JPWO2019237053A5 - - Google Patents
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- JPWO2019237053A5 JPWO2019237053A5 JP2021518056A JP2021518056A JPWO2019237053A5 JP WO2019237053 A5 JPWO2019237053 A5 JP WO2019237053A5 JP 2021518056 A JP2021518056 A JP 2021518056A JP 2021518056 A JP2021518056 A JP 2021518056A JP WO2019237053 A5 JPWO2019237053 A5 JP WO2019237053A5
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Description
均等物
本発明は、その精神または本質的特徴から逸脱することなく、他の特定の形態で具体化され得る。したがって、前述の実施態様は、すべての点で、本明細書に記載の発明を限定するものではなく、例示的なものであると見なされるべきである。よって、本発明の範囲は、前述の説明によってではなく、添付の特許請求の範囲によって示され、特許請求の範囲の意味および同等の範囲内にあるすべての変更は、そこに包含されることが意図される。
また、本発明は、以下の態様および実施態様を含む。
[1] 組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させることを必要とする前糖尿病の対象体または糖尿病、慢性腎疾患もしくはその組合せの対象体において、組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させる方法であって、該方法が、1日当たり少なくとも2 mgの実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与し、これにより組織石灰化を予防する、進行を遅らせるおよび／または停止させることを含み、MK7および／またはMKH2-7が、医薬組成物で投与される、方法。
[2] 対象体が、糖尿病を有する、[1]に記載の方法。
[3] 対象体が、II型糖尿病を有する、[2]に記載の方法。
[4] 対象体が、前糖尿病と診断されている、[1]に記載の方法。
[5] 対象体が、慢性腎疾患を有する、[1]～[4]のいずれかに記載の方法。
[6] 対象体が、ステージ4または5の慢性腎疾患/末期腎疾患を有する、[1]～[4]のいずれかに記載の方法。
[7] 対象体が、血液透析を受けている、[1]～[6]のいずれかに記載の方法。
[8] 対象体が、非ワルファリンベースの抗凝固療法を受けている、[1]～[7]のいずれかに記載の方法。
[9] 抗凝固療法が、経口抗凝固療法である、[8]に記載の方法。
[10] 抗凝固療法が、第Xa因子活性（例えば、アピキサバン、リバーロキサバン、ベトリキサバン、エドキサバン、オタミキサバン、レタキサバン、エリバキサバンまたはフォンダパリヌクス）または第IIa因子活性（例えば、ダビガトランまたはアルガトロバン）の阻害薬を含む、[9]に記載の方法。
[11] 組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させることを必要とする血液透析を受けている対象体において、組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させる方法であって、該方法が、1日当たり少なくとも2 mgの実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与し、これにより組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させることを含み、MK7および／またはMKH2-7が、医薬組成物で投与される、方法。
[12] 対象体が、糖尿病を有する、[11]に記載の方法。
[13] 糖尿病が、II型糖尿病である、[12]に記載の方法。
[14] 対象体が、前糖尿病と診断されている、[11]に記載の方法。
[15] 対象体が、慢性腎疾患を有する、[11]～[14]のいずれかに記載の方法。
[16] 対象体が、ステージ4またはステージ5の慢性腎疾患/末期腎疾患を有する、[15]に記載の方法。
[17] 対象体が、非ワルファリンベースの抗凝固療法を受けている、[11]～[16]のいずれかに記載の方法。
[18] 抗凝固療法が、経口抗凝固療法である、[17]に記載の方法。
[19] 抗凝固療法が、第Xa因子活性（例えば、アピキサバン、リバーロキサバン、ベトリキサバン、エドキサバンまたはフォンダパリヌクス）または第IIa因子活性（例えば、ダビガトランまたはアルガトロバン）の阻害薬を含む、[17]に記載の方法。
[20] 組織石灰化を予防する、進行を遅らせる、停止させるまたは反転させることを必要とするステージ5の慢性腎疾患を有し、経口非ワルファリンベースの抗凝固療法を受けている対象体において、組織石灰化を予防する、進行を遅らせる、停止させるまたは反転させる方法であって、該方法が、1日当たり少なくとも2 mgの実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与し、これにより対象体における組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させることを含み、MK7および／またはMKH2-7が、医薬組成物で投与される、方法。
[21] 対象体が、糖尿病である、[20]に記載の方法。
[22] 対象体が、前糖尿病と診断されている、[20]に記載の方法。
[23] 対象体が、血液透析を受けている、[21]または[22]に記載の方法。
[24] 抗凝固療法が、第Xa因子活性（例えば、アピキサバン、リバーロキサバン、ベトリキサバン、エドキサバンまたはフォンダパリヌクス）または第IIa因子活性（例えば、ダビガトランまたはアルガトロバン）の阻害薬を含む、[21]～[23]のいずれかに記載の方法。
