JP2021001902A - Evaluation method of composition suppressing increase in blood urate level - Google Patents
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Abstract
Description
本発明は、運動又は食事開始４時間前〜運動又は食事開始時に経口摂取する、運動又は食事に起因する血中尿酸値の上昇を抑制する物質を有効成分として含有する血中尿酸値上昇の抑制剤と、当該物質のスクリーニング方法に関する。 The present invention suppresses an increase in blood uric acid level, which is taken orally from 4 hours before the start of exercise or meal to the start of exercise or meal, and contains a substance that suppresses an increase in blood uric acid level due to exercise or meal as an active ingredient. The present invention relates to an agent and a method for screening the substance.
尿酸は、ヒトにおいてプリン体の最終代謝産物として存在する。尿酸の排泄能の低下、産生の過剰等の要因により、血中尿酸値が７ｍｇ／ｄｌ以上になると、高尿酸血症と診断される。高尿酸血症発症者は増加しており、９００万人程度が日本国内にいると言われている。 Uric acid is present in humans as the final metabolite of purines. Hyperuricemia is diagnosed when the blood uric acid level exceeds 7 mg / dl due to factors such as decreased excretion of uric acid and excessive production. The number of people with hyperuricemia is increasing, and it is said that about 9 million people are in Japan.
高尿酸血症が慢性化すると、血中の尿酸塩が結晶化して関節等に蓄積し、激痛を伴う痛風発作が起こる。症状が更に進むと、痛風結節が皮下に生じたり、尿酸結晶が腎臓及び尿路に蓄積して尿路結石が生じやすくなり、腎不全等の腎疾患に繋がることが知られている。従って、血中尿酸値の適正なコントロールは、これらの疾患の予防の観点から重要である。 When hyperuricemia becomes chronic, urate in the blood crystallizes and accumulates in joints and the like, causing severe painful gout attacks. It is known that when the symptom progresses further, tofu nodules occur subcutaneously, uric acid crystals accumulate in the kidney and urinary tract, and urinary tract stones are likely to occur, leading to renal diseases such as renal failure. Therefore, proper control of blood uric acid levels is important from the viewpoint of prevention of these diseases.
Ｌ−カルニチンの数週間にわたる摂取が血中尿酸値に及ぼす影響が検討された。健康な男性による１日当たり３ｇのＬ−カルニチン酒石酸（ＬＣＬＴ）の３週間にわたる摂取（１日当たり２ｇのＬ−カルニチンを摂取）は、血中尿酸値に影響しなかったことが報告されている（例えば、非特許文献１参照）。一方、健康な男性による１日当たり３ｇのＬＣＬＴの３週間にわたる摂取（１日当たり２ｇのＬ−カルニチンを摂取）と運動前のＬＣＬＴの摂取は、血中尿酸値を低下させたことが報告されている（例えば、非特許文献２参照）。 The effect of several weeks of intake of L-carnitine on blood uric acid levels was investigated. It has been reported that a three-week intake of 3 g of L-carnitine tartrate (LCLT) per day by healthy men (taking 2 g of L-carnitine per day) did not affect blood uric acid levels (eg,). , Non-Patent Document 1). On the other hand, it has been reported that the intake of 3 g of LCLT per day for 3 weeks (intake of 2 g of L-carnitine per day) and the intake of LCLT before exercise by healthy men lowered the blood uric acid level. (See, for example, Non-Patent Document 2).
オロト酸の数週間にわたる摂取が尿酸の尿への排泄、血中尿酸値に及ぼす影響も検討された。健常者による４週間のオロト酸の摂取が、尿酸の尿への排泄を促進することが報告されている（例えば、非特許文献３参照）。更に、健常者による４週間のオロト酸の摂取が、血中尿酸値を低下させることが報告されている（例えば、非特許文献４参照）。
一方、オロト酸又はその塩とアミノ酸を有効成分として含有する尿酸値低下用組成物が検討された（例えば、特許文献１参照）。
The effects of several weeks of orotic acid intake on urinary excretion of uric acid and blood uric acid levels were also investigated. It has been reported that the intake of orotic acid by a healthy person for 4 weeks promotes the excretion of uric acid into urine (see, for example, Non-Patent Document 3). Furthermore, it has been reported that the intake of orotic acid by a healthy person for 4 weeks lowers the blood uric acid level (see, for example, Non-Patent Document 4).
On the other hand, a composition for lowering the uric acid level containing orotic acid or a salt thereof and an amino acid as active ingredients has been studied (see, for example, Patent Document 1).
更に、尿酸値が高い（５．５〜８．０ｍｇ／ｄｌ）男性がプリン体を多く含む食事と同時に菊花ポリフェノールを摂取すると、血中尿酸値の上昇が抑制されることが報告されている（非特許文献５参照）。 Furthermore, it has been reported that when men with high uric acid levels (5.5-8.0 mg / dl) take chrysanthemum polyphenols at the same time as a purine-rich diet, the increase in blood uric acid levels is suppressed ( See Non-Patent Document 5).
