WO2016039426A1 - Méthode d'aide à la sélection de médicament thérapeutique pour un patient atteint du diabète de type 2, méthode de prédiction de l'effet de médicament thérapeutique, méthode d'inspection, et méthode de traitement - Google Patents

Méthode d'aide à la sélection de médicament thérapeutique pour un patient atteint du diabète de type 2, méthode de prédiction de l'effet de médicament thérapeutique, méthode d'inspection, et méthode de traitement Download PDF

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WO2016039426A1
WO2016039426A1 PCT/JP2015/075760 JP2015075760W WO2016039426A1 WO 2016039426 A1 WO2016039426 A1 WO 2016039426A1 JP 2015075760 W JP2015075760 W JP 2015075760W WO 2016039426 A1 WO2016039426 A1 WO 2016039426A1
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value
type
selenoprotein
diabetes
sep
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PCT/JP2015/075760
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Japanese (ja)
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博文 御簾
周一 金子
有美枝 竹下
俊成 篁
芳郎 斎藤
睦 田中
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国立大学法人金沢大学
学校法人同志社
アルフレッサファーマ株式会社
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor

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  • the present invention relates to a method for assisting selection of a therapeutic agent for type 2 diabetes, which comprises selecting metformin hydrochloride administration when a selenoprotein P value is higher than a cutoff value in a specimen derived from a type 2 diabetes patient
  • the present invention relates to a method for predicting an effect of a therapeutic agent, a test method, and a treatment method.
  • Type 2 diabetes Type 2 diabetes, which continues to increase on a global scale, threatens human QOL and life by promoting arteriosclerotic diseases such as retinal, renal and neurological complications and ischemic heart disease.
  • arteriosclerotic diseases such as retinal, renal and neurological complications and ischemic heart disease.
  • the development of is urgent.
  • the liver not only plays a major role in glucose and lipid metabolism, but is the largest organ in the body of various biologically active substances including angiogenic factors.
  • insulin resistance In type 2 diabetes, the action of insulin to suppress sugar release from the liver is attenuated, and this phenomenon is called insulin resistance. Insulin resistance leads to hyperglycemia due to increased glucose release from the liver and hyperlipidemia due to increased lipid production, and promotes arteriosclerotic diseases.
  • the liver is the largest producing organ in vivo of various physiologically active substances including angiogenic factors that lead to the risk of arteriosclerosis (see: Patent Document 1).
  • SeP Selenoprotein P
  • BD1, BD3, BF2, AE2, AH5, and AA3 monoclonal antibodies
  • ELISA enzyme-linked immunosorbent assay
  • SeP undergoes degradation with plasma kallikrein to produce N-terminal and C-terminal fragments, and among the above six monoclonal antibodies, BD1, BD3, BF2, AE2 and AH5 become N-terminal fragments.
  • AA3 reacts specifically with the C-terminal fragment.
  • AA3 reacts specifically with the C-terminal fragment.
  • Patent Document 2 discloses a method that can easily measure the presence or degree of SeP degradation by plasma kallikrein in vivo.
  • Patent Document 1 discloses “a method for detecting type 2 diabetes, including measuring selenoprotein P”. However, Patent Document 1 does not disclose or suggest a “method for selecting a therapeutic agent for type 2 diabetes using selenoprotein P value as an index”. Patent Document 2 states that “a method for separately measuring a long-chain type and a short-chain type of a substance to be measured (selenoprotein P) in a sample includes (a) the sample, the long-chain type, and the short-chain type.
  • Non-patent literature Non-patent literature
  • Non-Patent Document 1 states that “selenoprotein P expression is suppressed by treatment with metformin, but this suppression is inhibited by co-administration of an AMPK inhibitor or FoxO3a siRNA. Metformin is mediated through an AMPK inhibitor / FoxO3a pathway. In other words, the expression of selenoprotein P is suppressed.
  • Non-Patent Document 1 does not disclose or suggest a “method for selecting a therapeutic agent for type 2 diabetes using selenoprotein P value as an index”.
  • metformin is the first-line treatment or a DPP4 (dipeptidyl peptidase-4) inhibitor is the first-line treatment.
