subsequent extraction and determination of plasma immunoreactive ANP (iANP) levels.
  • EDTA aprotonin (1500 kallikrein- inactivator units
  • iANP soybean trypsin inhibitor
  • GFR Glomerular filtration rate
  • This blood was replaced volume for volume with plasma obtained from corres- pondingly glycemic diabetic rats. Catheters were also placed in the left femoral and right jugular veins, and the left ureter. To replace plasma losses associated with anethesia and surgery, iso-oncotic rat plasma obtained - from diabetic rats or from normal rats, equivalent in volume to 1% of body weight, was infused over 50 min, followed by a sustained infusion of 0.6 ml/h throughout the remainder of the experiment. Inulin (7%) in normal saline was infused at a rate of 1.2 ml/h.
  • Values are means ⁇ SEM. BW, body weight; KW, kidney weight.
  • Body weights were not different among groups at the beginning and at the completion of the study. Despite similar body weights, renal hypertrophy was apparent in the moderately hyperglycemic group IB rats, whereas kidney weight in normoglycemic diabetic rats was no higher on average than in nondiabetic control rats.
  • Plasma iANP levels in the three group of rats are shown in Fig. 1.
  • Plasma iANP levels were elevated in moderately hyperglycemic group IB rats, averaging 281 ⁇ 28 pg/ml (p ⁇ 0.005) as compared to the nondiabetic group 1A rats (137 ⁇ li pg/ml) .
  • normoglycemic diabetic rats (group 1C) exhibited values for plasma iANP (158 ⁇ 15 pg/ml) no different from those in nondiabetic controls.
  • moderate hyperglycemia in the rat is characterized by elevated plasma iANP levels, which may be normalized with strict glycemic control.
  • Renal hemodvnamic data Whole animal and hemo- dynamic data for rats that underwent clearance measure ⁇ ments are shown in Table 2. Again, body weight did not differ among the groups. Group 2B rats were moderately hyperglycemic, while blood glucose levels in group 2C were maintained at levels comparable to those ⁇ in nondiabetic rats (Group 2A) . Maintenance of chronic moderate hyperglycemia in group 2B was further confirmed by measurement of glycosylated hemoglobin. Glycosylated hemoglobin levels in group 2B rats were significantly higher at 19.9 ⁇ 0.2%, on average, than those of 3.5 ⁇ 0.02% in control rats (p ⁇ 0.01).
  • Plasma iANP levels measured in arterial blood from anesthetized rats undergoing clearance determinations were again elevated in the moderately hyperglycemic diabetic rats (group 2B) as compared to those in nondiabetic control rats (p ⁇ 0.05).
  • Plasma iANP levels in normoglycemic diabetic rats (group 2C) were equivalent to those in nondiabetic rats.
  • Plasma iANP levels in these anesthetized rats were generally lower than those determined in blood samples from conscious rats, in the previous protocol. These differences reflect the known effect of barbiturate anesthesia in suppressing plasma iANP levels.
  • Horky, K. et al.. Biochem. Biophvs. Res. Commun. 129:651-657 (1985) .
  • ANP antiserum infusions This example shows the role of endogenous ANP in hyperfiltration associated with diabetes mellitus.
  • the following protocol was designed to block the effects of endogenous ANP by administration of ANP antiserum.
  • Fourteen moderately hyperglycemic diabetic rats were infused with a high affinity sheep antiserum raised against ANP (obtained from Dr. Colin Johnston, University of Melbourne, Australia) , or with a nonim une sheep serum (Sigma Chemical Co., St. Louis, MO). Rats underwent surgery for GFR determination as described above on day 14 to 16 following streptozotocin injection.
  • This rate of infusion was calcu ⁇ lated to achieve a plasma antiserum concentration that could bind 50% of ANP every minute, assuming a plasma volume of 10 ml and a steady-state plasma ANP concentra ⁇ tion of approximately 75 pM (230 pg/ml) .
  • the non-immune serum was infused at the same rate. Measurements of GFR and urinary Na excretion were then repeated after a 90- min equilibration period. The blood glucose concentra ⁇ tion was determined at the beginning and at the end of the study.
  • the plasma ANP was extracted as described by Lang, R.E., et al.. Nature (London) 314:264-266 (1985). Plasma was diluted with 4% acetic acid (1:3, vol:vol) and was passed over a C18 Sep-Pak cartridge (Water Associates, Millipore Corp., Milford, MA) prewashed with 10 ml methanol, washed with 10 ml of distilled water, eluted with 90% ethanol and 0.4% acetic acid, and evaporated to dryness. The dried eluate was recon ⁇ stituted with ANP-radioimmunoassay buffer and all eluates were stored at -40 * C.
  • ANP antiserum infusions Individual values for GFR before and during infusion of the ANP antiserum or the nonimmune serum are shown in Fig. 2. As in the previous protocol, hyperfiltration was observed in these modera ⁇ tely hyperglycemic rats during the baseline period (2.38 ⁇ 0.09 ml/min in group 3B, 2.20 ⁇ 0.20 ml/min in group 4B) . Blood glucose concentrations measured at the initial and end points of the experiment did not change (308 ⁇ 13 mg/dl vs. 301 ⁇ 18 mg/dl).