激しい運動又はプリン体を多く含む食事で血中尿酸値が急激に上昇することがある。高尿酸血症患者を含む血中尿酸値が高いヒトは、運動又は食事後の血中尿酸値の上昇に特に注意しなければならない。血中尿酸値が高いヒトは、血中尿酸値の上昇を気にするあまり、激しい運動、美味であってもプリン体を多く含む食事を控える傾向がある。そこで、血中尿酸値の急激な上昇を防止するため、運動又は食事の開始以前に単回経口摂取すると、血中尿酸値の上昇を抑制する物質のスクリーニング方法と、当該物質を有効成分として含有する血中尿酸値上昇の抑制剤が望まれていた。非特許文献２〜４は、Ｌ−カルニチン又はオロト酸の数週間にわたる長期間の摂取による血中尿酸値上昇の抑制又は尿酸の尿への排泄の促進を開示しているが、血中尿酸値は、被験者の食事、運動、ストレス等により変動することから、被験者数を増やし、Ｌ−カルニチン又はオロト酸を被験者に長期間摂取してもらっても、Ｌ−カルニチン又はオロト酸の摂取が血中尿酸値に及ぼす影響の判定は困難であった。まして、非特許文献２〜４から、Ｌ−カルニチン又はオロト酸の運動又は食事開始以前の単回経口摂取による、運動又は食事後の血中尿酸値上昇抑制を予想することは不可能である。特許文献１に開示されている尿酸値低下用組成物の効果は、ラットへの１０日間の投与で確認されているが、ヒトに対する当該組成物の効果は確認されていない。よって、ヒトが運動又は食事開始以前に単回経口摂取すると、運動又は食事後の血中尿酸値上昇を抑制する物質があると認識されておらず、上記抑制剤は実現されていなかった。本発明の課題は、運動又は食事開始以前に経口摂取すると、運動又は食事に起因する血中尿酸値の上昇を抑制する物質を有効成分として含有する血中尿酸値上昇の抑制剤を提供することにある。本発明の別の課題は、当該物質のスクリーニング方法を提供することにある。 Blood uric acid levels may rise sharply with strenuous exercise or a diet high in purines. Humans with high blood uric acid levels, including patients with hyperuricemia, should pay particular attention to elevated blood uric acid levels after exercise or meals. People with high blood uric acid levels tend to refrain from strenuous exercise and diets high in purines, even if they are delicious, because they are too concerned about the rise in blood uric acid levels. Therefore, in order to prevent a rapid rise in blood uric acid level, a screening method for a substance that suppresses the rise in blood uric acid level when taken orally once before the start of exercise or meal, and the substance are contained as an active ingredient. An agent for suppressing an increase in blood uric acid level has been desired. Non-Patent Documents 2 to 4 disclose suppression of increase in blood uric acid level or promotion of excretion of uric acid in urine by long-term intake of L-carnitine or orotic acid for several weeks, but blood uric acid level. Because it fluctuates depending on the subject's diet, exercise, stress, etc., even if the number of subjects is increased and the subject takes L-carnitine or orotic acid for a long period of time, the intake of L-carnitine or orotic acid is blood uric acid. It was difficult to determine the effect on the value. Furthermore, from Non-Patent Documents 2 to 4, it is impossible to predict the suppression of increase in blood uric acid level after exercise or meal by exercising L-carnitine or orotic acid or by taking a single oral intake before the start of meal. The effect of the uric acid level lowering composition disclosed in Patent Document 1 has been confirmed by administration to rats for 10 days, but the effect of the composition on humans has not been confirmed. Therefore, it has not been recognized that there is a substance that suppresses an increase in blood uric acid level after exercise or meal when a human takes a single oral intake before the start of exercise or meal, and the above-mentioned inhibitor has not been realized. An object of the present invention is to provide an agent for suppressing an increase in blood uric acid level, which contains a substance that suppresses an increase in blood uric acid level due to exercise or meal as an active ingredient when taken orally before the start of exercise or meal. It is in. Another object of the present invention is to provide a method for screening the substance.
本発明の発明者らは、ヒトが運動又は食事開始数時間前〜運動又は食事開始時に単回経口摂取すると、運動又は食事後の血中尿酸値上昇を抑制する物質を鋭意検討した。その結果、カルニチン、レシチン及びオロト酸からなる群から選ばれる１以上の化合物が有効であることを見いだし、本発明を完成させるに至った。 The inventors of the present invention have diligently investigated a substance that suppresses an increase in blood uric acid level after exercise or meal when a human is ingested once from several hours before the start of exercise or meal to at the start of exercise or meal. As a result, they have found that one or more compounds selected from the group consisting of carnitine, lecithin and orotic acid are effective, and have completed the present invention.
すなわち、本発明は、
［１］運動開始直前に採血（ａ）した後、運動終了時〜８時間以内に採血（ｂ）する工程、
運動開始４時間前〜開始直前に評価対象成分を経口摂取してから運動開始直前に採血（ｘ）した後、あるいは、運動開始直前に採血（ｘ’）してから運動開始時に評価対象成分を経口摂取した後、運動終了時〜８時間以内に採血（ｙ）する工程、
下記式（１）又は（２）を満たす場合、評価対象成分を有効であると判定する工程、
（Ｂ／Ａ）＞（Ｙ／Ｘ） （１）
（Ｂ−Ａ）＞（Ｙ−Ｘ） （２）
（ただし、Ａ、Ｂ、Ｙは、それぞれ、採血（ａ）、（ｂ）、（ｙ）で測定される血中尿酸値であり、Ｘは採血（ｘ）又は（ｘ’）で測定される血中尿酸値であり、Ａ、Ｂ、Ｘ及びＹは同一の被験者において測定され、ＡとＢは同じ日、ＸとＹは同じ日に測定されるが、Ａ及びＢとＸ及びＹとは別の日に測定される。）
を含む、運動に起因する血中尿酸値上昇を抑制する成分の評価方法に関する。
That is, the present invention
[1] A step of collecting blood (a) immediately before the start of exercise and then collecting blood (b) within 8 hours from the end of exercise.
4 hours before the start of exercise to just before the start of exercise After ingesting the component to be evaluated orally and then collecting blood (x) immediately before the start of exercise, or after collecting blood (x') immediately before the start of exercise, the component to be evaluated is taken at the start of exercise. A step of collecting blood (y) within 8 hours from the end of exercise after ingestion,
A step of determining that the component to be evaluated is effective when the following formula (1) or (2) is satisfied.
(B / A)> (Y / X) (1)
(BA)> (YX) (2)
(However, A, B, and Y are blood uric acid levels measured by blood sampling (a), (b), and (y), respectively, and X is measured by blood sampling (x) or (x'), respectively. Blood uric acid levels, A, B, X and Y are measured in the same subject, A and B are measured on the same day, X and Y are measured on the same day, but A and B and X and Y are Measured on another day.)
The present invention relates to a method for evaluating a component that suppresses an increase in blood uric acid level due to exercise, including.