[25] MK-7および／またはMKH2-7の対象体への投与が、MK-7および／またはMKH2-7の投与前の対象体の血清T50値と比較して、対象体の血清T50値を（例えば少なくとも5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％または100％、またはそれ以上）増加させる、[1]～[24]のいずれかに記載の方法。
[26] MK-7および／またはMKH2-7の投与が、MK-7および／またはMKH2-7の投与前の比または量と比較して、(a)対象体の血漿中におけるビタミンK依存性タンパク質のカルボキシル化体対非カルボキシル化体の比を増加させるか、または(b)対象体の血漿中における非カルボキシル化ビタミンK依存性タンパク質の量を減少させる、[1]～[25]のいずれかに記載の方法。
[27] ビタミンK依存性タンパク質が、マトリックスGlaタンパク質、成長停止特異的遺伝子6（Gas-6）タンパク質、PIVKA-IIタンパク質、オステオカルシン、活性化プロテインCまたは活性化プロテインSより選択される、[26]に記載の方法。
[28] MK-7および／またはMKH2-7の対象体への投与が、MK-7および／またはMKH2-7の投与前のオステオプロテゲリンまたはフェチュインAの血漿レベルと比較して、オステオプロテゲリンまたはフェチュインAの血漿レベルを増加させる、[1]～[27]のいずれかに記載の方法。
[29] MK-7および／またはMKH2-7の対象体への投与が、MK-7および／またはMKH2-7の投与前のDダイマーまたは高感度C反応性タンパク質（hs-CRP）の血漿レベルと比較して、Dダイマーまたは高感度C反応性タンパク質（hs-CRP）の血漿レベルを減少させる、[1]～[28]のいずれかに記載の方法。
[30] 対象体が皮膚病変を有する場合、MK-7および／またはMKH2-7の投与が、皮膚および／または血管の病変サイズを減少させる、[1]～[29]のいずれかに記載の方法。
[31] MK-7および／またはMKH2-7の投与が、病変の総表面積を少なくとも5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％または100％減少させる、[30]に記載の方法。
[32] 組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させることを必要とする対象体において、組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させる方法であって、該方法が、1日当たり少なくとも2 mgの実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与することを含み、MK7および／またはMKH2-7が、下記：
(i)MK-7および／またはMKH2-7の投与前の対象体の血清T50値と比較して、対象体の血清T50値を（例えば、少なくとも5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％または100％、またはそれ以上）増加させる、
(ii)MK-7および／またはMKH2-7の投与前の比と比較して、対象体の血漿中におけるビタミンK依存性タンパク質のカルボキシル化体対非カルボキシル化体の比を（例えば、少なくとも5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％または100％、またはそれ以上）増加させる、
(iii)MK-7および／またはMKH2-7の投与前のオステオプロテゲリンまたはフェチュインAの血漿濃度と比較して、オステオプロテゲリンまたはフェチュインAの血漿レベルを（例えば、少なくとも5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％または100％、またはそれ以上）増加させる、または
(iv)MK-7および／またはMKH2-7の投与前のDダイマーまたは高感度C反応性タンパク質（hs-CRP）の血漿濃度と比較して、Dダイマーまたは高感度C反応性タンパク質（hs-CRP）の血漿レベルを（例えば、少なくとも5％、10％、15％、20％、25％、30％、35％、40％、45％、50％、55％、60％、65％、70％、75％、80％、85％、90％、95％または100％）減少させる
の少なくとも1つを引き起こし、これにより対象体における組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させるように、医薬組成物で投与される、方法。
[33] 対象体が、糖尿病を有する、[32]に記載の方法。
[34] 対象体が、前糖尿病と診断されている、[32]に記載の方法。
[35] 対象体が、慢性腎疾患を有する、[32]または[33]に記載の方法。
[36] 対象体が、血液透析を受けている、[32]～[35]のいずれかに記載の方法。
[37] 対象体が、非ワルファリンベースの抗凝固療法を受けている、[32]～[36]のいずれかに記載の方法。
[38] 抗凝固療法が、経口抗凝固療法である、[37]に記載の方法。
[39] 抗凝固療法が、第Xa因子活性（例えば、アピキサバン、リバーロキサバン、ベトリキサバン、エドキサバンまたはフォンダパリヌクス）または第IIa因子活性（例えば、ダビガトランまたはアルガトロバン）の阻害薬を含む、[38]に記載の方法。
[40] ビタミンK依存性タンパク質が、マトリックスGlaタンパク質、成長停止特異的遺伝子6（Gas-6）タンパク質、PIVKA-IIタンパク質、オステオカルシン、活性化プロテインCまたは活性化プロテインSより選択される、[33]～[39]のいずれかに記載の方法。
[41] 1日当たり約2 mg～約100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[1]～[40]のいずれかに記載の方法。
[42] 1日当たり約5 mg～約100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[1]～[41]のいずれかに記載の方法。