  • DPP4 dipeptidyl peptidase-4
  • patients with type 2 diabetes have large individual differences in treatment responsiveness depending on the therapeutic agent to be selected, and there are many cases in which there is no effect.
  • Metformin has little evidence of hypoglycemia, and there is evidence of life extension.
  • metformin has been reported to have anticancer effects, gastrointestinal side effects (diarrhea, decreased appetite), and the like, and there are considerable individual differences in treatment response.
  • DPP4 inhibitors have an effect of stimulating insulin secretion and there are individual differences in blood glucose lowering action.
  • an object of the present invention is to provide a method for assisting selection of a therapeutic drug for type 2 diabetes patients, a method for predicting the effect of the therapeutic drug, a test method, and a therapeutic method.
  • the present inventors have described that “in specimens (especially blood) derived from type 2 diabetes, the effect of metformin administration is high when the selenoprotein P value is higher than the cutoff value. And the present invention has been completed.
  • this invention consists of the following.
  • a method for assisting selection of a therapeutic agent for type 2 diabetes wherein in a specimen derived from a type 2 diabetes patient, metformin hydrochloride administration is selected when the selenoprotein P value is higher than the cutoff value.
  • the method for assisting selection of a therapeutic agent according to item 1 wherein the specimen is blood.
  • the cutoff value is 3.5 ⁇ g / mL to 4.7 ⁇ g / mL. 4.
  • Predicting the therapeutic effect of type 2 diabetes characterized in that metformin hydrochloride administration is judged to be effective when the selenoprotein P value is higher than the cut-off value in specimens derived from type 2 diabetes patients how to. 5. 5. The method for predicting a therapeutic effect according to item 4, wherein the specimen is blood. 6). 6. The method for predicting a therapeutic effect according to item 4 or 5, wherein the cut-off value is 4.5 ⁇ g / mL or more. 7. Type 2 for selecting a therapeutic agent for type 2 diabetes, characterized by selecting metformin hydrochloride administration when the selenoprotein P value is higher than the cut-off value in a sample derived from a type 2 diabetes patient A method for testing specimens from diabetic patients. 8). 8.
  • a method for treating type 2 diabetes comprising the following steps: (1) a step of determining whether a selenoprotein P value is higher than a cut-off value in a sample derived from a type 2 diabetes patient; and (2) metformin if the selenoprotein P value is higher than a cut-off value. Administering hydrochloride to the patient. 11. The treatment method according to item 10, wherein the cut-off value is 3.5 ⁇ g / mL to 4.7 ⁇ g / mL.
  • the present invention relates to a method for assisting selection of a therapeutic agent for type 2 diabetes, which comprises selecting metformin administration when a selenoprotein P value is higher than a cut-off value in a specimen derived from a type 2 diabetes patient.
  • a drug effect prediction method, a test method, and a treatment method can be provided.
  • the therapeutic effect of metformin administration can be predicted before administration, and a high therapeutic effect can be obtained by administering metformin from an early stage to patients with type 2 diabetes who are expected to have an effect of metformin administration. it can.
  • FIG. 1 Schematic diagram showing cleavage of selenoprotein P (SeP) by plasma kallikrein.
  • a graph (calibration curve) showing the relationship between the SeP concentration and the amount of change in absorbance in the FL-SeP measurement system.
  • the vertical axis represents the amount of change in absorbance, and the horizontal axis represents the SeP concentration ( ⁇ g / mL).
  • the graph which shows the change of a blood glucose level in a metformin administration group, and the change of a HbA1c value (using the Pearson product-moment correlation coefficient).
  • the graph which shows the change of the blood glucose level in a DPP4 inhibitor administration group, and the change of a HbA1c value (using the Pearson product-moment correlation coefficient).
  • the graph which shows the change of the selenoprotein P value in a metformin administration group and a DPP4 inhibitor administration group (using the Pearson product-moment correlation coefficient). Changes in blood glucose levels in the metformin administration group and the DPP4 inhibitor administration group (using Pearson product moment correlation coefficient). Change in selenoprotein P level in patients with high pre-dose SeP level (4.55 ⁇ g / mL or more) in the metformin group. Distribution map of selenoprotein P level in serum of type 2 diabetic patients before treatment. Changes in blood glucose levels in the metformin administration group and the DPP4 inhibitor administration group in cases with a selected cut-off value or higher.