更に、本発明は、
［２］食事開始直前に採血（ａ）した後、食事終了時〜８時間以内に採血（ｂ）する工程、
食事開始４時間前〜開始直前に評価対象成分を経口摂取してから食事開始直前に採血（ｘ）した後、あるいは、食事開始直前に採血（ｘ’）してから食事開始時に評価対象成分を経口摂取した後、食事終了時〜８時間以内に採血（ｙ）する工程、
下記式（１）又は（２）を満たす場合、評価対象成分を有効であると判定する工程、
（Ｂ／Ａ）＞（Ｙ／Ｘ） （１）
（Ｂ−Ａ）＞（Ｙ−Ｘ） （２）
（ただし、Ａ、Ｂ、Ｙは、それぞれ、採血（ａ）、（ｂ）、（ｙ）で測定される血中尿酸値であり、Ｘは採血（ｘ）又は（ｘ’）で測定される血中尿酸値であり、Ａ、Ｂ、Ｘ及びＹは同一の被験者において測定され、ＡとＢは同じ日、ＸとＹは同じ日に測定されるが、Ａ及びＢとＸ及びＹとは別の日に測定される。）
を含む、食事に起因する血中尿酸値上昇を抑制する成分の評価方法、
［３］食事がビール飲酒を含む、［２］に記載の評価方法に関する。
Furthermore, the present invention
[2] A step of collecting blood (a) immediately before the start of a meal and then collecting blood (b) within 8 hours from the end of the meal.
4 hours before the start of a meal to just before the start of the meal, the component to be evaluated is taken orally and then blood is collected (x) immediately before the start of the meal, or blood is collected (x') immediately before the start of the meal and then the component to be evaluated is taken at the start of the meal. A step of collecting blood (y) within 8 hours from the end of a meal after oral ingestion,
A step of determining that the component to be evaluated is effective when the following formula (1) or (2) is satisfied.
(B / A)> (Y / X) (1)
(BA)> (YX) (2)
(However, A, B, and Y are blood uric acid levels measured by blood sampling (a), (b), and (y), respectively, and X is measured by blood sampling (x) or (x'), respectively. Blood uric acid levels, A, B, X and Y are measured in the same subject, A and B are measured on the same day, X and Y are measured on the same day, but A and B and X and Y are Measured on another day.)
Evaluation method of ingredients that suppress the increase in blood uric acid level caused by diet, including
[3] The evaluation method according to [2], wherein the meal includes beer drinking.
本発明の血中尿酸値上昇の抑制剤を運動又は食事開始４時間前〜運動又は食事開始時に単回経口摂取すると、運動又は食事後の血中尿酸値上昇が抑制される。本発明のスクリーニング方法は、運動又は食事の前後の採血における血中尿酸値の測定により、日常生活における運動、食事、ストレス等の影響を受けず、運動又は食事開始４時間前〜運動又は食事開始時に経口摂取する血中尿酸値上昇を抑制する物質を短時間でスクリーニングする。 When the inhibitor of the blood uric acid level increase of the present invention is orally ingested 4 hours before the start of exercise or meal to once at the start of exercise or meal, the increase in blood uric acid level after exercise or meal is suppressed. The screening method of the present invention measures the blood uric acid level in blood sampling before and after exercise or meal, and is not affected by exercise, meal, stress, etc. in daily life, and 4 hours before the start of exercise or meal to the start of exercise or meal. Screen for substances that suppress the increase in blood uric acid level that is sometimes taken orally in a short time.
本発明の運動又は食事開始４時間前〜運動又は食事開始時に経口摂取する血中尿酸値上昇の抑制剤（以下、「本発明の抑制剤」という。）は、カルニチン、レシチン及びオロト酸からなる群から選ばれる１以上を有効成分として含有する。 The inhibitor of an increase in blood uric acid level orally ingested from 4 hours before the start of exercise or meal of the present invention to the start of exercise or meal (hereinafter referred to as "suppressant of the present invention") comprises carnitine, lecithin and orotoic acid. Contains one or more selected from the group as an active ingredient.
本発明の抑制剤が含有するカルニチンは、４−トリメチルアミノ−３−ヒドロキシ酪酸のことである。市販のカルニチン、化学合成により得られるカルニチン、微生物由来のカルニチン、肉類・乳等から抽出したカルニチンのいずれも用いられる。化学合成により得られるカルニチンの製造方法は、例えば、国際公開第２００８／０５６８２７号パンフレットに開示されている。カルニチンの立体異性体としてＤ体とＬ体が存在し、混合物としてＤＬ体が知られている。本発明の抑制剤が含有するカルニチンは、Ｌ−カルニチン、Ｄ−カルニチン、Ｌ−カルニチンとＤ−カルニチンの混合物のいずれでもよいが、好ましいカルニチンは、Ｌ−カルニチン、Ｌ−カルニチンとＤ−カルニチンの混合物である。また、本発明の抑制剤が含有するカルニチンは、塩酸塩、酢酸塩、硫酸塩等のカルニチンの塩；カルニチンアシルエステル等のカルニチンの誘導体であってもよい。 The carnitine contained in the inhibitor of the present invention is 4-trimethylamino-3-hydroxybutyric acid. Any of commercially available carnitine, carnitine obtained by chemical synthesis, carnitine derived from microorganisms, and carnitine extracted from meat, milk and the like can be used. A method for producing carnitine obtained by chemical synthesis is disclosed in, for example, International Publication No. 2008/056827 pamphlet. D-form and L-form exist as the three isomers of carnitine, and DL-form is known as a mixture. The carnitine contained in the inhibitor of the present invention may be any of L-carnitine, D-carnitine, and a mixture of L-carnitine and D-carnitine, but the preferred carnitine is L-carnitine, L-carnitine and D-carnitine. It is a mixture. Further, the carnitine contained in the inhibitor of the present invention may be a carnitine salt such as a hydrochloride, an acetate or a sulfate; or a carnitine derivative such as a carnitine acyl ester.
本発明の抑制剤が含有するレシチンは、卵黄由来レシチン、大豆由来レシチン等、その由来が特に制限されないレシチンであり、酵素処理されたレシチンであってもよい。 The lecithin contained in the inhibitor of the present invention is a lecithin whose origin is not particularly limited, such as egg yolk-derived lecithin and soybean-derived lecithin, and may be an enzyme-treated lecithin.
