JPWO2021214497A5 - - Google Patents

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JPWO2021214497A5
JPWO2021214497A5 JP2022563957A JP2022563957A JPWO2021214497A5 JP WO2021214497 A5 JPWO2021214497 A5 JP WO2021214497A5 JP 2022563957 A JP2022563957 A JP 2022563957A JP 2022563957 A JP2022563957 A JP 2022563957A JP WO2021214497 A5 JPWO2021214497 A5 JP WO2021214497A5
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Priority claimed from GR20200100200A external-priority patent/GR1010068B/en
Priority claimed from GR20200100695A external-priority patent/GR1010182B/en
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通常心臓(対照)及びT3処理心臓(T3)における低酸素臓器灌流条件下での4時間にわたる左心室拡張末期圧(LVEDP)を示す。*対照に対してp<0.05Left ventricular end-diastolic pressure (LVEDP) over 4 hours under hypoxic organ perfusion conditions in normal hearts (control) and T3-treated hearts (T3). *p<0.05 vs. control 通常心臓(対照)及びT3処理心臓(T3)における低酸素臓器灌流条件下での4時間にわたる左心室圧(LVEDP)の低下を示す。*対照に対してp<0.05Decrease in left ventricular pressure (LVEDP) over 4 hours under hypoxic organ perfusion conditions in normal hearts (control) and T3-treated hearts (T3). *p<0.05 vs. control. 通常心臓(対照)及びT3処理心臓(T3)における低酸素臓器灌流条件下での4時間にわたる灌流圧を示す。*対照に対してp<0.05Perfusion pressure over 4 hours under hypoxic organ perfusion conditions in normal hearts (control) and T3-treated hearts (T3). *p<0.05 vs. control 通常心臓(対照)及びT3処理心臓(T3)における低酸素臓器灌流条件下でのp38 MAPKの活性化を示す。*対照に対してp<0.05Activation of p38 MAPK under hypoxic organ perfusion conditions in normal hearts (control) and T3-treated hearts (T3) is shown. *p<0.05 vs. control (a)体重の変化、(b)臨床状態の変化(LPSスケール)、及び、(c)プラセボ群及びT3群における敗血症後の動物の生存率、を示す。(a) Change in body weight, (b) change in clinical condition (LPS scale), and (c) survival rate of animals after sepsis in the placebo and T3 groups. プラセボ群とT3群の、手術前(対照)の乳酸値と、敗血症の(a)18時間後及び(b)24時間後の乳酸値を示す。Lactate levels before surgery ( control ) and (a) 18 hours and (b) 24 hours after sepsis in the placebo and T3 groups are shown. 心エコー図分析によって示される、プラセボ群及びT3群における敗血症誘発の18時間後の(a)左心室駆出率及び(b)脈容量を示す。Figure 1 shows (a) left ventricular ejection fraction and (b) pulse volume 18 hours after sepsis induction in the placebo and T3 groups as demonstrated by echocardiographic analysis. (a)ピモニダゾールで標識された組織低酸素症後の心筋組織を示す代表的な顕微鏡画像(茶色、強い画像)を示す。正常組織(対照-左)、ならびにプラセボ(中央)及びT3(右)を投与された実験動物からの組織を示す。(b)特殊なソフトウェアによる画像処理後の組織低酸素症の定量化を示す。(a) Representative microscopic images showing myocardial tissue after tissue hypoxia labeled with pimonidazole (brown, intense image). Shown is normal tissue (control - left) and tissue from experimental animals administered placebo (center) and T3 (right). (b) Quantification of tissue hypoxia after image processing with specialized software. (a)腎臓のさまざまな領域(皮質、OSOM、ISOM)において、ピモニダゾール(茶色、強いイメージング)で組織低酸素症を標識した後の腎臓組織を示す代表的な顕微鏡画像を示す。これは、正常な組織(対照-左)、ならびにプラセボ(中央)及びT3(右)を投与された実験動物の組織を示す。(b)特殊なソフトウェアによる画像処理後の組織低酸素症の定量化を示す図である。(a) Representative microscopic images showing kidney tissue after labeling of tissue hypoxia with pimonidazole (brown, intense imaging) in different regions of the kidney (cortex, OSOM, ISOM), showing normal tissue (control - left) and tissue from experimental animals administered placebo (middle) and T3 (right). (b) Quantification of tissue hypoxia after image processing with specialized software. プラセボ群とT3群における手術前(正常)ならびに敗血症の18時間後及び24時間後の血清クレアチニン値を示す。