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Abstract

Procédé permettant de traiter la micro-angiopathie, l'hyperfiltration glomérulaire, la glomérulopathie et la vasodilatation rénale et de l'organisme chez un animal, par administration d'un composé sélectionné à partir du groupe se composant d'anticorps anti-ANP (peptide matriurétique atrial), d'antagonistes de récepteurs d'ANP et d'inhibiteurs de synthèse d'ANP.
PCT/US1988/002427 1987-07-17 1988-07-18 Utilisation d'anticorps du peptide atrial , d'antagonistes de recepteurs et d'inhibiteurs de synthese de peptide atrial afin de reguler la vasodilatation renale et du systeme dans le diabete sucre WO1989000428A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992009306A1 (fr) * 1990-11-28 1992-06-11 Fondation Nationale De Transfusion Sanguine Utilisation d'immunoglobulines administrees localement dans le traitement des infections epitheliales
US5132112A (en) * 1990-04-10 1992-07-21 Kyowa Hakko Kogyo Kabushiki Kaisha Hs-142-1 compounds
US5965533A (en) * 1997-05-23 1999-10-12 Baxter International Inc. Atrial natriuretic peptide (ANP) as an additive to peritoneal dialysis solutions
WO2009095454A2 (fr) * 2008-02-01 2009-08-06 Brahms Aktiengesellschaft Procédé d'identification de patients présentant de légers troubles cognitifs, nécessitant un traitement, et traitement de ces patients

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4557864A (en) * 1984-01-10 1985-12-10 Washington University Atrial peptides
US4757048A (en) * 1985-11-05 1988-07-12 Biotechnology Research Associates J.V. Synthetic analogs of atrial natriuretic peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4557864A (en) * 1984-01-10 1985-12-10 Washington University Atrial peptides
US4757048A (en) * 1985-11-05 1988-07-12 Biotechnology Research Associates J.V. Synthetic analogs of atrial natriuretic peptides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
EUROPEAN JOURNAL OF PHARMACOLOGY, Vol. 129, No. 1, issued January 1986 (England, UK), STASCH et al., "The elevation of cyclic GMP as a response to acute hypervolemia is blocked by a monoclonal antibody directed against atrial natriuretic peptides", pages 165 to 168. *
PEPTIDES, Vol. 7, No. 1, issued January 1986 (USA), NARUSE et al., "Immunoreactive alpha-Human Atrial Natriuretic Polypeptide in Human Plasma", pages 141 to 145. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132112A (en) * 1990-04-10 1992-07-21 Kyowa Hakko Kogyo Kabushiki Kaisha Hs-142-1 compounds
WO1992009306A1 (fr) * 1990-11-28 1992-06-11 Fondation Nationale De Transfusion Sanguine Utilisation d'immunoglobulines administrees localement dans le traitement des infections epitheliales
US5965533A (en) * 1997-05-23 1999-10-12 Baxter International Inc. Atrial natriuretic peptide (ANP) as an additive to peritoneal dialysis solutions
WO2009095454A2 (fr) * 2008-02-01 2009-08-06 Brahms Aktiengesellschaft Procédé d'identification de patients présentant de légers troubles cognitifs, nécessitant un traitement, et traitement de ces patients
WO2009095454A3 (fr) * 2008-02-01 2009-10-01 Brahms Aktiengesellschaft Procédé d'identification de patients présentant de légers troubles cognitifs, nécessitant un traitement, et traitement de ces patients

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