JP2020073890A - 全身骨格筋量の定量方法 - Google Patents
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/103—Detecting, measuring or recording devices for testing the shape, pattern, colour, size or movement of the body or parts thereof, for diagnostic purposes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/15—Devices for taking samples of blood
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61B5/00—Measuring for diagnostic purposes; Identification of persons
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
- G01N30/72—Mass spectrometers
- G01N30/7233—Mass spectrometers interfaced to liquid or supercritical fluid chromatograph
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- G—PHYSICS
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- 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
- G01N33/70—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving creatine or creatinine
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- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/0027—Methods for using particle spectrometers
- H01J49/0036—Step by step routines describing the handling of the data generated during a measurement
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- H—ELECTRICITY
- H01—ELECTRIC ELEMENTS
- H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
- H01J49/00—Particle spectrometers or separator tubes
- H01J49/004—Combinations of spectrometers, tandem spectrometers, e.g. MS/MS, MSn
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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
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/493—Physical analysis of biological material of liquid biological material urine
Abstract
Description
(a)10〜200mgのD3−クレアチン、その塩、またはこれらの水和物を上記被検体に経口投与するステップと、
(b)上記D3−クレアチンの投与後、少なくとも12時間経過させるステップと、
(c)上記被検体から生体試料を取得するステップと、
(d)上記生体試料中のクレアチニン濃度およびD3−クレアチニン濃度を定量するステップと、
(e)上記被検体の全身骨格筋量を計算するために、定量した上記クレアチニン濃度およびD3クレアチニン濃度を用いるステップとを含んでいる。
(a)上記被検体から生体試料を取得するステップと、
(b)上記生体試料を分析して、上記生体試料のクレアチニンM+2同位体ピークのピーク面積を求めるステップと、
(c)(b)で求めたピーク面積と、D3−クレアチニンを用いて作成した検量線とを比較して、上記生体試料中のクレアチニンM+2同位体濃度を定量するステップと、
(d)(c)で取得した濃度を、生体試料中のクレアチニンM+0濃度に対するクレアチニンM+2濃度の比である希釈係数で割るステップとを含んでいる。
(a)10〜200mgのD3−クレアチン、その塩、またはこれらの水和物を上記被検体に経口投与するステップと、
(b)上記D3−クレアチンの投与後、少なくとも12時間経過させるステップと、
(c)上記被検体から尿試料を取得するステップと、
(d)上記尿試料中のクレアチニン濃度およびD3−クレアチニン濃度を定量するステップと、
(e)上記被検体の全身骨格筋量を算出するために、定量した上記クレアチニン濃度およびD3クレアチニン濃度を用いるステップとを含んでいる。
(a)上記被検体から生体試料を取得するステップと、
(b)上記生体試料を分析して、上記生体試料のクレアチニンM+2同位体ピークのピーク面積を求めるステップと、
(c)(b)で求めた上記ピーク面積と、D3−クレアチニンを用いて作成した検量線とを比較して、上記生体試料中のクレアチニンM+2同位体濃度を定量するステップと、
(d)(c)で取得した濃度を、生体試料中のクレアチニンM+0濃度に対するクレアチニンM+2濃度の比である希釈係数で割るステップとを含んでいる。
D3−クレアチントレーサー希釈法を用いた前臨床モデルの全身骨格筋量の定量
ラット1匹あたり0.475mgのD3−クレアチンを投与し、尿への流出最小限に止めて、D3−クレアチンが直ちに完全に吸収されて全身に循環するようにし、99%以上のD3−クレアチントレーサーを、体内のクレアチン貯蔵量と平衡になるようにした。
ヒト被検者に、30、60または100mgのD3−クレアチン一水和物を単回経口投与する。その後、D3クレアチン一水和物の投与から1、2、3、4、5または6日後に尿試料を採取する。
式中、tは、定常状態の間の尿の採取間隔である。
クレアチン貯蔵量は、総尿クレアチニン(モル/日)をK(1/日)で割ることによって概算することもできる。
D3−クレアチン一水和物およびD3クレアチニンの参照標準物質をC/D/N Isotopes, Montreal Canadaから購入した。
D3−クレアチンの分離をZorbax Hilic Plusのシリカ分析カラム(50×2.1mm,Rapid Resolution HD 1.8μ,Agilent Corp., Santa Clara CA.)を備えたAcquity UPLC(Waters Corp., Milford, Ma.)を用いて実施した。注入量は概して8μLである。
化学薬品および試薬:Sigma Aldrich(St.Louis,Mo.)から購入したアセトニトリルおよび水(すべてHPLCグレードまたはそれ以上)。Sigma Aldrich(St.Louis,Mo.)から購入したギ酸アンモニウム。CDN Isotopes, Montreal Canadaから購入したd3−クレアチン(一水和物)およびd3−クレアチニンの参照標準。
