Acetaminophen (Paracetamol; APAP)   中文名称: 醋氨酚

COX-2 (IC50 = 25.8 μM); COX-1 (IC50 =113.7 μM); cyclooxygenase-2

对乙酰氨基酚在体外抑制 COX-2 的选择性是 COX-1 的 4.4 倍（COX-1 的 IC50 为 113.7 μM，COX-2 的 IC50 为 25.8 μM）。口服药物治疗后的最大体外抑制率为 56% (COX-1) 和 83% (COX-2)。注射后至少 5 小时，对乙酰氨基酚血浆浓度保持高于 COX-2 的体外 IC50。对乙酰氨基酚的离体 IC50 值（COX-1：105.2 μM；COX-2：26.3 μM）与其体外 IC50 值相比效果良好。与其他理论不同，对乙酰氨基酚可抑制 COX-2 超过 80%，这意味着它的抑制程度与选择性 COX-2 抑制剂和非甾体类抗炎药物 (NSAID) 相似。不可能建立 >95% 的 COX-1 阻断，而 COX-1 阻断是抑制血小板功能所必需的[1]。根据 MTT 测定，50 mM 剂量的对乙酰氨基酚 (APAP) 显着 (p<0.001) 将细胞活力降低至 61.5±6.65%。有趣的是，当将对乙酰氨基酚/HV110 共同处理的细胞与对乙酰氨基酚处理的细胞进行比较时，细胞活力显着 (p<0.01) 增加至 79.7±2.47%[2]。

在动物模型中，对乙酰氨基酚可用于创建急性肝损伤的小鼠模型。

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高剂量的对乙酰氨基酚（APAP）会导致急性肝损伤。在这项研究中，我们评估了柠檬醛在APAP诱导的小鼠肝毒性模型中的作用。测定肝功能标志物丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、碱性磷酸酶（ALP）和γ-谷氨酰转移酶（γGT），以评估柠檬醛的保肝作用。肝脏用于测定髓过氧化物酶（MPO）活性和一氧化氮（NO）的产生，并用于组织学分析。在体外评估柠檬醛对白细胞迁移和抗氧化活性的影响。柠檬醛预处理显著降低了ALT、AST、ALP和γGT的水平、MPO活性和NO的产生。组织病理学分析显示，柠檬醛预处理后小鼠肝脏病变有所改善。柠檬醛抑制中性粒细胞迁移并显示抗氧化活性。我们的研究结果表明，柠檬醛可以保护肝脏免受APAP引起的肝毒性[3]。

三十多年来，对乙酰氨基酚（国际非专利药品名称，扑热息痛）一直被认为对外周前列腺素没有明显的抑制作用。同时，试图通过抑制中心环氧化酶（COX）-3来解释其作用的尝试被拒绝了。对乙酰氨基酚具有选择性COX-2抑制剂的功能，这一事实促使我们研究了它是否通过优先阻断COX-2起作用的假设。在5名接受单次1000mg口服剂量的志愿者中评估了对乙酰氨基酚的体外COX抑制和药代动力学。在人全血中离体和体外测量凝血诱导的血栓素B（2）和脂多糖诱导的前列腺素E（2），作为COX-1和COX-2活性的指标。在体外，对乙酰氨基酚对COX-2抑制的选择性是4.4倍（COX-1的IC（50）=113.7微摩尔/升；COX-2的IC（50）=25.8微摩尔/升）。口服该药物后，最大离体抑制率为56%（COX-1）和83%（COX-2）。给药后至少5小时，对乙酰氨基酚血浆浓度仍高于COX-2的体外IC（50）。对乙酰氨基酚的体外IC（50）值（COX-1:105.2微摩尔/L；COX-2：26.3微摩尔/L）与其体外IC（50中）值相比是有利的。与之前的概念相反，对乙酰氨基酚抑制COX-2的程度超过80%，即与非甾体抗炎药（NSAIDs）和选择性COX-2抑制剂相当。然而，没有实现与抑制血小板功能相关的>95%的COX-1阻断。我们的数据可以解释对乙酰氨基酚的镇痛和抗炎作用，以及与非甾体抗炎药相比其优越的整体胃肠道安全性。鉴于其对COX-2的显著抑制作用，最近定义的对乙酰氨基酚使用COX-2抑制剂的心血管警告也应考虑[1]。