Serum creatinine values before surgery (normal) and 18 and 24 hours after sepsis in the placebo and T3 groups are shown. (a)ピモニダゾールで組織低酸素症を標識した後の肝臓組織を示す代表的な顕微鏡画像(茶色、明るい画像)を示す。正常組織:対照-左、ならびに、プラセボ(中央)とT3(右)を受けた実験動物の組織。(b)特殊なソフトウェアによる画像処理後の組織低酸素症の定量化を示す。(a) Representative microscopic images (brown, light image) showing liver tissue after labeling of tissue hypoxia with pimonidazole. Normal tissues: control - left, as well as tissues of experimental animals receiving placebo (middle) and T3 (right). (b) Quantification of tissue hypoxia after image processing with specialized software. 高用量T3投与後最初の48時間における各患者の血中T3値を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)The blood T3 levels of each patient are shown in the first 48 hours after administration of high dose T3. (Patients A3 and A4 received T3, A1, A2 and A5 received placebo.) 高用量T3投与後最初の48時間における各患者のd-ダイマー値を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)The d-dimer values for each patient are shown in the first 48 hours after high-dose T3 administration (patients A3 and A4 received T3, A1, A2 and A5 received placebo). 高用量T3投与後最初の48時間における各患者の心拍数(1分あたりの脈拍数)を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)The heart rate (beats per minute) of each patient is shown during the first 48 hours after administration of high dose T3. (Patients A3 and A4 received T3, A1, A2 and A5 received placebo.) 高用量T3投与後最初の48時間における各患者のトロポニンI値を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)Troponin I values for each patient are shown in the first 48 hours after high-dose T3 administration. (Patients A3 and A4 received T3, A1, A2 and A5 received placebo.) 高用量T3投与後最初の48時間における各患者の左心室駆出率を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)The left ventricular ejection fraction of each patient during the first 48 hours after administration of high dose T3 is shown. (Patients A3 and A4 received T3, A1, A2 and A5 received placebo.) 高用量T3投与後48時間での右心室収縮機能を示す。Right ventricular systolic function 48 hours after high dose T3 administration is shown. 高用量T3投与後最初の24時間における各患者の中心静脈圧を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)Figure 1 shows the central venous pressure for each patient during the first 24 hours after administration of high dose T3. (Patients A3 and A4 received T3, A1, A2 and A5 received placebo.) 高用量T3投与後の最初の24時間における各患者のクレアチニン値を示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)Creatinine values for each patient in the first 24 hours after administration of high dose T3 are shown (patients A3 and A4 received T3, A1, A2 and A5 received placebo). 高用量T3投与後最初の24時間における各患者の肝酵素のレベルを示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)The liver enzyme levels of each patient are shown in the first 24 hours after administration of high dose T3. (Patients A3 and A4 received T3, A1, A2 and A5 received placebo.) 高用量T3投与後最初の48時間における各患者の赤血球沈降速度レベルを示す。(患者A3及びA4はT3が投与され、A1、A2及びA5はプラセボが投与された。)The erythrocyte sedimentation rate levels of each patient are shown in the first 48 hours after administration of high dose T3 (patients A3 and A4 received T3, A1, A2 and A5 received placebo). 高用量T3を投与された患者とプラセボを投与された患者との間の赤血球沈降速度を示す。1 shows the erythrocyte sedimentation rate between patients receiving high dose T3 and patients receiving placebo.