[43] 1日当たり約10 mg～約100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[1]～[42]のいずれかに記載の方法。
[44] 1日当たり10、25、50、75、100 mgまたはそれ以上のMK-7および／またはMKH2-7を対象体に投与することを含む、[1]～[43]のいずれかに記載の方法。
[45] MK-7および／またはMKH2-7が、少なくとも2週間対象体に投与される、[1]～[44]のいずれかに記載の方法。
[46] MK-7および／またはMKH2-7が、少なくとも6週間対象体に投与される、[1]～[45]のいずれかに記載の方法。
[47] 対象体が、血液透析を受けている場合、MK-7および／またはMKH2-7が、血液透析の期間を含む一定期間対象体に投与される、[1]～[46]のいずれかに記載の方法。
[48] MK-7および／またはMKH2-7が、経口投与される、[1]～[47]のいずれかに記載の方法。
[49] MK-7および／またはMKH2-7が、錠剤、カプレット剤またはカプレット剤内に配置される、[1]～[48]のいずれかに記載の方法。
[50] 対象体が、ワルファリンベースの抗凝固療法に以前曝露されていた、[1]～[49]のいずれかに記載の方法。
[51] 対象体が、スタチンを受けている、[1]～[50]のいずれかに記載の方法。
[52] スタチンが、シンバスタチン、ロバスタチン、アトルバスタチン、プラバスタチン、ピタバスタチン、ロスバスタチンおよびフルバスタチンより選択される、[51]に記載の方法。
[53] 組織石灰化が、血管石灰化である、[1]～[52]のいずれかに記載の方法。
[54] 組織石灰化が、皮膚石灰化である、[1]～[53]のいずれかに記載の方法。
[55] 組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させることを必要とする対象体において、組織石灰化を予防する、進行を遅らせる、停止させるおよび／または反転させる方法であって、該方法が、
(a)1日当たり少なくとも2 mgの実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）；および
(b)スタチン
を対象体に投与することを含む、方法。
[56] スタチンが、シンバスタチン、ロバスタチン、アトルバスタチン、プラバスタチン、ピタバスタチン、ロスバスタチンおよびフルバスタチンより選択される、[55]に記載の方法。
[57] MK-7および／またはMKH2-7が、スタチンと同一の剤形中において投与される、[55]または[56]に記載の方法。
[58] MK-7および／またはMKH2-7が、スタチンと別個の剤形中において投与される、[55]または[56]に記載の方法。
[59] 大動脈コンプライアンスを改善することを必要とする対象体において、大動脈コンプライアンスを改善する方法であって、該方法が、1日当たり有効量の実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与することを含む、方法。
[60] 末梢血管障害を停止させるおよび／または反転させることを必要とする対象体において、末梢血管障害を停止させるおよび／または反転させる方法であって、対象体が、ESRDまたはCKDを有し、該方法が、1日当たり有効量の実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与することを含む、方法。
[61] 慢性閉塞性肺疾患（COPD）の1つ以上の症状を予防する、進行を遅らせる、停止させるおよび／または反転させることを必要とする対象体おいて、慢性閉塞性肺疾患（COPD）の1つ以上の症状を予防する、進行を遅らせる、停止させるおよび／または反転させる方法であって、該方法が、1日当たり少なくとも2 mgの実質的に純粋なメナキノン-7（MK-7）および／またはメナキノール-7（MKH2-7）を対象体に投与し、これによりCOPDの1つ以上の症状を予防する、または進行を遅らせる、停止させるおよび／または反転させることを含み、MK7および／またはMKH2-7が、医薬組成物で投与される、方法。
[62] 1つ以上の症状が、呼吸困難、咳、粘液産生、喘鳴およびエラスチン分解からなる群より選択される、[61]に記載の方法。
[63] 1日当たり約2 mg～約100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[59]～[62]のいずれかに記載の方法。
[64] 1日当たり約5 mg～約100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[59]～[63]のいずれかに記載の方法。
[65] 1日当たり約10 mg～約100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[59]～[64]のいずれかに記載の方法。
[66] 1日当たり10、25、50、75または100 mgのMK-7および／またはMKH2-7を対象体に投与することを含む、[59]～[65]のいずれかに記載の方法。
[67] MK-7および／またはMKH2-7が、少なくとも2週間対象体に投与される、[59]～[66]のいずれかに記載の方法。
[68] MK-7および／またはMKH2-7が、少なくとも6週間対象体に投与される、[59]～[67]のいずれかに記載の方法。
[69] MK-7および／またはMKH2-7が、無期限に対象体に投与される、[59]～[67]のいずれかに記載の方法。
[70] MK-7および／またはMKH2-7が、経口投与される、[59]～[69]のいずれかに記載の方法。
[71] MK-7および／またはMKH2-7が、錠剤、カプレット剤またはカプレット剤内に配置される、[59]～[70]のいずれかに記載の方法。
[72] 対象体が、スタチンを受けている、[59]～[71]のいずれかに記載の方法。
[73] MK-7および／またはMKH2-7の投与が、スタチンのビタミンK枯渇効果を予防するかまたは減少させる、[72]に記載の方法。