  • the administration of metformin hydrochloride in a specimen derived from a type 2 diabetes patient, when the selenoprotein P value is higher than the cut-off value, the administration of metformin hydrochloride is selected.
  • Method Method for predicting therapeutic effect, characterized in that metformin hydrochloride administration is judged to be effective when the selenoprotein P value is higher than the cut-off value in a specimen derived from a type 2 diabetic patient " “In a specimen derived from a type 2 diabetic patient, if the selenoprotein P value is higher than the cut-off value, the administration of metformin hydrochloride is selected.
  • metformin A therapeutic method comprising administering hydrochloride to the patient. This will be described in detail below.
  • the method for assisting selection of a therapeutic agent for type 2 diabetes includes the following steps. (1) A step of determining whether a selenoprotein P value is higher than a cutoff value in a sample derived from a type 2 diabetes patient. (2) A step of determining that metformin hydrochloride administration is selected when the selenoprotein P value is higher than the cutoff value.
  • the method for predicting the therapeutic effect of metformin hydrochloride administration of type 2 diabetes includes the following steps. (1) A step of determining whether a selenoprotein P value is higher than a cutoff value in a sample derived from a type 2 diabetes patient. (2) A step of determining that metformin hydrochloride administration is effective when the selenoprotein P value is higher than the cut-off value. “Effective” means that administration of metformin hydrochloride has an effect of improving blood glucose level, improving HbA1c level, lowering SeP level in blood, and / or treating diabetes.
  • the method for examining a specimen derived from a type 2 diabetes patient for selecting a therapeutic agent for type 2 diabetes includes the following steps. (1) A step of determining whether a selenoprotein P value is higher than a cutoff value in a sample derived from a type 2 diabetes patient. (2) A step of determining that metformin hydrochloride administration is selected when the selenoprotein P value is higher than the cutoff value.
  • the method for treating type 2 diabetes includes the following steps. (1) A step of determining whether a selenoprotein P value is higher than a cutoff value in a sample derived from a type 2 diabetes patient. (2) A step of administering metformin hydrochloride to the patient when the selenoprotein P value is higher than the cutoff value. Furthermore, the following processes are included as needed. (3) A step of changing to DPP4 inhibitor administration or a combination of DPP4 inhibitor when metformin hydrochloride administration does not improve patient symptoms.
  • the specimen of the present invention is not particularly limited as long as it is derived from a type 2 diabetic patient and selenoprotein P is present.
  • examples thereof include whole blood, blood (peripheral mononuclear cells), serum, plasma, urine, cerebrospinal fluid, ascites, lymph, liver-derived fluid, and milk.
  • peripheral mononuclear cells, serum and the like are most preferable in terms of easy handling such as collection and low invasiveness.
  • the method for obtaining a sample from a type 2 diabetes patient is not particularly limited, and a method known per se can be used.
  • Selenoprotein P is a protein containing 10 residues of selenocysteine.
  • Selenoprotein P acts as an enzyme having glutathione peroxidase-like activity that reduces hydrogen peroxide and lipid peroxide to detoxify and controls intracellular redox.
  • the present inventors have disclosed that selenoprotein P is a detection marker for type 2 diabetes (see: Patent Document 1).
  • Selenoprotein P is contained in human serum and can be isolated and purified from human serum according to the method described in the literature “Saito Y. et al., J Biol chem 274: 2866-2871, 1999”. it can.
  • Selenoprotein P is cleaved by plasma kallikrein (see: FIG. 1).
  • the upper part of FIG. 1 represents full-length SeP, and the middle and lower parts represent SeP fragments generated by plasma kallikrein cleavage.
  • N and C represent the N-terminal side and the C-terminal side, respectively
  • Sec represents a selenocysteine residue.
  • Kallikrein consists of arginine at position 235 (“R235” in FIG. 1) and glutamine at position 236 (“Q236” in FIG. 1), and arginine at position 242 (“R242” in FIG. 1) and asparagine at position 243.