本文以酪氨酸酶为癌症分子治疗靶点，研究了对乙酰氨基酚（APAP）对SK-MEL-28黑色素瘤细胞毒性的生化机制。我们的结果表明，在2小时的孵育下，APAP被酪氨酸酶代谢了87%。在酪氨酸酶氧化APAP的过程中，醌还原剂AA和NADH被显著消耗。APAP对SK-MEL-28、MeWo、SK-MEL-5、B16-F0和B16-F10黑色素瘤细胞的IC（50）（48小时）为100微M，而对BJ、Saos-2、SW-620和PC-3非黑色素瘤电池没有明显毒性，表明对黑色素瘤的选择性毒性。黄递酶抑制剂二香豆素和谷胱甘肽耗竭剂1-溴庚烷增强了APAP对SK-MEL-28细胞的毒性。AA和GSH能有效预防APAP诱导的黑色素瘤细胞毒性。三氟拉嗪和环孢素A是线粒体通透性转换孔的抑制剂，可显著预防APAP黑色素瘤细胞毒性。APAP导致SK-MEL-28细胞内GSH含量的时间和剂量依赖性下降，这先于细胞毒性。APAP导致SK-MEL-28细胞中ROS的形成，而双香豆素和1-溴庚烷会加剧这种形成，而胱孢菌素A和三氟拉嗪则会阻止这种形成。我们的研究表明，APAP是一种酪氨酸酶底物，细胞内GSH耗竭、ROS形成和诱导的线粒体毒性是APAP在SK-MEL-28细胞中的选择性毒性的原因[2]。

The experimental animals (Male Swiss mice, 30–40 g) were divided into six groups of five animals each. Firstly, each group received orally during seven days the following treatment: Group I: the mice did not receive any treatment (normal). Group II: the mice received citral vehicle (0.1% Tween 80 solution). Groups III–V: the mice were pretreated with citral at doses of 125, 250, and 500 mg/kg, respectively. Group VI: the mice were pretreated with the hepatoprotective standard drug silymarin (SLM) (200 mg/kg). After this time, the animals fasted for 8 h and then received oral APAP on the seventh day at a dose of 250 mg/kg in Groups II–VI. Group I orally received saline that contained 0.1% Tween 80 solution ( APAP vehicle). The stock solution was used as the first concentration of 50 mg/mL and after that was diluted in 0.1% Tween 80 solution to prepare the solutions of 25 and 12.5 mg/mL. After 12 h of APAP administration, serum samples and liver tissue were collected followed by biochemistry and histological analysis[3].

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Dissolved in DMSO and diluted to a final concentration 20 mg/mL in aqueous solutions; 350 mg/kg; p.o. administration

B6C3F1 mice

[1]. FASEB J.2008 Feb;22(2):383-90;
[2]. J Pharm Sci.2009 Apr;98(4):1409-25.
[3]. Evid Based Complement Alternat Med. 2017;2017:1796209.

4-hydroxyacetanilide is an odorless white crystalline solid. Bitter taste. pH (saturated aqueous solution) about 6.
Paracetamol is a member of the class of phenols that is 4-aminophenol in which one of the hydrogens attached to the amino group has been replaced by an acetyl group. It has a role as a cyclooxygenase 2 inhibitor, a cyclooxygenase 1 inhibitor, a non-narcotic analgesic, an antipyretic, a non-steroidal anti-inflammatory drug, a cyclooxygenase 3 inhibitor, a xenobiotic, an environmental contaminant, a human blood serum metabolite, a hepatotoxic agent, a ferroptosis inducer and a geroprotector. It is a member of phenols and a member of acetamides. It is functionally related to a 4-aminophenol.