本発明の抑制剤が含有するオロト酸は、ウラシル−６−カルボン酸のことである。市販のオロト酸、化学合成により得られるオロト酸、微生物由来のオロト酸、乳清等食品から抽出されるオロト酸のいずれも用いられる。微生物由来のオロト酸の取得方法が、例えば米国特許第５，０１３，６５６号明細書に記載されている。本発明の抑制剤が含有するオロト酸は、オロト酸のフリー体（遊離体）、オロト酸の水和物、オロト酸の誘導体、それらの薬理学的に許容される塩のいずれも含まれる。好ましいオロト酸は、オロト酸のフリー体（遊離体）、その水和物である。 The orotic acid contained in the inhibitor of the present invention is uracil-6-carboxylic acid. Commercially available orotic acid, orotic acid obtained by chemical synthesis, orotic acid derived from microorganisms, orotic acid extracted from foods such as whey are all used. A method for obtaining orotic acid derived from a microorganism is described, for example, in US Pat. No. 5,013,656. The orotic acid contained in the inhibitor of the present invention includes any of a free form of orotic acid (free form), a hydrate of orotic acid, a derivative of orotic acid, and a pharmacologically acceptable salt thereof. Preferred orotic acid is a free form of orotic acid, a hydrate thereof.
カルニチン、レシチン、オロト酸の好ましい経口摂取量は、それぞれ、１００〜３，０００ｍｇ／日、５０〜８，０００ ｍｇ／日、５０〜８００ｍｇ／日である。カルニチン、レシチン及びオロト酸からなる群から選ばれる１又は２以上の有効成分が、それぞれ、好ましくは前記範囲となるように、本発明の抑制剤の摂取量を調節して、本発明の抑制剤を運動又は食事開始４時間前〜運動又は食事開始時に単回経口摂取する。 Preferred oral intakes of carnitine, lecithin and orotic acid are 100-3,000 mg / day, 50-8,000 mg / day and 50-800 mg / day, respectively. The inhibitor of the present invention is prepared by adjusting the intake of the inhibitor of the present invention so that one or more active ingredients selected from the group consisting of carnitine, lecithin and orotic acid are each preferably in the above range. Is taken orally 4 hours before the start of exercise or meal to once at the start of exercise or meal.
本発明の抑制剤を経口摂取する対照となる運動は、特定の運動に限定されない。本発明の抑制剤の経口摂取が特に効果的な運動は、下記式で示される運動強度４０％以上の運動である。
運動強度（％）＝（心拍数−安静時心拍数）／（推定最大心拍数−安静時心拍数）×１００
ただし、推定最大心拍数＝２２０−年齢 とする。
例えば、年齢満３０歳（推定最大心拍数＝２２０−３０＝１９０）、安静時心拍数６０のヒトが、心拍数１３８の運動をしているときの運動強度は、（１３８−６０）／（１９０−６０）×１００＝６０（％）である。
高尿酸血症患者を含む血中尿酸値が高いヒトは、本発明の抑制剤を運動開始４時間前〜運動開始時に単回経口摂取すれば、血中尿酸値の上昇を過度に気にせず、激しい運動を実施できる。
The control exercise for ingesting the inhibitor of the present invention is not limited to a specific exercise. Exercise for which oral intake of the inhibitor of the present invention is particularly effective is exercise with an exercise intensity of 40% or more represented by the following formula.
Exercise intensity (%) = (heart rate-resting heart rate) / (estimated maximum heart rate-resting heart rate) x 100
However, the estimated maximum heart rate = 220-age.
For example, a person who is 30 years old (estimated maximum heart rate = 220-30 = 190) and has a resting heart rate of 60 has an exercise intensity of (138-60) / (when exercising at a heart rate of 138). 190-60) × 100 = 60 (%).
Humans with high blood uric acid levels, including patients with hyperuricemia, can take the inhibitor of the present invention once orally from 4 hours before the start of exercise to the start of exercise without being overly concerned about the increase in blood uric acid levels. , Can carry out strenuous exercise.
本発明の抑制剤を経口摂取する対照となる食事は、特定の食事に限定されない。本発明の抑制剤の経口摂取が特に効果的な食事は、プリン体の含有量が多い食品を摂取する食事である。尿酸血症患者を含む血中尿酸値が高いヒトは、本発明の抑制剤を食事開始４時間前〜食事開始時に単回経口摂取すれば、血中尿酸値の上昇を過度に気にせず、ビール、紹興酒、レバー類、エビ、イワシ、カツオ、白子等のプリン体の含有量が多い食品を飲食できる。 The control diet for ingesting the inhibitor of the present invention is not limited to a specific diet. A diet in which oral ingestion of the inhibitor of the present invention is particularly effective is a diet in which a food containing a large amount of purines is ingested. Humans with high blood uric acid levels, including patients with hyperuricemia, can take the inhibitor of the present invention orally once from 4 hours before the start of the meal to the start of the meal without being overly concerned about the increase in the blood uric acid level. You can eat and drink foods with a high content of purines such as beer, uric acid, livers, shrimp, sardines, bonito, and milt.
本発明の抑制剤の形状は、ヒトが経口摂取できる形状であり、特定の形状に限定されない。本発明の抑制剤は、固形状、液状、半液状、顆粒状、粒状、粉末状、カプセル状、クリーム状、ペースト状であり得る。 The shape of the inhibitor of the present invention is a shape that can be orally ingested by humans, and is not limited to a specific shape. The inhibitor of the present invention may be solid, liquid, semi-liquid, granular, granular, powdery, capsule-like, cream-like or paste-like.
カルニチン、レシチン及びオロト酸からなる群から選ばれる１又は２以上をそのまま本発明の抑制剤として経口摂取できる。更に、本発明の効果を損なわない範囲で、他の成分を本発明の抑制剤に適宜配合し、本発明の抑制剤を食品の形態で提供できる。 One or more selected from the group consisting of carnitine, lecithin and orotic acid can be orally ingested as they are as the inhibitor of the present invention. Further, the inhibitor of the present invention can be provided in the form of a food by appropriately blending other ingredients with the inhibitor of the present invention as long as the effects of the present invention are not impaired.