Equivalents The present invention may be embodied in other particular forms without departing from its spirit or essential characteristics. Therefore, the aforementioned embodiments should be considered in all respects as exemplary, but not limiting, to the inventions described herein. Thus, the scope of the invention is set forth by the appended claims, not by the aforementioned description, which may include the meaning of the claims and any modifications within the equivalent scope. Intended.
The present invention also includes the following embodiments and embodiments.
[1] Preventing tissue calcification in pre-diabetic subjects or subjects with diabetes, chronic renal disease or combinations thereof that require tissue calcification to be prevented, slowed, stopped and / or reversed. A method of slowing, stopping and / or reversing, wherein the method is at least 2 mg of substantially pure menaquinone-7 (MK-7) and / or menaquinol-7 (MKH2-) per day. A method of administering 7) to a subject, thereby preventing, slowing and / or stopping tissue calcification, wherein MK7 and / or MKH2-7 is administered in a pharmaceutical composition.
[2] The method according to [1], wherein the subject has diabetes.
[3] The method according to [2], wherein the subject has type II diabetes.
[4] The method according to [1], wherein the subject has been diagnosed with prediabetes.
[5] The method according to any one of [1] to [4], wherein the subject has chronic renal disease.
[6] The method according to any one of [1] to [4], wherein the subject has stage 4 or 5 chronic kidney disease / end-stage renal disease.
[7] The method according to any one of [1] to [6], wherein the subject is undergoing hemodialysis.
[8] The method according to any of [1] to [7], wherein the subject is receiving non-warfarin-based anticoagulant therapy.
[9] The method according to [8], wherein the anticoagulant therapy is an oral anticoagulant therapy.
[10] Anticoagulant therapy is an inhibitor of factor Xa activity (eg, apixaban, rivaroxaban, betrixaban, edoxaban, otamixaban, retaxaban, erivaxaban or fondaparinux) or factor IIa activity (eg, dabigatran or argatroban). The method described in [9], including.
[11] Preventing, slowing, stopping and / or preventing tissue calcification in subjects undergoing hemodialysis that require preventing, slowing, stopping and / or reversing tissue calcification. / Or a method of inversion, wherein at least 2 mg of substantially pure menaquinone-7 (MK-7) and / or menaquinol-7 (MKH2-7) per day is administered to the subject. A method in which MK7 and / or MKH2-7 is administered in a pharmaceutical composition, which comprises preventing, slowing, stopping and / or reversing tissue calcification.