  • the “long chain type” is an uncut full length SeP (amino acid residues 1 to 361: sometimes referred to as “FL-SeP” in this specification), and the “short chain type” is generated by cleavage. It is a SeP fragment (sometimes referred to herein as “S-SeP”), and the SeP fragment can be, for example, an N-terminal fragment (amino acid residues 1 to 235).
  • Metformin hydrochloride Metformin hydrochloride
  • Metformin hydrochloride (Chemical name: 1,1-Dimethylbiguanide monohydrochloride) is “Metgluco Tablets”, “Glycolane Tablets”, “Metformin Hydrochloride Tablets”, and other brand names from several pharmaceutical companies as a treatment for type 2 diabetes. It is sold (hereinafter referred to as “Metogluco Tablet”).
  • Metformin hydrochloride is “Metgluco Tablets”, “Glycolane Tablets”, “Metformin Hydrochloride Tablets”, and other brand names from several pharmaceutical companies as a treatment for type 2 diabetes. It is sold (hereinafter referred to as “Metogluco Tablet”).
  • the maintenance dose is determined while observing the effect, but is usually 750 mg to 1,500 mg per day.
  • the dose may be adjusted according to the patient's condition, but the maximum daily dose is 2,250 mg.
  • DPP4 inhibitor is an antidiabetic drug, which means a drug that inhibits the DPP4 (dipeptidyl peptidase-4) enzyme, and the generic names sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin and anagliptin are known .
  • the dosage and administration timing can be exemplified as follows, but are not particularly limited. ⁇ Sitagliptin Normally, for adults, 50 mg of sitagliptin is orally administered once a day. If the effect is insufficient, 100 mg can be increased once a day while observing the progress sufficiently.
  • ⁇ Vildagliptin Usually, for adults, 50 mg of vildagliptin is orally administered twice a day in the morning and evening. Depending on the patient's condition, 50 mg can be administered once a day in the morning.
  • Alogliptin Usually, for adults, 25 mg of alogliptin is orally administered once a day, preferably after breakfast.
  • Linagliptin Usually, for adults, 5 mg of linagliptin is orally administered once a day.
  • Tenerigliptin Usually, for adults, 20 mg of tenerigliptin is orally administered once a day. If the effect is insufficient, 40 mg can be increased once a day while observing the progress sufficiently.
  • Anagliptin Normally, for adults, 100 mg of anagliptin is orally administered twice a day in the morning and evening. If the effect is insufficient, the single dose can be increased to 200 mg while observing the progress sufficiently.
  • the range of the cut-off value for selecting a therapeutic agent for patients with type 2 diabetes according to the present invention is 3.5 ⁇ g / mL to 4.7 ⁇ g / mL, preferably 3.7 ⁇ g in the specimen (particularly serum) from Example 4 below.
  • the range of the cut-off value for judging that the administration of metformin hydrochloride of the present invention is effective is 4.5 ⁇ g / mL or more, for example, 4.5 ⁇ g / mL in the sample (particularly in serum) from Example 3 below. It is ⁇ 6.0 ⁇ g / mL, more preferably 4.5 ⁇ g / mL to 5.5 ⁇ g / mL, and most preferably 4.5 ⁇ g / mL to 5.0 ⁇ g / mL.
  • One indicator that metformin hydrochloride administration was effective is a significant decrease in blood selenoprotein P level.
  • the method for assisting selection of a therapeutic agent for type 2 diabetes patients, the method for predicting the effect of a therapeutic agent, the method for measuring the selenoprotein P value in the test method and the therapeutic method of the present invention are not particularly limited.
  • selenoprotein P mRNA may be calculated by measuring mRNA of selenoprotein P.
  • As a method of directly measuring selenoprotein P it can be performed by an immunoassay using an anti-selenoprotein P antibody that specifically recognizes and binds to selenoprotein P.
  • Anti-selenoprotein P antibody can be prepared by a known method.
  • Examples of the immunological measurement method include a method using a carrier on which an anti-selenoprotein P antibody is immobilized, western blotting, and the like.
  • Examples of the method using a solid-phase support include, but are not limited to, ELISA using a solid-phase microtiter plate, and an aggregation method using solid-phase particles.
  • Adopted, blood selenoprotein P can be measured.