上記他の成分は、特定の成分に限定されない。上記他の成分は、タンパク質、糖類、微量元素、ビタミン類、有機酸（クエン酸、酢酸等）の塩、甘味料（アスパルテーム、ステビア等）、酸味料（クエン酸、リンゴ酸、酒石酸）、賦形剤（デキストリン、デンプン等）、着色料、香料、苦味料、緩衝剤、増粘安定剤、ゲル化剤、安定剤、ガムベース、結合剤、希釈剤、乳化剤、分散剤、懸濁化剤、酸化防止剤、保存料、防腐剤、膨黴剤、発色剤、漂白剤、光沢剤、酵素、調味料、香辛料であってよい。 The above other components are not limited to specific components. The other components mentioned above are proteins, sugars, trace elements, vitamins, salts of organic acids (citric acid, acetic acid, etc.), sweeteners (aspartame, stevia, etc.), acidulants (citric acid, malic acid, tartrate acid), and additives. Shapers (dextrin, starch, etc.), colorants, fragrances, bitterness agents, buffers, thickening stabilizers, gelling agents, stabilizers, gum bases, binders, diluents, emulsifiers, dispersants, suspending agents, It may be an antioxidant, a preservative, a preservative, a starching agent, a color former, a bleaching agent, a brightener, an enzyme, a seasoning, a spice.
本発明の抑制剤は食品の形態であってよい。上記食品は特定の食品に限定されない。上記食品は、飲料（清涼飲料、炭酸飲料、栄養飲料、果実飲料、乳飲料、飲料の濃縮原液、飲料の調整用粉末等）、飯類、麺類、パン類、パスタ類、洋菓子類、和菓子類（羊羹、饅頭等）、キャンディー類、ガム類、冷菓（プリン、ゼリー等）、氷菓、水産・畜産加工食品（かまぼこ、ちくわ、ハンバーグ、ハム、ソーセージ等）、乳製品（加工乳、発酵乳、ヨーグルト、バター、チーズ等）、油脂及び油脂加工食品（マーガリン、マヨネーズ、ショートニング、ホイップクリーム、ドレッシング等）、調味料（ソース、たれ、醤油等）であってよい。 The inhibitor of the present invention may be in the form of food. The above foods are not limited to specific foods. The above foods include beverages (soft beverages, carbonated beverages, nutritional beverages, fruit beverages, dairy beverages, concentrated stock solutions of beverages, powders for adjusting beverages, etc.), rice, noodles, breads, pasta, Western confectionery, Japanese confectionery. (Sheeps, buns, etc.), candy, gums, frozen desserts (pudding, jelly, etc.), frozen desserts, processed marine and livestock foods (kamaboko, chikuwa, hamburger, ham, sausage, etc.) It may be yogurt, butter, cheese, etc.), fats and oils and processed fats and oils foods (margarine, mayonnaise, shortening, whipped cream, dressings, etc.), and seasonings (sauce, sauce, soy sauce, etc.).
生活習慣、体質、遺伝等により血中尿酸値が高いヒトばかりでなく、健常者も、激しい運動、プリン体を多く含む食品の摂取等による血中尿酸値の上昇の抑制を目的として、本発明の抑制剤を経口摂取できる。 The present invention aims to suppress an increase in blood uric acid level due to strenuous exercise, ingestion of foods containing a large amount of purines, etc., not only for humans with high blood uric acid level due to lifestyle, constitution, heredity, etc. Can be taken orally.
本発明の運動又は食事開始４時間前〜運動又は食事開始時に経口摂取する、運動又は食事に起因する血中尿酸値上昇を抑制する物質のスクリーニング方法（以下、「本発明のスクリーニング方法」という。）は、上記３つの工程を含む。以下、本発明のスクリーニング方法の一実施形態を説明する。なお、本発明のスクリーニング方法は、この実施形態に限定されない。 The screening method for a substance that suppresses an increase in blood uric acid level due to exercise or meal, which is orally ingested from 4 hours before the start of exercise or meal of the present invention to the start of exercise or meal (hereinafter, referred to as "screening method of the present invention". ) Including the above three steps. Hereinafter, an embodiment of the screening method of the present invention will be described. The screening method of the present invention is not limited to this embodiment.
まず、経口摂取により血中尿酸値の上昇を抑制する効果を期待できる成分をスクリーニング対象成分として選択する。 First, a component that can be expected to have an effect of suppressing an increase in blood uric acid level by oral ingestion is selected as a screening target component.
被験者の運動又は食事開始直前に採血（ａ）し、運動又は食事終了時から８時間以内に再度採血（ｂ）し、採血（ａ）、（ｂ）のそれぞれで採取された血液中の尿酸値Ａ、Ｂを測定する。また、同一被験者に運動又は食事開始４時間前〜運動又は食事開始直前にスクリーニング対象成分を経口摂取してもらってから運動又は食事開始直前に採血（ｘ）し、若しくは、被験者の運動又は食事開始直前に採血（ｘ’）してから、運動又は食事開始時にスクリーニング対象成分を経口摂取してもらい、運動又は食事終了時から８時間以内に再度採血（ｙ）する。そして、採血（ｘ）又は（ｘ’）で採取された血液中の尿酸値Ｘ、採血（ｙ）で採取された血液中の尿酸値Ｙを測定する。 Blood was collected (a) immediately before the start of exercise or meal of the subject, blood was collected again within 8 hours from the end of exercise or meal (b), and the uric acid level in the blood collected in each of blood collection (a) and (b). Measure A and B. In addition, after having the same subject orally ingest the component to be screened from 4 hours before the start of exercise or meal to immediately before the start of exercise or meal, blood is collected (x) immediately before the start of exercise or meal, or immediately before the start of exercise or meal of the subject. After collecting blood (x'), the component to be screened is taken orally at the start of exercise or meal, and blood is collected again (y) within 8 hours from the end of exercise or meal. Then, the uric acid value X in the blood collected by blood sampling (x) or (x') and the uric acid level Y in the blood collected by blood sampling (y) are measured.