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Acetaminophen (paracetamol), also commonly known as Tylenol, is the most commonly taken analgesic worldwide and is recommended as first-line therapy in pain conditions by the World Health Organization (WHO). It is also used for its antipyretic effects, helping to reduce fever. This drug was initially approved by the U.S. FDA in 1951 and is available in a variety of forms including syrup form, regular tablets, effervescent tablets, injection, suppository, and other forms. Acetaminophen is often found combined with other drugs in more than 600 over the counter (OTC) allergy medications, cold medications, sleep medications, pain relievers, and other products. Confusion about dosing of this drug may be caused by the availability of different formulas, strengths, and dosage instructions for children of different ages. Due to the possibility of fatal overdose and liver failure associated with the incorrect use of acetaminophen, it is important to follow current and available national and manufacturer dosing guidelines while this drug is taken or prescribed.

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Acetaminophen is a widely used nonprescription analgesic and antipyretic medication for mild-to-moderate pain and fever. Harmless at low doses, acetaminophen has direct hepatotoxic potential when taken as an overdose and can cause acute liver injury and death from acute liver failure. Even in therapeutic doses, acetaminophen can cause transient serum aminotransferase elevations.

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Acetaminophen is a natural product found in Streptomyces xiamenensis and Euglena gracilis with data available.
Acetaminophen is a p-aminophenol derivative with analgesic and antipyretic activities. Although the exact mechanism through which acetaminophen exert its effects has yet to be fully determined, acetaminophen may inhibit the nitric oxide (NO) pathway mediated by a variety of neurotransmitter receptors including N-methyl-D-aspartate (NMDA) and substance P, resulting in elevation of the pain threshold. The antipyretic activity may result from inhibition of prostaglandin synthesis and release in the central nervous system (CNS) and prostaglandin-mediated effects on the heat-regulating center in the anterior hypothalamus.

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Theraflu is any of the commercial combination preparations, by Novartis, containing a combination of any of the following agents: the analgesic antipyretic acetaminophen, an antihistamine (chlorpheniramine maleate, diphenhydramine hydrochloride, doxylamine succinate or pheniramine maleate), the antitussive dextromethorphan maleate and/or a decongestant (phenylephrine hydrochloride or pseudoephedrine hydrochloride). Theraflu preparations are used to relieve symptoms of cold and flu. Acetaminophen exerts its actions by inhibiting prostaglandin synthesis. The antihistamines block the effects of histamine. Dextromethorphan exerts its activity by raising the threshold for coughing in the cough center. The decongestants are sympathomimetic agents that cause vasoconstriction mediated through alpha-adrenergic receptors. This reduces blood flow, decreases swelling and prevents nasal and sinus congestion.

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Acetaminophen, also known as paracetamol, is commonly used for its analgesic and antipyretic effects. Its therapeutic effects are similar to salicylates, but it lacks anti-inflammatory, antiplatelet, and gastric ulcerative effects. The excellent tolerability of therapeutic doses of paracetamol (acetaminophen) is a major factor in the very wide use of the drug. The major problem in the use of paracetamol is its hepatotoxicity after an overdose. Hepatotoxicity has also been reported after therapeutic doses, but critical analysis indicates that most patients with alleged toxicity from therapeutic doses have taken overdoses. Importantly, prospective studies indicate that therapeutic doses of paracetamol are an unlikely cause of hepatotoxicity in patients who ingest moderate to large amounts of alcohol. (A7820). Single doses of paracetamol are effective analgesics for acute postoperative pain and give rise to few adverse effects. (A7821). Acetaminophen (AAP) overdose and the resulting hepatotoxicity is an important clinical problem. In addition, AAP is widely used as a prototype hepatotoxin to study mechanisms of chemical-induced cell injury and to test the hepatoprotective potential of new drugs and herbal medicines. Because of its importance, the mechanisms of AAP-induced liver cell injury have been extensively investigated and controversially discussed for many years.

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Analgesic antipyretic derivative of acetanilide. It has weak anti-inflammatory properties and is used as a common analgesic, but may cause liver, blood cell, and kidney damage.