  • the selenoprotein P mRNA can be measured by Northern blotting, RT-PCR, a method using a DNA chip (DNA microarray), or the like. These methods can also be performed by a known method.
  • the method for measuring selenoprotein P is preferably an enzyme-linked immunosorbent method using two types of monoclonal antibodies ⁇ Reference: Saito, Y. et al., J. Health Sci. (2001) 47, 346-352 ⁇ , Examples thereof include a measurement method using an antigen-antibody reaction using a gold colloid shown in the following Examples (see Patent Document 2).
  • AH5 and AA3 Anti-human selenoprotein P rat monoclonal antibodies AH5 and AA3 were obtained according to the procedure described in the literature ⁇ Saito, Y. et al., J. Health Sci. (2001) 47, 346-352 ⁇ .
  • AH5 is a monoclonal antibody that recognizes the N-terminal side of selenoprotein P generated by kallikrein cleavage of selenoprotein P
  • AA3 is a monoclonal antibody that recognizes the C-terminal side of selenoprotein P.
  • antibody-bound gold colloid reagents were prepared as follows.
  • the antibody was diluted with 10 mM 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid (hereinafter “HEPES”) buffer (pH 7.1) containing 0.05 w / v% sodium azide.
  • HEPES 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid
  • colloidal gold reagent AH5 and colloidal gold reagent AA3 were used as colloidal gold reagent 1 and colloidal gold reagent 2, respectively.
  • FL-SeP measurement system For measurement of full-length SeP (“FL-SeP”), measurement using gold colloid particles bound with antibodies recognizing the N-terminal side of selenoprotein P and gold colloid particles bound with antibodies recognizing the C-terminal side A system was designed (also referred to herein as “FL-SeP measurement system”). In the FL-SeP measurement system, only FL-SeP can participate in the agglutination reaction.
  • Purified SeP (FL-SeP) was purified from human plasma as described in the literature ⁇ Saito, Y. et al., J. Biol. Chem. (1999) 274, 2866-2871 ⁇ .
  • the purified SeP was added to a standard matrix (3 w / v) at concentrations of 0.0 ⁇ g / mL, 0.75 ⁇ g / mL, 1.5 ⁇ g / mL, 3.0 ⁇ g / mL, 6.0 ⁇ g / mL, and 9.0 ⁇ g / mL, respectively.
  • FL-SeP standard solution prepared in 50 mM 2- [bis (2-hydroxyethyl) amino] -2- (hydroxymethyl) propane-1,3-diol buffer (pH 6.5)) containing% BSA did. 170 ⁇ L of the FL-SeP measurement reagent of Preparation Example 3 is dispensed into 3 ⁇ L of the obtained FL-SeP standard solution, heated at 37 ° C. for about 5 minutes, and then gold colloid reagent 1 and gold colloid reagent 2 are added. 85 ⁇ L of the mixture was dispensed and reacted at 37 ° C.
  • the obtained reaction solution was subjected to a Hitachi 7070 automatic analyzer, and the change in absorbance from the photometry point 18 to 31 was measured at a main wavelength of 505 nm and a sub wavelength of 660 nm, and the change in absorbance at 505 nm was changed to the change in absorbance at 660 nm.
  • the value obtained by adding the absolute value was determined and used as the amount of change in absorbance.
  • a calibration curve showing the relationship between the SeP concentration and the amount of change in absorbance in the FL-SeP measurement system was prepared (see FIG. 2).
  • Type 2 diabetics 79 patients were assigned to DPP4 inhibitor Alogliptin (Neshina TM) 25 mg / after breakfast oral group with metformin hydrochloride (Metoguruko ®) 1,000 mg / breakfast and after dinner oral group randomly. At the discretion of the attending physician, it was possible to increase the amount of Metogluco up to 2,250 mg / day. Changes in blood glucose levels and HbA1c (hemoglobin, A1 sea) levels before and after oral administration of each therapeutic drug for 3 months are measured by a method known per se, and changes in serum selenoprotein P levels are measured by the methods described below. did.
  • Serum 3 ⁇ L obtained from 79 patients with type 2 diabetes by a method known per se is subjected to the FL-SeP measurement system described in Example 1, and the seleno in the serum is obtained with reference to a calibration curve (see FIG. 2). Protein P value was measured.
