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米力农

米力农用途

Milrinone 是 PDE3 抑制剂,也是一种强心药、血管舒张药。

米力农名称

[ CAS 号 ]:
78415-72-2

[ 中文名 ]:
米力农

[ 英文名 ]:
Milrinone

[中文别名 ]:

[英文别名 ]:

6-Hydroxy-2-methyl-3,4'-bipyridine-5-carbonitrile
EINECS 278-903-6
MFCD00133539
Milrinonum
Milrila
Milrinone
Corotrope
Milrinona
Primacor
Corotrop

米力农生物活性

[ 描述 ]:

Milrinone 是 PDE3 抑制剂,也是一种强心药、血管舒张药。

[ 相关类别 ]:

信号通路 >> 代谢酶/蛋白酶 >> 磷酸二酯酶(PDE)

研究领域 >> 心血管疾病

[体外研究]

米力农(1μM)使缺氧肌细胞中的PKA活性增加至含氧量正常水平。米力农(50 nM)通过恢复PKA介导的调节性TP受体磷酸化来使缺氧心肌细胞中的TP受体敏感性正常化[1]。米力农显着降低NE诱导的血管收缩,减弱NE敏感性和最大张力产生。 ATP敏感性K +通道或电压门控K +通道的抑制不能阻止米力农诱导的NE反应衰减[4]。

[体内研究]

米力农(1μg/ kg/min,iv)显着降低充血性心力衰竭(CHF)大鼠的PAP,PVR(-18.96±1.7％)和LAP(-26.03±2.3％)。米力农(1mg/mL,吸入)导致PAP的几乎最大降低而对AP没有显着影响,类似地在更大的CHF大鼠集体中降低肺动脉压。米力农吸入选择性地增加两组中的cAMP但不增加cGMP血浆浓度。重复吸入米力农甚至可降低肺湿/干重比[2]。米力农(49.5μg)在很大程度上使ESPVR向上移动并显着增加收缩末期压力(ESP(0.08))和中等LV容积(0.08 mL/g心肌)的收缩压-体积面积(PVA(0.08)) 。米力农还略微降低LV ESP(ESV)并降低Ea [3]。

[动物实验]

在100±8g体重（bw）的幼年大鼠中，通过冠状动脉上主动脉条带诱导CHF。简言之，通过腹膜内注射氯胺酮（87mg / kg体重）和甲苯噻嗪（13mg / kg体重）麻醉大鼠。将大鼠置于仰卧位，剃去胸壁，并在通气期间用100％O 2在第三肋间进行左胸廓切开术。升主动脉从结缔组织中脱离，并通过植入具有0.8mm的限定内径的钛夹而部分闭塞。在手术闭合胸腔后，允许大鼠从麻醉中恢复。对于术后镇痛，大鼠在手术后和术后第一天肌肉注射250mg / kg体重的安乃近。假手术大鼠作为对照。从麻醉中恢复后，将动物置于笼中，自由饮水和标准实验室饮食。对于吸入，使用超声雾化器雾化米力农（0.2-5mg / mL）或NaCl（0.9％），并在整个实验中使用的相同峰值吸气压力下吸入3分钟。如通过微量重量测定所确定的，1mg / mL米力农的3分钟雾化导致14μg磷酸二酯酶-3抑制剂的蒸发。因此，39μg/ kg的相应剂量与人类研究中的吸入剂量类似。对于静脉输送，米力农（初始推注量为2-10μg/ kg，然后是0.2-1μg/ kg / min）或等量的NaCl（0.9％;初始推注量为1.6 mL / kg，然后是10μL/ kg） / h）通过输液泵给药10分钟。

[参考文献]

[1]. Santhosh KT, et al. Milrinone attenuates thromboxane receptor-mediated hyperresponsiveness in hypoxic pulmonary arterial myocytes. Br J Pharmacol. 2011 Jul;163(6):1223-36.

[2]. Hentschel T, et al. Inhalation of the phosphodiesterase-3 inhibitor milrinone attenuates pulmonary hypertension in a rat model of congestive heart failure. Anesthesiology. 2007 Jan;106(1):124-31.

[3]. Kishi T, et al. Effects of milrinone on left ventricular end-systolic pressure-volume relationship of rat hearts in situ. Clin Exp Pharmacol Physiol. 2001 Sep;28(9):737-42.

[4]. Taylor MS, et al. Effect of milrinone on small mesenteric artery vasoconstriction: role of K(+) channels. Am J Physiol. 1999 Jul;277(1 Pt 1):G69-78.