[12] The method according to [11], wherein the subject has diabetes.
[13] The method according to [12], wherein the diabetes is type II diabetes.
[14] The method according to [11], wherein the subject has been diagnosed with prediabetes.
[15] The method according to any one of [11] to [14], wherein the subject has chronic renal disease.
[16] The method according to [15], wherein the subject has stage 4 or stage 5 chronic kidney disease / end-stage renal disease.
[17] The method according to any of [11] to [16], wherein the subject is receiving non-warfarin-based anticoagulant therapy.
[18] The method according to [17], wherein the anticoagulant therapy is an oral anticoagulant therapy.
[19] Anticoagulant therapy comprises an inhibitor of factor Xa activity (eg, apixaban, rivaroxaban, betrixaban, edoxaban or fondaparinux) or factor IIa activity (eg, dabigatran or argatroban). [17] The method described in.
[20] In subjects with stage 5 chronic renal disease requiring oral non-warfarin-based anticoagulant therapy to prevent, slow, stop or reverse tissue calcification. A method of preventing, slowing, stopping or reversing tissue calcification, wherein the method is at least 2 mg of substantially pure menaquinone-7 (MK-7) and / or menaquinol-7 per day. MK7 and / or MKH2-7 comprises administering (MKH2-7) to a subject, thereby preventing, slowing, stopping and / or reversing tissue calcification in the subject. A method of administration by substance.
[21] The method according to [20], wherein the subject is diabetic.
[22] The method according to [20], wherein the subject has been diagnosed with prediabetes.
[23] The method according to [21] or [22], wherein the subject is undergoing hemodialysis.
[24] Anticoagulant therapy comprises an inhibitor of factor Xa activity (eg, apixaban, rivaroxaban, betrixaban, edoxaban or fondaparinux) or factor IIa activity (eg, dabigatran or argatroban). [21] The method described in any of [23].
[25] Administration of MK-7 and / or MKH2-7 to the subject compared to the serum T50 value of the subject prior to administration of MK-7 and / or MKH2-7. (For example, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80 %, 85%, 90%, 95% or 100%, or more) the method according to any of [1] to [24].
[26] Administration of MK-7 and / or MKH2-7 is (a) vitamin K dependent in subject plasma compared to pre-administration ratio or amount of MK-7 and / or MKH2-7. Either [1]-[25] to increase the ratio of the carboxylated to non-carboxylated protein or (b) decrease the amount of non-carboxylated vitamin K-dependent protein in the plasma of the subject. The method described in Crab.
[27] Vitamin K-dependent proteins are selected from matrix Gla protein, growth arrest specific gene 6 (Gas-6) protein, PIVKA-II protein, osteocalcin, activated protein C or activated protein S, [26] ] The method described in.
[28] Administration of MK-7 and / or MKH2-7 to a subject compared to plasma levels of osteoprotegerin or fetuin A prior to administration of MK-7 and / or MKH2-7. Alternatively, the method according to any one of [1] to [27], which increases plasma levels of fetuin A.
[29] Administration of MK-7 and / or MKH2-7 to a subject is plasma levels of D-dimer or sensitive C-reactive protein (hs-CRP) prior to administration of MK-7 and / or MKH2-7. The method according to any of [1] to [28], which reduces plasma levels of D-dimer or sensitive C-reactive protein (hs-CRP) as compared to.
[30] Described in any of [1]-[29], where administration of MK-7 and / or MKH2-7 reduces skin and / or vascular lesion size when the subject has skin lesions. Method.
[31] Administration of MK-7 and / or MKH2-7 reduces the total surface area of the lesion by at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50. %, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% reduction, the method according to [30].