  • FIG. 3 shows changes in blood glucose level and changes in HbA1c value in the metformin administration group.
  • the SeP level lowering degree and the blood glucose level lowering degree and the SeP level lowering degree and the HbA1c level lowering degree for three months tended to correlate.
  • the blood glucose level tended to improve well in cases where the SeP level decreased well.
  • FIG. 4 shows changes in blood glucose level and changes in HbA1c value in the DPP4 inhibitor administration group.
  • the SeP value lowering degree and the blood sugar level lowering degree and the SeP value lowering degree and the HbA1c lowering degree for three months were not correlated.
  • FIG. 5 shows changes in SeP values in the metformin administration group and the DPP4 inhibitor administration group.
  • the SeP value before administration correlated with the degree of decrease in SeP value for 3 months after administration.
  • the SeP value before administration did not correlate with the degree of decrease in SeP value for 3 months after administration. That is, in cases where the SeP value before the start of treatment was high, the SeP value was further reduced by administration of metformin.
  • FIG. 6 shows changes in blood glucose levels in the metformin administration group and the DPP4 inhibitor administration group.
  • the SeP value before administration correlated with the blood glucose level decrease for 3 months after administration.
  • the SeP level before administration did not correlate with the degree of blood glucose decrease for 3 months after administration. That is, the blood SeP value before administration of the therapeutic agent was able to predict the blood glucose level lowering level only after metformin administration.
  • FIG. 7 shows changes in the SeP value in cases where the pre-administration SeP value in the metformin administration group was high (4.55 ⁇ g / mL or more). As is clear from the graph shown in FIG. 7, the blood SeP value was significantly reduced by administration of metformin for 3 months.
  • SeP value distribution in the serum of type 2 diabetic patients before treatment is shown in FIG. From the distribution chart shown in FIG. 8, 4.1 ⁇ g / mL, which is higher than the median, was selected as the cutoff value.
  • FIG. 9 shows changes in blood glucose levels in the metformin administration group and the DPP4 inhibitor administration group in cases with a selected cutoff value of 4.1 ⁇ g / mL or more. As is apparent from the results of the graph shown in FIG. 9, the blood glucose level was significantly improved in the metformin administration group.
  • the SeP value in the serum of type 2 diabetic patients before treatment is 4.5 ⁇ g / mL or more, for example, 4.5 ⁇ g / mL to 6.0 ⁇ g / mL, more preferably 4.5 ⁇ g / mL to 5.5 ⁇ g / mL, most preferably In the case of 4.5 ⁇ g / mL to 5.0 ⁇ g / mL, it was confirmed that metformin administration improved blood glucose levels (diabetes treatment effect).
  • metformin administration improves blood glucose level, improves HbA1c level, and decreases blood SeP level. Furthermore, it can be predicted that there is the effectiveness of diabetes treatment.
  • metformin administration is selected. Providing methods, testing methods and treatment methods.

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Abstract

　La présente invention aborde le problème consistant à pourvoir à une méthode d'aide à la sélection d'un médicament thérapeutique pour un patient atteint du diabète de type 2, à une méthode de prédiction de l'effet d'un médicament thérapeutique, à une méthode d'inspection, et à une méthode de traitement. Les inventeurs ont découvert que l'effet de l'administration de métformine est élevé lorsque la valeur de sélénoprotéine P est supérieure à une valeur seuil dans un échantillon (en particulier, sanguin) provenant d'un patient atteint du diabète de type 2, et ont de ce fait mis au point la présente invention.
PCT/JP2015/075760 2014-09-10 2015-09-10 Méthode d'aide à la sélection de médicament thérapeutique pour un patient atteint du diabète de type 2, méthode de prédiction de l'effet de médicament thérapeutique, méthode d'inspection, et méthode de traitement WO2016039426A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
DE102020002289A1 (de) 2020-04-07 2021-10-07 selenOmed GmbH Selenoprotein P als Marker für eine Selenvergiftung
DE102020002289B4 (de) 2020-04-07 2023-08-17 selenOmed GmbH Selenoprotein P als Marker für eine Selenvergiftung

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