[相关活性小分子]

米力农物理化学性质

[ 密度 ]:
1.3±0.1 g/cm3

[ 沸点 ]:
448.7±45.0 °C at 760 mmHg

[ 熔点 ]:
>3000C

[ 分子式 ]:
C₁₂H₉N₃O

[ 分子量 ]:
211.219

[ 闪点 ]:
225.2±28.7 °C

[ 精确质量 ]:
211.074554

[ PSA ]:
69.54000

[ LogP ]:
0.41

[ 外观性状 ]:
灰白色固体

[ 蒸汽压 ]:
0.0±1.1 mmHg at 25°C

[ 折射率 ]:
1.622

[ 储存条件 ]:
2-8°C

[ 稳定性 ]:
Stable. Incompatible with strong oxidizing agents.

[ 水溶解性 ]:
DMSO: >10 mg/mL

米力农MSDS

详细MSDS(安全技术说明书)

米力农毒性和生态

CHEMICAL IDENTIFICATION

RTECS NUMBER :: DW1762000

CHEMICAL NAME :: (3,4'-Bipyridine)-5-carbonitrile, 1,6-dihydro-2-methyl-6-oxo-

CAS REGISTRY NUMBER :: 78415-72-2

LAST UPDATED :: 199712

DATA ITEMS CITED :: 16

MOLECULAR FORMULA :: C12-H9-N3-O

MOLECULAR WEIGHT :: 211.24

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 91 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 58 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 27,652,1996

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 73 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 137 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Subcutaneous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 62 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: IYKEDH Iyakuhin Kenkyu. Study of Medical Supplies. (Nippon Koteisho Kyokai, 12-15, 2-chome, Shibuya, Shibuya-ku, Tokyo 150, Japan) V.1- 1970- Volume(issue)/page/year: 27,652,1996

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 79 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: LD - Lethal dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: >25 mg/kg

TOXIC EFFECTS :: Behavioral - somnolence (general depressed activity) Cardiac - other changes Lungs, Thorax, or Respiration - fibrosis, focal (pneumoconiosis)

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 21,2891,1993

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rabbit

DOSE/DURATION :: 40 mg/kg

TOXIC EFFECTS :: Details of toxic effects not reported other than lethal dose value

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rabbit

DOSE/DURATION :: 44400 ug/kg

TOXIC EFFECTS :: Behavioral - ataxia Cardiac - cardiomyopathy including infarction Lungs, Thorax, or Respiration - dyspnea

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985 ** OTHER MULTIPLE DOSE TOXICITY DATA **

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 4550 mg/kg/13W-I

TOXIC EFFECTS :: Behavioral - muscle weakness Gastrointestinal - changes in structure or function of salivary glands

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 11375 mg/kg/65W-I

TOXIC EFFECTS :: Related to Chronic Data - death

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Rodent - rat

DOSE/DURATION :: 1200 mg/kg/30D-I

TOXIC EFFECTS :: Cardiac - cardiomyopathy including infarction Kidney, Ureter, Bladder - changes in bladder weight Related to Chronic Data - death

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Rodent - mouse

DOSE/DURATION :: 14560 mg/kg/1Y-I

TOXIC EFFECTS :: Blood - pigmented or nucleated red blood cells Nutritional and Gross Metabolic - other changes

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Oral

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 910 mg/kg/13W-I

TOXIC EFFECTS :: Cardiac - cardiomyopathy including infarction Cardiac - pulse rate increase, without fall in BP Cardiac - changes in heart weight

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 60 mg/kg/2W-I

TOXIC EFFECTS :: Cardiac - cardiomyopathy including infarction Cardiac - EKG changes not diagnostic of specified effects Biochemical - Enzyme inhibition, induction, or change in blood or tissue levels - phosphatases

REFERENCE :: NCDREP New Cardiovascular Drugs. (Raven Press, 1185 Ave. of the Americas, New York, NY 10036) 1985- Volume(issue)/page/year: 3,245,1985

TYPE OF TEST :: TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :: Intravenous

SPECIES OBSERVED :: Mammal - dog

DOSE/DURATION :: 455 mg/kg/13W-I

TOXIC EFFECTS :: Lungs, Thorax, or Respiration - fibrosis, focal (pneumoconiosis)

REFERENCE :: YACHDS Yakuri to Chiryo. Pharmacology and Therapeutics. (Raifu Saiensu Shuppan K.K., 2-5-13, Yaesu, Chuo-ku, Tokyo 104, Japan) V.1- 1972- Volume(issue)/page/year: 21,2891,1993