[32] In a subject that requires tissue calcification to be prevented, slowed, stopped and / or reversed, in a manner that prevents, slows, stops and / or reverses tissue calcification. There, the method comprises administering to the subject at least 2 mg of substantially pure menaquinone-7 (MK-7) and / or menaquinol-7 (MKH2-7) per day, MK7 and /. Or MKH2-7, below:
(i) The serum T50 of the subject compared to the serum T50 of the subject prior to administration of MK-7 and / or MKH2-7 (eg, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, or it. Above) to increase,
(ii) The ratio of carboxylated to non-carboxylated vitamin K-dependent proteins in the subject's plasma compared to the pre-dose ratio of MK-7 and / or MKH2-7 (eg, at least 5). %, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100%, or more) increase,
(iii) Plasma levels of osteoprotegerin or fetuin A (eg, at least 5%, 10%,) compared to plasma levels of osteoprotegerin or fetuin A prior to administration of MK-7 and / or MKH2-7. 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% Or 100% or more) increase, or
(iv) D-dimer or sensitive C-reactive protein (hs-) compared to plasma concentrations of D-dimer or sensitive C-reactive protein (hs-CRP) prior to administration of MK-7 and / or MKH2-7. Plasma levels of CRP (eg, at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70) %, 75%, 80%, 85%, 90%, 95% or 100%) decrease
A method of being administered in a pharmaceutical composition to cause at least one of, thereby preventing, slowing, stopping and / or reversing tissue calcification in the subject.
[33] The method according to [32], wherein the subject has diabetes.
[34] The method according to [32], wherein the subject has been diagnosed with prediabetes.
[35] The method according to [32] or [33], wherein the subject has chronic renal disease.
[36] The method according to any of [32] to [35], wherein the subject is undergoing hemodialysis.
[37] The method according to any of [32] to [36], wherein the subject is receiving non-warfarin-based anticoagulant therapy.
[38] The method according to [37], wherein the anticoagulant therapy is an oral anticoagulant therapy.
[39] Anticoagulant therapy comprises an inhibitor of factor Xa activity (eg, apixaban, rivaroxaban, betrixaban, edoxaban or fondaparinux) or factor IIa activity (eg, dabigatran or argatroban). [38] The method described in.
[40] Vitamin K-dependent proteins are selected from matrix Gla protein, growth arrest specific gene 6 (Gas-6) protein, PIVKA-II protein, osteocalcin, activated protein C or activated protein S, [33]. ]-[39] The method described in any of.
[41] The method according to any of [1] to [40], comprising administering to a subject about 2 mg to about 100 mg of MK-7 and / or MKH2-7 per day.
[42] The method according to any of [1] to [41], comprising administering to a subject about 5 mg to about 100 mg of MK-7 and / or MKH2-7 per day.
[43] The method according to any of [1] to [42], comprising administering to a subject about 10 mg to about 100 mg of MK-7 and / or MKH2-7 per day.
[44] Described in any of [1]-[43], comprising administering to a subject 10, 25, 50, 75, 100 mg or more of MK-7 and / or MKH2-7 per day. the method of.
[45] The method of any of [1]-[44], wherein MK-7 and / or MKH2-7 is administered to the subject for at least 2 weeks.
[46] The method of any of [1]-[45], wherein MK-7 and / or MKH2-7 is administered to the subject for at least 6 weeks.
[47] If the subject is undergoing hemodialysis, MK-7 and / or MKH2-7 is administered to the subject for a period of time, including the period of hemodialysis, any of [1]-[46]. The method described in Crab.
[48] The method of any of [1]-[47], wherein MK-7 and / or MKH2-7 is orally administered.
[49] The method of any of [1]-[48], wherein MK-7 and / or MKH2-7 is placed in a tablet, caplet or caplet.
[50] The method according to any of [1]-[49], wherein the subject was previously exposed to warfarin-based anticoagulant therapy.
[51] The method according to any of [1] to [50], wherein the subject is receiving a statin.
[52] The method according to [51], wherein the statin is selected from simvastatin, lovastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin and fluvastatin.
[53] The method according to any of [1] to [52], wherein the tissue calcification is vascular calcification.
[54] The method according to any of [1] to [53], wherein the tissue calcification is skin calcification.
[55] In a subject that requires tissue calcification to be prevented, slowed, stopped and / or reversed, in a manner that prevents, slows, stops and / or reverses tissue calcification. There, the method is
(a) At least 2 mg of substantially pure menaquinone-7 (MK-7) and / or menaquinol-7 (MKH2-7) per day; and
(b) Statins
A method comprising administering to a subject.
[56] The method according to [55], wherein the statin is selected from simvastatin, lovastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin and fluvastatin.
[57] The method according to [55] or [56], wherein MK-7 and / or MKH2-7 is administered in the same dosage form as statin.