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Drug Indication
In general, acetaminophen is used for the treatment of mild to moderate pain and reduction of fever. It is available over the counter in various forms, the most common being oral forms. Acetaminophen _injection_ is indicated for the management of mild to moderate pain, the management of moderate to severe pain with adjunctive opioid analgesics, and the reduction of fever. Because of its low risk of causing allergic reactions, this drug can be administered in patients who are intolerant to salicylates and those with allergic tendencies, including bronchial asthmatics. Specific dosing guidelines should be followed when administering acetaminophen to children.

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Drug Warnings
The U.S. Food and Drug Administration (FDA) is informing the public that acetaminophen has been associated with a risk of rare but serious skin reactions. These skin reactions, known as Stevens-Johnson Syndrome (SJS), toxic epidermal necrolysis (TEN), and acute generalized exanthematous pustulosis (AGEP), can be fatal. Acetaminophen is a common active ingredient to treat pain and reduce fever; it is included in many prescription and over-the-counter (OTC) products. Reddening of the skin, rash, blisters, and detachment of the upper surface of the skin can occur with the use of drug products that contain acetaminophen. These reactions can occur with first-time use of acetaminophen or at any time while it is being taken. ... Anyone who develops a skin rash or reaction while using acetaminophen or any other pain reliever/fever reducer should stop the drug and seek medical attention right away. Anyone who has experienced a serious skin reaction with acetaminophen should not take the drug again and should contact their health care professional to discuss alternative pain relievers/fever reducers. Health care professionals should be aware of this rare risk and consider acetaminophen, along with other drugs already known to have such an association, when assessing patients with potentially drug-induced skin reactions.

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Reported Fatal Dose
In adults, hepatic toxicity rarely has occurred with acute overdoses of less than 10 g, although hepatotoxicity has been reported in fasting patients ingesting 4-10 g of acetaminophen. Fatalities are rare with less than 15 g.

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Drug Tolerance
Although psychologic dependence on acetaminophen may occur, tolerance and physical dependence do not appear to develop even with prolonged use. Bingham, E.; Cohrssen, B.; Powell, C.H.; Patty's Toxicology Volumes 1-9 5th ed. John Wiley & Sons. New York, N.Y. (2001)., p. 2181

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Pharmacodynamics
Animal and clinical studies have determined that acetaminophen has both antipyretic and analgesic effects. This drug has been shown to lack anti-inflammatory effects. As opposed to the _salicylate_ drug class, acetaminophen does not disrupt tubular secretion of uric acid and does not affect acid-base balance if taken at the recommended doses. Acetaminophen does not disrupt hemostasis and does not have inhibitory activities against platelet aggregation. Allergic reactions are rare occurrences following acetaminophen use.

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Absorption
Acetaminophen has 88% oral bioavailability and reaches its highest plasma concentration 90 minutes after ingestion. Peak blood levels of free acetaminophen are not reached until 3 hours after rectal administration of the suppository form of acetaminophen and the peak blood concentration is approximately 50% of the observed concentration after the ingestion of an equivalent oral dose (10-20 mcg/mL). The percentage of a systemically absorbed rectal dose of acetaminophen is inconsistent, demonstrated by major differences in the bioavailability of acetaminophen after a dose administered rectally. Higher rectal doses or an increased frequency of administration may be used to attain blood concentrations of acetaminophen similar to those attained after oral acetaminophen administration.

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Route of Elimination
Acetaminophen metabolites are mainly excreted in the urine. Less than 5% is excreted in the urine as free (unconjugated) acetaminophen and at least 90% of the administered dose is excreted within 24 hours.
Volume of Distribution
Volume of distribution is about 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Acetaminophen appears to be widely distributed throughout most body tissues except in fat.
Clearance
Adults: 0.27 L/h/kg following a 15 mg/kg intravenous (IV) dose. Children: 0.34 L/h/kg following a 15 mg/kg intravenous (IV dose).