血中尿酸値Ａ及びＢの測定日と血中尿酸値Ｘ及びＹの測定日は、好ましくは別の日である。血中尿酸値Ｂ及びＹの測定における運動又は食事終了時からの経過時間は、好ましくは同一である。 The measurement dates of the blood uric acid levels A and B and the measurement dates of the blood uric acid levels X and Y are preferably different days. The elapsed time from the end of exercise or meal in the measurement of blood uric acid levels B and Y is preferably the same.
下記式（１）を満たす場合、スクリーニング対象成分を有効であると判定し、運動又は食事開始４時間前〜運動又は食事開始時に経口摂取する血中尿酸値上昇の抑制剤の有効成分とする。
（Ｂ／Ａ）＞（Ｙ／Ｘ） （１）
When the following formula (1) is satisfied, the component to be screened is judged to be effective, and is used as the active ingredient of an agent for suppressing an increase in blood uric acid level, which is orally ingested from 4 hours before the start of exercise or meal to the start of exercise or meal.
(B / A)> (Y / X) (1)
カルニチン、レシチン及びオロト酸は、本発明のスクリーニング方法により、運動又は食事開始４時間前〜運動又は食事開始時に経口摂取する血中尿酸値上昇の抑制剤の有効成分としてスクリーニングされた。 Carnitine, lecithin and orotic acid were screened by the screening method of the present invention as active ingredients of an agent for suppressing an increase in blood uric acid level taken orally from 4 hours before the start of exercise or meal to the start of exercise or meal.
本発明のスクリーニング方法は、被験者の血中尿酸値の日変動の影響を回避するから、簡便かつ極めて精度が高い評価法である。痛風発作は、血中尿酸濃度の一時的上昇により発生する。本発明のスクリーニング方法で選ばれた成分を長期間摂取しなくても、当該成分の運動又は食事前の単回投与で血中尿酸濃度の一時的上昇が抑制され、痛風発作のリスク低減効果を期待できる。 The screening method of the present invention is a simple and extremely accurate evaluation method because it avoids the influence of daily fluctuations in the blood uric acid level of the subject. Gout attacks are caused by a temporary increase in blood uric acid levels. Even if the component selected by the screening method of the present invention is not ingested for a long period of time, a temporary increase in blood uric acid concentration is suppressed by exercise or a single administration of the component before meals, and the risk of gout attack can be reduced. You can expect it.
以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されない。血中尿酸値の測定方法は、以下のとおりである。
検体中の尿酸がウリカーゼの作用によって酸化分解されるときに発生する過酸化水素（Ｈ２Ｏ２）にペルオキシダーゼ（ＰＯＤ）を作用させ４−アミノアンチピリン（４−ＡＡ）及び発色剤で酸化縮合せしめることにより生じるキノン色素を比色測定することにより尿酸濃度を求めた（ウリカーゼ−ＰＯＤ法）。
Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited to these examples. The method for measuring the blood uric acid level is as follows.
Peroxidase (POD) is allowed to act on hydrogen peroxide (H 2 O 2 ) generated when uric acid in a sample is oxidatively decomposed by the action of uricase, and oxidative condensation is carried out with 4-aminoantipyrine (4-AA) and a color former. The uric acid concentration was determined by colorimetrically measuring the resulting quinone pigment (uricase-POD method).
実施例１〜４
被験者１（２２歳の女性健常者）が、自転車漕ぎ運動の３０分前に何も摂食せず（コントロール）、又は、２．９ｇのレシチン（キューピー（株）製卵黄レシチンPL-30S）（実施例１）、７５０ｍｇのＬ−カルニチン（実施例２）、２．９ｇのレシチン（キューピー（株）製卵黄レシチンPL-30S）及び７５０ｍｇのＬ−カルニチン（実施例３）、７５０ｍｇのＬ−カルニチン及び４７０ｇの白米（実施例４）を経口摂取し、自転車漕ぎ運動直前に血中尿酸値を測定した。被験者１に心拍数１４０回／分程度の自転車漕ぎ運動を３０分続けてもらい、自転車漕ぎ運動終了から３．５時間後の血中尿酸値を測定した。血中尿酸値変化率は下記の式（２）により算出した。結果を図１に示す。なお、コントロール、実施例１、実施例２、実施例３及び実施例４は、別の日に行われた。
血中尿酸値変化率（％）＝自転車漕ぎ運動終了から３．５時間後の血中尿酸値／自転車漕ぎ運動直前に血中尿酸値×１００
Examples 1-4
Subject 1 (22-year-old healthy female) did not eat anything (control) 30 minutes before the bicycle rowing exercise, or 2.9 g of lecithin (Kupy Co., Ltd. egg yolk lecithin PL-30S) (implemented) Example 1), 750 mg L-carnitine (Example 2), 2.9 g lecithin (Egg yolk lecithin PL-30S manufactured by Cupy Co., Ltd.) and 750 mg L-carnitine (Example 3), 750 mg L-carnitine and 470 g of white rice (Example 4) was orally ingested, and the blood uric acid level was measured immediately before the bicycle rowing exercise. Subject 1 was asked to continue a bicycle rowing exercise with a heart rate of about 140 beats / minute for 30 minutes, and the blood uric acid level was measured 3.5 hours after the end of the bicycle rowing exercise. The rate of change in blood uric acid level was calculated by the following formula (2). The results are shown in FIG. The control, Example 1, Example 2, Example 3 and Example 4 were performed on different days.
Blood uric acid level change rate (%) = Blood uric acid level 3.5 hours after the end of the bicycle rowing exercise / Blood uric acid level immediately before the bicycle rowing exercise x 100
被験者１が何も経口摂取せずに自転車漕ぎ運動をしたときよりも、被験者１がレシチン、Ｌ−カルニチン、レシチン及びＬ−カルニチン、Ｌ−カルニチン及び白米を経口摂取してから自転車漕ぎ運動をしたときは、血中尿酸値の上昇が抑制されることがわかった。 Subject 1 took lecithin, L-carnitine, lecithin and L-carnitine, L-carnitine and white rice orally and then did the biking exercise than when subject 1 did the biking exercise without taking anything orally. Occasionally, it was found that the increase in blood uric acid level was suppressed.