[58] The method of [55] or [56], wherein MK-7 and / or MKH2-7 is administered in a dosage form separate from the statin.
[59] In subjects in need of improved aortic compliance, a method of improving aortic compliance that is effective daily doses of substantially pure menaquinone-7 (MK-7) and / Or a method comprising administering menaquinol-7 (MKH2-7) to a subject.
[60] A method of stopping and / or reversing a peripheral angiopathy in a subject that requires stopping and / or reversing the peripheral angiopathy, wherein the subject has an ESRD or CKD. The method comprises administering to the subject a substantially pure menaquinone-7 (MK-7) and / or menaquinol-7 (MKH2-7) in effective daily doses.
[61] Chronic obstructive pulmonary disease (COPD) in subjects who need to prevent, slow, stop and / or reverse one or more symptoms of chronic obstructive pulmonary disease (COPD). A method of preventing, slowing, stopping and / or reversing one or more of the symptoms of a substantially pure menaquinone-7 (MK-7) and at least 2 mg daily. / Or administer menaquinol-7 (MKH2-7) to the subject, thereby preventing or delaying, stopping and / or reversing one or more symptoms of COPD, MK7 and / or A method in which MKH2-7 is administered in a pharmaceutical composition.
[62] The method according to [61], wherein one or more symptoms are selected from the group consisting of dyspnea, cough, mucus production, wheezing and elastin degradation.
[63] The method according to any of [59] to [62], comprising administering to a subject about 2 mg to about 100 mg of MK-7 and / or MKH2-7 per day.
[64] The method according to any of [59] to [63], comprising administering to a subject about 5 mg to about 100 mg of MK-7 and / or MKH2-7 per day.
[65] The method according to any of [59] to [64], comprising administering to a subject about 10 mg to about 100 mg of MK-7 and / or MKH2-7 per day.
[66] The method according to any of [59] to [65], comprising administering to a subject 10, 25, 50, 75 or 100 mg of MK-7 and / or MKH2-7 per day.
[67] The method of any of [59]-[66], wherein MK-7 and / or MKH2-7 is administered to the subject for at least 2 weeks.
[68] The method of any of [59]-[67], wherein MK-7 and / or MKH2-7 is administered to the subject for at least 6 weeks.
[69] The method of any of [59]-[67], wherein MK-7 and / or MKH2-7 is administered to the subject indefinitely.
[70] The method according to any of [59] to [69], wherein MK-7 and / or MKH2-7 is orally administered.
[71] The method of any of [59]-[70], wherein MK-7 and / or MKH2-7 is placed within a tablet, caplet or caplet.
[72] The method according to any of [59] to [71], wherein the subject is receiving a statin.
[73] The method according to [72], wherein administration of MK-7 and / or MKH2-7 prevents or reduces the vitamin K depleting effect of statins.
Claims (23)
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| IL279245B2 (en) | 2018-06-08 | 2024-03-01 | Epizon Pharma Inc | Compositions comprising menaquinone-7 (mk-7) and/or menquinol for prophylaxis of tissue calcification |
| US10822295B2 (en) * | 2018-09-12 | 2020-11-03 | Epizon Pharma, Inc. | Menaquinol compositions and methods of treatment |
| CN113557032A (en) * | 2019-03-12 | 2021-10-26 | 凯丹斯制药公司 | Combined use of vitamin K and anticoagulant |
| KR20240045216A (en) * | 2021-07-05 | 2024-04-05 | 위니베르시테이트 마스트리흐트 | Means and methods of treating calcium crystal deposition disease |
| WO2023129413A1 (en) * | 2021-12-31 | 2023-07-06 | Ingredient Fusion, Llc | Molecular complexing method, formulation and manufacturing for enhanced nutrient delivery |
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| US10159787B2 (en) | 2012-06-18 | 2018-12-25 | Fresenius Kabi Deutschland Gmbh | Port cannula system for puncturing port catheters |
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| CN107428645A (en) | 2015-03-20 | 2017-12-01 | 诺西斯有限公司 | The reduction menadione of solid form |
| IT201700085412A1 (en) | 2017-07-26 | 2019-01-26 | Pharmanutra S P A | Composition for use in the prevention and treatment of cardiovascular diseases |
| US10368858B1 (en) | 2018-01-25 | 2019-08-06 | Ring Orthopedics, Inc. | Suture passer |
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