Claims (28)

敗血症、重傷、癌及び/又は体外臓器保護によって引き起こされた組織低酸素症及び微小血管機能障害の患者における、腎臓、肝臓、脳、心臓、胃腸系、造血系又は凝固系の治療を含む、炎症反応又は一臓器もしくは多臓器不全の治療に使用するための、L-トリヨードチロニン又はその薬学的に許容される塩を含む医薬組成物であって、前記組成物は、体重1kg当たり5~9μgの範囲のL-トリヨードチロニンを、投与されるものであることを特徴とする医薬組成物。 1. A pharmaceutical composition comprising L-triiodothyronine or a pharma- ceutical acceptable salt thereof for use in the treatment of inflammatory responses or single or multiple organ failure, including treatment of the kidney, liver, brain, heart, gastrointestinal system, hematopoietic system or coagulation system, in patients with tissue hypoxia and microvascular dysfunction caused by sepsis , severe injury, cancer and/or extracorporeal organ protection, wherein the composition is administered in the range of 5-9 μg L-triiodothyronine per kg of body weight. 少なくとも30分、又は少なくとも3時間、又は少なくとも4、6、12、18、又は24時間の敗血症による長期低酸素症の治療における、請求項1に記載の使用のための医薬組成物。 The pharmaceutical composition according to claim 1 for use in the treatment of long-term hypoxia due to sepsis for at least 30 minutes, or at least 3 hours, or at least 4, 6, 12, 18, or 24 hours. 三尖弁輪の収縮期変動(TAPSE)が、16mmと30mmの間である、右心室収縮機能の治療における、請求項2に記載の使用のための医薬組成物。 3. A pharmaceutical composition for use according to claim 2 in the treatment of right ventricular systolic function, in which the tricuspid annular systolic excursion (TAPSE) is between 16mm and 30mm. 中心静脈圧の値が1から10mmHgの間で測定される、右心室収縮機能の治療における、請求項2又は請求項3に記載の使用のための医薬組成物。 4. A pharmaceutical composition for use according to claim 2 or claim 3 in the treatment of right ventricular systolic function, with central venous pressure values measured between 1 and 10 mmHg. 赤血球沈降速度が48時間にわたって50%減少する、炎症反応及び凝固系機能障害の治療における、請求項2に記載の使用のための医薬組成物。 3. A pharmaceutical composition for use according to claim 2 in the treatment of inflammatory responses and coagulation system dysfunction, in which the erythrocyte sedimentation rate is reduced by 50% over 48 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、注射用溶液として、又は再構成用の凍結乾燥粉末として処方される、請求項1から請求項5のいずれか1項に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to any one of claims 1 to 5, wherein L-triiodothyronine or a pharma- ceutically acceptable salt thereof is formulated as a solution for injection or as a lyophilized powder for reconstitution. L-トリヨードチロニン又はその薬学的に許容される塩は、2~20μg/mLの濃度の注射用溶液の形態である、請求項6に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 6, wherein L-triiodothyronine or a pharma- ceutically acceptable salt thereof is in the form of an injectable solution having a concentration of 2 to 20 μg/mL. L-トリヨードチロニン又はその薬学的に許容される塩は、0.08から0.20μg/kg/hの速度で、48時間持続注入により投与される、請求項7に記載の使用のための医薬組成物。 8. The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutically acceptable salt thereof is administered by continuous infusion for 48 hours at a rate of 0.08 to 0.20 μg/kg/h . L-トリヨードチロニン又はその薬学的に許容される塩は、0.6μg/kgから1.0μg/kg体重の初期ボーラスとして、その後、0.10から0.20μg/kg/hのレートで持続注入して24から72時間投与される、請求項7に記載の使用のための医薬組成物。 8. The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutically acceptable salt thereof is administered as an initial bolus of 0.6 μg/kg to 1.0 μg/kg of body weight , followed by continuous infusion at a rate of 0.10 to 0.20 μg/kg/h for 24 to 72 hours . 75Kgの被験者は、合計で375μgから675μgのT3を静脈内投与される、請求項7から請求項9のいずれか1項に記載の使用のための医薬組成物。 10. The pharmaceutical composition for use according to any one of claims 7 to 9, wherein a 75 kg subject is administered a total of 375 μg to 675 μg of T3 intravenously. 薬学的に許容される賦形剤を含む、請求項1から請求項10のいずれか1項に記載の使用のための医薬組成物。 A pharmaceutical composition for use according to any one of claims 1 to 10, comprising a pharma- ceutical acceptable excipient. 1つ又は複数のさらなる活性物質を含む、請求項1から請求項11のいずれか1項に記載の使用のための医薬組成物。 A pharmaceutical composition for use according to any one of claims 1 to 11, comprising one or more further active substances. 前記組成物は、体重1kg当たり6~8μgの範囲のL-トリヨードチロニンを、投与されるものであることを特徴とする請求項1から請求項12のいずれか1項に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to any one of claims 1 to 12, characterized in that the composition is administered in the range of 6 to 8 μg of L-triiodothyronine per kg of body weight. 前記組成物は、体重1kg当たり7μgの範囲のL-トリヨードチロニンを、投与されるものであることを特徴とする請求項1から請求項13のいずれか1項に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to any one of claims 1 to 13, characterized in that the composition is administered in the range of 7 μg L-triiodothyronine per kg of body weight. 三尖弁輪の収縮期変動(TAPSE)が、20mmと25mmの間である、右心室収縮機能の治療における、請求項2に記載の使用のための医薬組成物。 The pharmaceutical composition according to claim 2 for use in the treatment of right ventricular systolic function in which the tricuspid annulus systolic excursion (TAPSE) is between 20 mm and 25 mm. 中心静脈圧の値が3.7から7.4mmHgの間で測定される、右心室収縮機能の治療における、請求項2又は請求項3に記載の使用のための医薬組成物。 