米力农安全信息

[ 符号 ]:

GHS06

[ 信号词 ]:
Danger

[ 危害声明 ]:
H301 + H311 + H331

[ 警示性声明 ]:
Missing Phrase - N15.00950417-P261-P280-P302 + P352 + P312-P304 + P340 + P312-P403 + P233

[ 个人防护装备 ]:
Eyeshields;Faceshields;Gloves;type P2 (EN 143) respirator cartridges

[ 危害码 (欧洲) ]:
T:Toxic

[ 风险声明 (欧洲) ]:
R23/24/25

[ 安全声明 (欧洲) ]:
S36/37/39-S45

[ 危险品运输编码 ]:
UN 2811 6.1/PG 3

[ WGK德国 ]:
3

[ RTECS号 ]:
DW1762000

[ 包装等级 ]:
III

[ 危险类别 ]:
6.1(b)

[ 海关编码 ]:
2933399090

米力农合成路线

详细合成路线

米力农上下游产品

米力农上游产品

米力农下游产品

米力农制备

方法1：4-甲基吡啶溶于无水乙醚，通氮气保护，搅拌下于室温滴加苯基锂的乙醚溶液，加毕继续反应。停止通氮，冷至0℃，滴加乙酸乙酯，在10℃以下反应。用浓盐酸酸化至Ph=1～2，分出水层，用饱和碳酸钠碱化至Ph=9，析出油状物，用氯仿提取数次，干燥，蒸去氯仿，减压分馏，收集130～132℃/1.47kPa的馏分，即为1-(4-吡啶基)丙酮。
1-(4-吡啶基)丙酮、乙腈和N，N-二甲基甲酰胺二甲基缩醛一起回流。减压蒸去溶剂，剩余物用适量氯仿溶解，用氧化铝柱(索氏抽提器)加热回流抽提，浓缩抽提液，用四氯化碳-环己烷(4：1)重结晶，得1-(4-吡啶基)-2-(二甲氨基)乙烯基甲基酮。
1-(4-吡啶基)-2-(二甲氨基)乙烯基甲基酮、氰乙酰胺、甲醇钠和二甲基甲酰胺加热回流，减压蒸出溶剂，剩余物加乙腈温热溶解，冷至10℃；析出固体，过滤，适量水溶解，活性炭脱色，用6mol/L的盐酸酸化至Ph=6.5～7，析出固体，用二甲基甲酰胺重结晶，得淡黄色粒状结晶，即为米力农，熔点＞300℃。

方法2：以4-吡啶基丙酮为原料，和原甲酸三乙酯缩合后，再和2-氰基乙酰胺反应，即得到米力农。

方法3：吡啶基丙酮和2，2-二氰基乙烯基乙基醚反应，即可生成米力农。

米力农海关

[ 海关编码 ]: 2933399090

[ 中文概述 ]:
2933399090. 其他结构含非稠合吡啶环的化合物. 增值税率:17.0%. 退税率:13.0%. 监管条件:无. 最惠国关税:6.5%. 普通关税:20.0%

[ 申报要素 ]: 品名, 成分含量, 用途, 乌洛托品请注明外观, 6－己内酰胺请注明外观, 签约日期

[ Summary ]:
2933399090. other compounds containing an unfused pyridine ring (whether or not hydrogenated) in the structure. VAT:17.0%. Tax rebate rate:13.0%. . MFN tariff:6.5%. General tariff:20.0%

米力农文献

A rapid method for determination of 22 selected drugs in human urine by UHPLC/MS/MS for clinical application.

J. AOAC Int. 97(6) , 1526-37, (2015)

A rapid and sensitive ultra-HPLC/MSIMS (UHPLC/MSIMS) assay method for the simultaneous determination in human urine of 22 drugs belonging to different pharmaceutical groups was developed. The drugs we...

Clinical effects of phosphodiesterase 3A mutations in inherited hypertension with brachydactyly.

Hypertension 66 , 800-8, (2015)

Autosomal-dominant hypertension with brachydactyly is a salt-independent Mendelian syndrome caused by activating mutations in the gene encoding phosphodiesterase 3A. These mutations increase the prote...

Multiplexed phosphospecific flow cytometry enables large-scale signaling profiling and drug screening in blood platelets.

J. Thromb. Haemost. 12(10) , 1733-43, (2014)

Dissecting the signaling events that contribute to platelet activation will increase our understanding of platelet function and aid in the development of new antiplatelet agents. However, high-through...

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米力农