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Metabolism / Metabolites
Acetaminophen is the major metabolite of _phenacetin_ and _acetanilid_. Acetaminophen is mainly metabolized in the liver by first-order kinetics and its metabolism of comprised of 3 pathways: conjugation with glucuronide, conjugation with sulfate, and oxidation through the cytochrome P450 enzyme pathway, mainly CYP2E1, to produce a reactive metabolite (N-acetyl-p-benzoquinone imine or NAPQI). At normal therapeutic doses, NAPQI undergoes fast conjugation with glutathione and is subsequently metabolized to produce both cysteine and mercapturic acid conjugates. High doses of acetaminophen (overdoses) can lead to hepatic necrosis due to the depletion of glutathione and of binding of high levels of reactive metabolite (NAPQI) to important parts of liver cells. The abovementioned damage to the liver can be prevented by the early administration of sulfhydryl compounds, for example, methionine and N-acetylcysteine.

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Biological Half-Life
The half-life for adults is 2.5 h after an intravenous dose of 15 mg/kg. After an overdose, the half-life can range from 4 to 8 hours depending on the severity of injury to the liver, as it heavily metabolizes acetaminophen.
The elimination half life is 1-3 hours after a therapeutic dose but may be greater than 12 hours after an overdose. OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 69

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Mechanism of Action
According to its FDA labeling, acetaminophen's exact mechanism of action has not been fully established - despite this, it is often categorized alongside NSAIDs (nonsteroidal anti-inflammatory drugs) due to its ability to inhibit the cyclooxygenase (COX) pathways. It is thought to exert central actions which ultimately lead to the alleviation of pain symptoms. One theory is that acetaminophen increases the pain threshold by inhibiting two isoforms of cyclooxygenase, COX-1 and COX-2, which are involved in prostaglandin (PG) synthesis. Prostaglandins are responsible for eliciting pain sensations. Acetaminophen does not inhibit cyclooxygenase in peripheral tissues and, therefore, has no peripheral anti-inflammatory effects. Though acetylsalicylic acid (aspirin) is an irreversible inhibitor of COX and directly blocks the active site of this enzyme, studies have shown that acetaminophen (paracetamol) blocks COX indirectly. Studies also suggest that acetaminophen selectively blocks a variant type of the COX enzyme that is unique from the known variants COX-1 and COX-2. This enzyme has been referred to as _COX-3_. The antipyretic actions of acetaminophen are likely attributed to direct action on heat-regulating centers in the brain, resulting in peripheral vasodilation, sweating, and loss of body heat. The exact mechanism of action of this drug is not fully understood at this time, but future research may contribute to deeper knowledge.
Acetaminophen produces analgesia and antipyresis by a mechanism similar to that of salicylates. Unlike salicylates, however, acetaminophen does not have uricosuric activity. There is some evidence that acetaminophen has weak anti-inflammatory activity in some nonrheumatoid conditions (e.g., in patients who have had oral surgery). ... Acetaminophen lowers body temperature in patients with fever but rarely lowers normal body temperature. The drug acts on the hypothalamus to produce antipyresis; heat dissipation is increased as a result of vasodilation and increased peripheral blood flow. American Society of Health-System Pharmacists 2013; Drug Information 2013. Bethesda, MD. 2013, p. 2211

C8H9NO2

151.16

151.063

C, 63.56; H, 6.00; N, 9.27; O, 21.17

103-90-2

Acetaminophen;103-90-2

White to off-white solid powder

1.3±0.1 g/cm3

387.8±25.0 °C at 760 mmHg

168-172 °C(lit.)

188.4±23.2 °C

0.0±0.9 mmHg at 25°C

1.619

0.34

49.33

RZVAJINKPMORJF-UHFFFAOYSA-N

InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)

Acetamide, N-(4-hydroxyphenyl)-

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: This product is not stable in solution, please use freshly prepared working solution for optimal results.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

配方 1 中的溶解度: 6.67 mg/mL (44.13 mM) in PBS (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶。

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配方 2 中的溶解度: 10 mg/mL (66.16 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 3 中的溶解度: 10 mg/mL (66.16 mM) in saline 0.5% Tween-80 (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液; 超声助溶.
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。