The pharmaceutical composition according to claim 2 or claim 3 for use in the treatment of right ventricular systolic function in which the central venous pressure is measured at a value between 3.7 and 7.4 mmHg. 赤血球沈降速度が48時間にわたって50%減少し、最初の1時間以内に30mm未満で測定される、炎症反応及び凝固系機能障害の治療における、請求項2に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 2 in the treatment of inflammatory responses and coagulation system dysfunction, in which the erythrocyte sedimentation rate is reduced by 50% over 48 hours and measured at less than 30 mm within the first hour. L-トリヨードチロニン又はその薬学的に許容される塩は、5~15μg/mLの濃度の注射用溶液の形態である、請求項6に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 6, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is in the form of an injectable solution having a concentration of 5 to 15 μg/mL. L-トリヨードチロニン又はその薬学的に許容される塩は、10μg/mLの濃度の注射用溶液の形態である、請求項6に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 6, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is in the form of an injectable solution having a concentration of 10 μg/mL. L-トリヨードチロニン又はその薬学的に許容される塩は、0.12から0.16μg/kg/hの速度で、48時間持続注入により投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered by continuous infusion at a rate of 0.12 to 0.16 μg/kg/h for 48 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、0.14μg/kg/hの速度で、48時間持続注入により投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered by continuous infusion at a rate of 0.14 μg/kg/h for 48 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、0.7μg/kgから0.9μg/kg体重の初期ボーラスとして、その後、0.10から0.20μg/kg/hのレートで持続注入して24から72時間投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered as an initial bolus of 0.7 μg/kg to 0.9 μg/kg of body weight, followed by continuous infusion at a rate of 0.10 to 0.20 μg/kg/h for 24 to 72 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、0.8μg/kg体重の初期ボーラスとして、その後、0.10から0.20μg/kg/hのレートで持続注入して24から72時間投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered as an initial bolus of 0.8 μg/kg body weight, followed by continuous infusion at a rate of 0.10 to 0.20 μg/kg/h for 24 to 72 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、0.6μg/kgから1.0μg/kg体重の初期ボーラスとして、その後、0.10から0.14μg/kg/hのレートで持続注入して24から72時間投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered as an initial bolus of 0.6 μg/kg to 1.0 μg/kg of body weight, followed by continuous infusion at a rate of 0.10 to 0.14 μg/kg/h for 24 to 72 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、0.6μg/kgから1.0μg/kg体重の初期ボーラスとして、その後、0.112μg/kg/hのレートで持続注入して24から72時間投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered as an initial bolus of 0.6 μg/kg to 1.0 μg/kg of body weight, followed by continuous infusion at a rate of 0.112 μg/kg/h for 24 to 72 hours. L-トリヨードチロニン又はその薬学的に許容される塩は、0.6μg/kgから1.0μg/kg体重の初期ボーラスとして、その後、0.10から0.20μg/kg/hのレートで持続注入して48時間投与される、請求項7に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to claim 7, wherein L-triiodothyronine or a pharma- ceutical acceptable salt thereof is administered as an initial bolus of 0.6 μg/kg to 1.0 μg/kg of body weight, followed by continuous infusion at a rate of 0.10 to 0.20 μg/kg/h for 48 hours. 75Kgの被験者は、合計で450μgから600μgのT3を静脈内投与される、請求項7から請求項9のいずれか1項に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to any one of claims 7 to 9, wherein a subject weighing 75 kg is administered a total of 450 μg to 600 μg of T3 intravenously. 75Kgの被験者は、合計で525μgのT3を静脈内投与される、請求項7から請求項9のいずれか1項に記載の使用のための医薬組成物。 The pharmaceutical composition for use according to any one of claims 7 to 9, wherein a subject weighing 75 kg is administered a total of 525 μg of T3 intravenously.
JP2022563957A 2020-04-21 2021-04-15 Pharmaceutical compositions comprising L-triiodothyronine (T3) for use in the treatment of tissue hypoxia and sepsis Pending JP2023538984A (en)

Applications Claiming Priority (7)

Application Number Priority Date Filing Date Title
GR20200100200A GR1010068B (en) 2020-04-21 2020-04-21 Pharmaceutical composition containing triiodothyronine - t3 for patients infected by coronavirus
GR20200100200 2020-04-21
GR20200100695 2020-11-23
GR20200100695A GR1010182B (en) 2020-11-23 2020-11-23 Pharmaceutical composition containing l-triiodothyronine (t3) for use in the treatment of tissue hypoxia
GR20210100216 2021-03-29
GR20210100216A GR1010261B (en) 2021-03-29 2021-03-29 Pharmaceutical composition containing l-triiodothyronine (t3) for use in the treatment of the inflammatory reaction and the dysfunction of the cardiovascular system due to sepsis
PCT/GR2021/000019 WO2021214497A1 (en) 2020-04-21 2021-04-15 Pharmaceutical composition comprising l-triiodothyronine (t3) for use in the treatment of tissue hypoxemia and sepsis

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JP2023538984A JP2023538984A (en) 2023-09-13
JPWO2021214497A5 true JPWO2021214497A5 (en) 2024-04-23

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