実施例５
５名の被験者２〜６（２１歳の女性健常者５名）が、自転車漕ぎ運動の３０分前に何も摂食せず（コントロール）、又は、４００ｍｇのオロト酸を経口摂取し、自転車漕ぎ運動直前に血中尿酸値を測定した。被験者２〜６に心拍数１４０回／分程度の自転車漕ぎ運動を３０分続けてもらい、自転車漕ぎ運動終了から３．５時間後の血中尿酸値を測定した。結果を表１に示す。なお、コントロール及び実施例５は、別の日に行われた。
Example 5
Five subjects 2 to 6 (five 21-year-old healthy female subjects) did not eat anything (control) 30 minutes before the bicycle rowing exercise, or took 400 mg of orotic acid orally and performed the bicycle rowing exercise. Immediately before, the blood uric acid level was measured. Subjects 2 to 6 were asked to continue a bicycle rowing exercise with a heart rate of about 140 beats / minute for 30 minutes, and the blood uric acid level was measured 3.5 hours after the end of the bicycle rowing exercise. The results are shown in Table 1. The control and Example 5 were performed on another day.
被験者２〜６全員の血中尿酸値の上昇が、自転車漕ぎ運動３０分前のオロト酸の経口摂取により抑制されたことがわかった。 It was found that the increase in blood uric acid level of all subjects 2 to 6 was suppressed by oral ingestion of orotic acid 30 minutes before cycling exercise.
実施例６及び７
被験者７（２１歳の女性健常者）に下記表２に示される高プリン体含有食品の摂食３０分前に何も摂食せず（コントロール）、又は、４００ｍｇのオロト酸（実施例６）、２．
９ｇのレシチン（キューピー（株）製卵黄レシチンPL-30S）及び４００ｍｇのオロト酸（実施例７）をサプリメントとして摂取してもらい、高プリン体含有食品の摂食直前に被験者７の血中尿酸値を測定した後、被験者７に高プリン体含有食品を摂食してもらい、サプリメント摂食後５時間後及び７時間後に被験者７の血中尿酸値を測定した。結果を図２に示す。なお、コントロール、実施例６及び実施例７は、別の日に行われた。高プリン体含有食品の栄養素バランス構成は下記表３に示されているとおりである。
Examples 6 and 7
Subject 7 (a 21-year-old healthy female) did not eat anything 30 minutes before eating the high purine-containing food shown in Table 2 below (control), or 400 mg of orotic acid (Example 6). 2. 2.
9 g of lecithin (egg yolk lecithin PL-30S manufactured by Cupy Co., Ltd.) and 400 mg of orotoic acid (Example 7) were taken as supplements, and the blood uric acid level of subject 7 immediately before eating the high purine-containing food. After the measurement, the subject 7 was asked to eat a food containing a high purine body, and the blood uric acid level of the subject 7 was measured 5 hours and 7 hours after the supplement was ingested. The results are shown in FIG. The controls, Example 6 and Example 7 were performed on different days. The nutrient balance composition of foods containing high purines is as shown in Table 3 below.
高プリン体含有食品の摂食直前の血中尿酸値を１００％とすると、サプリメント摂食後５時間後及び７時間後の血中尿酸値は１００％を超えており、高プリン体含有食品の摂食により血中尿酸値が上昇していた。ただし、被験者７が何も経口摂取せずに高プリン体含有食品を摂取したときよりも、被験者７がサプリメントを経口摂取してから高プリン体含有食品を摂取したときは、血中尿酸値の上昇が抑制されることがわかった。 Assuming that the blood uric acid level immediately before eating the high purine-containing food is 100%, the blood uric acid level 5 hours and 7 hours after eating the supplement exceeds 100%, and the high purine-containing food is consumed. Blood uric acid level was elevated by food. However, the blood uric acid level was higher when subject 7 ingested the high purine-containing food after ingesting the supplement than when subject 7 ingested the high-purine-containing food without ingesting anything. It was found that the rise was suppressed.
参考例１
飲酒を好む尿酸値が高めの被験者８〜１２（４０〜５５才の男性）の血中尿酸値を測定した後、２週間普通に生活してもらい、再度血中尿酸値を測定した。結果を表４に示す。
Reference example 1
After measuring the blood uric acid level of subjects 8 to 12 (male aged 40 to 55 years) having a high uric acid level who prefers to drink, they were asked to live normally for 2 weeks, and the blood uric acid level was measured again. The results are shown in Table 4.
普通に生活していても、短期間に血中尿酸値が変動することが確認された。経口摂取により血中尿酸値の上昇を抑制する効果を期待できる成分の効果は、従来、当該成分の長期間摂取前後でのプラセボ群との比較により評価されるが、血中尿酸値は、上記されるとおり、日常生活の運動、食事、ストレス等の影響を受けるから、当該成分の血中尿酸値の上昇抑制効果の評価は困難であることがわかった。 It was confirmed that the blood uric acid level fluctuates in a short period of time even if the person lives normally. Conventionally, the effect of a component that can be expected to suppress an increase in blood uric acid level by oral ingestion is evaluated by comparison with the placebo group before and after long-term ingestion of the component, but the blood uric acid level is described above. As described above, it was found that it is difficult to evaluate the effect of the component on suppressing the increase in blood uric acid level because it is affected by exercise, diet, stress, etc. in daily life.
実施例８
被験者８〜１２にビール飲酒１時間前に何も摂食せず（コントロール）、又は、４００ｍｇのオロト酸をサプリメントとして摂取してもらい（実施例８）、ビール飲酒直前に被験者８〜１２の血中尿酸値を測定した後、被験者８〜１２に５００ｍｌのビールを飲酒してもらい、サプリメント摂食後３時間後に被験者８〜１２の血中尿酸値を測定した。結果を表５に示す。なお、コントロール及び実施例８は、別の日に行われた。
Example 8
Subjects 8 to 12 were asked to eat nothing 1 hour before drinking beer (control) or to take 400 mg of orotic acid as a supplement (Example 8), and the blood of subjects 8 to 12 immediately before drinking beer. After measuring the uric acid level, subjects 8 to 12 were asked to drink 500 ml of beer, and the blood uric acid level of subjects 8 to 12 was measured 3 hours after eating the supplement. The results are shown in Table 5. The control and Example 8 were performed on another day.