上記内部標準として機能するアセトニトリル溶液(500ng/mL)を200μLの分取し、アセトニトリルを加えるダブルブランクサンプル以外の各ウェルに加えた。試料、検量線用標準試料、またはQC試料を40μL分取し、SILを含有するプレート内の適切なウェルに移す。上記プレートを密封し、約3分間撹拌混合した。上記プレートを約3000gで5分間遠心分離する。上清を未使用の96ウェルプレートに移し、その後HPLC−MS/MSシステムに注入して分析する。別々のヒトの尿試料からのD3−クレアチンおよびd3−クレアチニンを分析する。
d3−クレアチン、d3−クレアチニンおよびクレアチニンの分離を、Agilent
Zorbax Hilic Plusのシリカ分析カラム(寸法:50×2.1mm,Rapid Resolution HD 1.8μ,Agilent Corp., Santa Clara CA.)を備えたAcquity UPLC(Waters Corp., Milford, Ma.)を用いて実施する。注入量は概して2μLである。
LC/MS/MSを用いてバイオマーカーの生体分析定量を行うために、代替マトリックスまたは代替分析物を用いる必要がある。このアッセイでは、d3−クレアチニンが内因的に検出されないのでヒトの尿を使用することができ、d3―クレアチニン検量線からクレアチニンの定量を行うことができる。d3−クレアチニンおよびクレアチニンの等価性が示された。
クレアチニンを定量するための代替分析物としてd3クレアチニンが利用可能であること、および116/44(M+2)のMRMトランジションを同位体比の補正係数とともに利用可能であることを立証するために多くの実験が行われた。
この方法は、d3クレアチンの投与によって変換されたヒトの尿中のd3クレアチニン量を定量するために用いられる。さらに、内因性クレアチニン量はd3クレアチニン検量線を用いて定量される。
Claims (11)
- 被検体の全身骨格筋量の定量方法であって、
(a)D3−クレアチンが被検体に経口投与され、D3−クレアチンが全身骨格筋クレアチンプールに希釈され、全身骨格筋クレアチンプールの同位体が定常状態となった被検体から取得された、クレアチニンおよびD3−クレアチニンを含有する生体試料である尿試料中のクレアチニンおよびD3−クレアチニンを、HPLC/MS、HPLC/MS/MS、LCMS、LC/MS/MS、および同位体比質量分析(IRMS)からなる群から選択される方法によって検出するステップと、
(b)時間tにおけるクレアチニンおよびD3−クレアチニンを測定することによって上記生体試料中のD3−クレアチニンの濃縮率を測定するステップと、
(c)D3−クレアチンの投与から時間tまでの尿中D3−クレアチンの総量を測定するステップと、
(d)上記被検体の全身クレアチン貯蔵量を、下記の式(1)を用いて決定するステップと、
式(1):
全身クレアチン貯蔵量
=[D3−クレアチン投与量(g)−尿中D3−クレアチン総量(0-t)(g)]/上記(b)で求めた濃縮率(t)
(e)下記の式(2)に基づいて、上記被検体の全身骨格筋量を定量するステップ、
式(2):
全身骨格筋量=(全身クレアチン貯蔵量)/(骨格筋のクレアチン濃度)
とを含む方法。 - 上記被検体に投与されたD3−クレアチンが、5〜250mgのD3−クレアチン、その塩、またはこれらの水和物であることを特徴とする請求項1に記載の方法。
- 上記被検体に投与されたD3−クレアチンが、D3−クレアチン水和物であることを特徴とする請求項1に記載の方法。
- 上記被検体に投与されたD3−クレアチンが、D3−クレアチン一水和物であることを特徴とする請求項3に記載の方法。
- 上記D3−クレアチンの投与から少なくとも24時間経過後に取得された生体試料を用いることを特徴とする請求項1に記載の方法。
- 上記D3−クレアチンの投与から少なくとも36時間経過後に取得された生体試料を用いることを特徴とする請求項1に記載の方法。
- 上記D3−クレアチンの投与から少なくとも48時間経過後に取得された生体試料を用いることを特徴とする請求項1に記載の方法。
- 上記D3−クレアチンの投与から少なくとも60時間経過後に取得された生体試料を用いることを特徴とする請求項1に記載の方法。
- 上記D3−クレアチンの投与から少なくとも72時間経過後に取得された生体試料を用いることを特徴とする請求項1に記載の方法。
- 尿中への流出が最小限にとどまるように被検体にD3−クレアチンが投与され、投与されたD3−クレアチンの99%以上が、全身骨格筋クレアチンプールに希釈され、全身骨格筋クレアチンプールの同位体が定常状態となった被検体から取得された生体試料を用いることを特徴とする請求項1に記載の方法。
- 骨格筋中のクレアチン濃度を、4.3g/kgとすることを特徴とする請求項1に記載の方法。
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EP3435088A1 (en) | 2011-12-07 | 2019-01-30 | GlaxoSmithKline LLC | Methods for determining total body skeletal muscle mass |
US9134319B2 (en) | 2013-03-15 | 2015-09-15 | The Regents Of The University Of California | Method for replacing biomarkers of protein kinetics from tissue samples by biomarkers of protein kinetics from body fluids after isotopic labeling in vivo |
AU2014278023B2 (en) * | 2013-06-12 | 2019-11-07 | Glaxosmithkline Intellectual Property (No. 2) Limited | Methods for determining total body skeletal muscle mass |
JP6886241B2 (ja) * | 2016-01-07 | 2021-06-16 | 味の素株式会社 | 骨格筋面積の評価方法 |
JP7407596B2 (ja) * | 2017-12-25 | 2024-01-04 | 株式会社明治 | 脱脂粉乳 |
US11182920B2 (en) | 2018-04-26 | 2021-11-23 | Jerry NAM | Automated determination of muscle mass from images |
WO2023073588A1 (en) * | 2021-11-01 | 2023-05-04 | Dh Technologies Development Pte. Ltd. | Utilizing natural isotopic abundance of compounds to extend the dynamic range of an instrument |
CN115078584B (zh) * | 2022-06-27 | 2023-06-27 | 四川大学 | 一种简单快速、低成本、高通量的肌肉质量测量方法及检测试剂盒 |
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EP3435088A1 (en) | 2019-01-30 |
EP2788772A1 (en) | 2014-10-15 |
ES2668678T3 (es) | 2018-05-21 |
JP6294233B2 (ja) | 2018-03-14 |
EP2788772A4 (en) | 2015-04-15 |
CA2858368A1 (en) | 2013-06-13 |
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