被験者８〜１２全員の血中尿酸値の上昇が、ビール飲酒１時間前のオロト酸の経口摂取により抑制されたことがわかった。 It was found that the increase in blood uric acid level of all subjects 8 to 12 was suppressed by oral ingestion of orotic acid 1 hour before drinking beer.
本発明の抑制剤は、運動又は食事開始時以前に単回摂取して血中尿酸値の上昇を抑制するサプリメント又は食品として有用である。本発明のスクリーニング方法は、運動又は食事前後の血中尿酸値の測定のみで運動又は食事開始時以前に単回摂取して血中尿酸値の上昇を抑制する物質をスクリーニングする方法として有用である。 The inhibitor of the present invention is useful as a supplement or food that is taken once before the start of exercise or meal to suppress an increase in blood uric acid level. The screening method of the present invention is useful as a method for screening a substance that suppresses an increase in blood uric acid level by taking a single dose before the start of exercise or meal only by measuring the blood uric acid level before and after exercise or meal. ..
Claims (3)
運動開始４時間前〜開始直前に評価対象成分を経口摂取してから運動開始直前に採血（ｘ）した後、あるいは、運動開始直前に採血（ｘ’）してから運動開始時に評価対象成分を経口摂取した後、運動終了時〜８時間以内に採血（ｙ）する工程、
下記式（１）又は（２）を満たす場合、評価対象成分を有効であると判定する工程、
（Ｂ／Ａ）＞（Ｙ／Ｘ） （１）
（Ｂ−Ａ）＞（Ｙ−Ｘ） （２）
（ただし、Ａ、Ｂ、Ｙは、それぞれ、採血（ａ）、（ｂ）、（ｙ）で測定される血中尿酸値であり、Ｘは採血（ｘ）又は（ｘ’）で測定される血中尿酸値であり、Ａ、Ｂ、Ｘ及びＹは同一の被験者において測定され、ＡとＢは同じ日、ＸとＹは同じ日に測定されるが、Ａ及びＢとＸ及びＹとは別の日に測定される。）
を含む、運動に起因する血中尿酸値上昇を抑制する成分の評価方法。 A step of collecting blood (a) immediately before the start of exercise and then collecting blood (b) within 8 hours from the end of exercise.
4 hours before the start of exercise to just before the start of exercise After ingesting the component to be evaluated orally and then collecting blood (x) immediately before the start of exercise, or after collecting blood (x') immediately before the start of exercise, the component to be evaluated is taken at the start of exercise. A step of collecting blood (y) within 8 hours from the end of exercise after ingestion,
A step of determining that the component to be evaluated is effective when the following formula (1) or (2) is satisfied.
(B / A)> (Y / X) (1)
(BA)> (YX) (2)
(However, A, B, and Y are blood uric acid levels measured by blood sampling (a), (b), and (y), respectively, and X is measured by blood sampling (x) or (x'), respectively. Blood uric acid levels, A, B, X and Y are measured in the same subject, A and B are measured on the same day, X and Y are measured on the same day, but A and B and X and Y are Measured on another day.)
A method for evaluating a component that suppresses an increase in blood uric acid level due to exercise, including.
食事開始４時間前〜開始直前に評価対象成分を経口摂取してから食事開始直前に採血（ｘ）した後、あるいは、食事開始直前に採血（ｘ’）してから食事開始時に評価対象成分を経口摂取した後、食事終了時〜８時間以内に採血（ｙ）する工程、
下記式（１）又は（２）を満たす場合、評価対象成分を有効であると判定する工程、
（Ｂ／Ａ）＞（Ｙ／Ｘ） （１）
（Ｂ−Ａ）＞（Ｙ−Ｘ） （２）
（ただし、Ａ、Ｂ、Ｙは、それぞれ、採血（ａ）、（ｂ）、（ｙ）で測定される血中尿酸値であり、Ｘは採血（ｘ）又は（ｘ’）で測定される血中尿酸値であり、Ａ、Ｂ、Ｘ及びＹは同一の被験者において測定され、ＡとＢは同じ日、ＸとＹは同じ日に測定されるが、Ａ及びＢとＸ及びＹとは別の日に測定される。）
を含む、食事に起因する血中尿酸値上昇を抑制する成分の評価方法。 A step of collecting blood (a) immediately before the start of a meal and then collecting blood (b) within 8 hours from the end of the meal.
4 hours before the start of a meal to just before the start of the meal, the component to be evaluated is taken orally and then blood is collected (x) immediately before the start of the meal, or blood is collected (x') immediately before the start of the meal and then the component to be evaluated is taken at the start of the meal. A step of collecting blood (y) within 8 hours from the end of a meal after oral ingestion,
A step of determining that the component to be evaluated is effective when the following formula (1) or (2) is satisfied.
(B / A)> (Y / X) (1)
(BA)> (YX) (2)
(However, A, B, and Y are blood uric acid levels measured by blood sampling (a), (b), and (y), respectively, and X is measured by blood sampling (x) or (x'), respectively. Blood uric acid levels, A, B, X and Y are measured in the same subject, A and B are measured on the same day, X and Y are measured on the same day, but A and B and X and Y are Measured on another day.)
A method for evaluating a component that suppresses an increase in blood uric acid level due to diet, including.
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Citations (5)
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| JP2001163788A (en) * | 1999-12-03 | 2001-06-19 | Kobayashi Pharmaceut Co Ltd | Modulator for digestion and absorption of purine body |
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| JP2001163788A (en) * | 1999-12-03 | 2001-06-19 | Kobayashi Pharmaceut Co Ltd | Modulator for digestion and absorption of purine body |
| JP2005187405A (en) * | 2003-12-25 | 2005-07-14 | Lion Corp | Uric acid value inhibitor and purine body adsorbent |
| JP2006001898A (en) * | 2004-06-18 | 2006-01-05 | Chisso Corp | Purine body-adsorbing agent |
| US20090105160A1 (en) * | 2007-10-22 | 2009-04-23 | Lytone Enterprise, Inc. | Pharmaceutical composition, package and method for rapidly reducing the uric acid in blood |
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