MAO (monoamine oxidase)

过氧亚硝酸盐是血管内室中由超氧化物阴离子和一氧化氮产生的一种活性氮。过氧亚硝酸盐破坏血浆蛋白、红细胞和血小板的膜。这就解释了为什么过亚硝酸盐的过量生产会导致疾病和衰老。拮抗过氧亚硝酸盐的治疗方法可以延缓衰老和疾病进展。我们开发了一种体外测定法，可以研究过氧亚硝酸盐在血管内室中引起的氧化损伤。该测定将损伤与蛋白质羰基、3-硝基酪氨酸（3-NT）和硫代巴比妥酸反应物质的形成速率相关联。使用该测定法，我们评估了酚嗪（一种活性醛的清除剂）拮抗过氧亚硝酸盐作用的能力。在此，我们发现吩噻嗪显著降低了血浆和血小板中过氧亚硝酸盐引起的脂质过氧化损伤。此外，它还抑制了血浆和血小板蛋白中羰基和3-NT的形成。

在小鼠中，与媒介物对照治疗的小鼠相比，在严重胸部压迫后立即腹膜内注射酚嗪，此后每天注射一次，持续6周，在脊髓损伤后4周和5周改善后肢功能，减少星形胶质细胞增生，促进轴突再生/发芽。Phenelzine的应用上调了脊髓中L1的表达，并刺激了脊髓组织中同源L1介导的细胞内信号级联。在炎症的急性期，经吩嗪治疗的小鼠损伤脊髓中的促炎细胞因子水平降低，如白细胞介素-1β、白细胞介素-6和肿瘤坏死因子-α[2]。

这项研究开发了一种体外测定法，可以研究过氧亚硝酸盐在血管内室中引起的氧化损伤。该测定将损伤与蛋白质羰基、3-硝基酪氨酸（3-NT）和硫代巴比妥酸反应物质的形成速率相关联。使用该测定法，本研究评估了酚嗪（一种活性醛的清除剂）拮抗过氧亚硝酸盐作用的能力。在此，本研究表明，吩噻嗪可显著降低血浆和血小板中过氧亚硝酸盐引起的脂质过氧化损伤[1]。

In mice, intraperitoneal injection of phenelzine immediately after severe thoracic compression, and thereafter once daily for 6 weeks, improved hind limb function, reduced astrogliosis and promoted axonal regrowth/sprouting at 4 and 5 weeks after spinal cord injury compared to vehicle control-treated mice[2].

Absorption, Distribution and Excretion
Phenelzine is rapidly absorbed from the gastrointestinal tract. The decay of the drug action is not dependent on the pharmacokinetic parameters but on the rate of protein synthesis which restores the functional levels of monoamine oxidase. The mean Cmax is 19.8 ng/ml and it occurs after 43 minutes of dose administration.
The elimination of the administered dose is mainly composed of the phenelzine metabolites, phenylacetic acid and parahydroxyphenylacetic acid that constitute 79% of the dose found in the urine in the first 96 hours.
The volume of distribution of phenelzine is hard to determine as drugs from this kind penetrate the CNS very well into the tissue where their activity is desired.
Following ip injection of 2.5 mg/kg bw phenelzine-1-(14)C sulfate to rats, 62% of the dose was recovered in the urine within 24 hours.
Following a single 30 mg dose of Nardil (2 X 15 mg tablets), a mean peak plasma concentration (Cmax) of 19.8 ng/mL occurred at a time (Tmax) of 43 minutes post dose.
Phenelzine is readily absorbed from the gastrointestinal tract. There is little excretion in the urine.

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Metabolism / Metabolites
For the metabolic studies, it is assumed that phenelzine is acetylated. Some of the metabolites of phenelzine are phenylacetic acid, 2-phenylethylamine and 4-hydroxyphenylacetic acid as major metabolites and N-acetyl-phenelzine as a minor metabolite.
Nardil is extensively metabolized, primarily by oxidation via monoamine oxidase. After oral administration of (13)C6-phenelzine, 73% of the administered dose was recovered in urine as phenylacetic acid and parahydroxyphenylacetic acid within 96 hours. Acetylation to N2-acetylphenelzine is a minor pathway.
Following ip injection of 2.5 mg/kg bw phenelzine-1-(14)C sulfate to rats, 62% of the dose was recovered in the urine within 24 hours. The major excretion product was phenylacetic acid, which is also a metabolite of phenelzine in mice. The first enzyme involved in this elimination process is monoamine oxidase.
Hepatic. Acetylation of phenelzine appears to be a minor metabolic pathway. Beta-phenylethylamine is a metabolite of phenelzine, and there is indirect evidence that phenelzine may also be ring-hydroxylated and N-methylated.
Route of Elimination: NARDIL® is extensively metabolized, primarily by oxidation via monoamine oxidase.
Half Life: 1.2-11.6 hours following single dose administration. Multiple-dose pharmacokinetics have not been studied.

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Biological Half-Life
After administration phenelzine presents a very short half-life of 11.6 hours in humans.
The mean apparent half-life, estimated from urinary excretion data in patients who received oral doses of 30 mg thrice daily, was 0.87 hours following the initial dose and 3.11 hours after 13 days of treatment.
The mean elimination half-life after a single 30 mg dose is 11.6 hours.

Toxicity Summary
Although the exact mechanism of action has not been determined, it appears that the irreversible, nonselective inhibition of MAO by phenelzine relieves depressive symptoms by causing an increase in the levels of serotonin, norepinephrine, and dopamine in the neuron.

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Hepatotoxicity
Phenelzine, like most monoamine oxidase inhibitors, can cause transient serum aminotransferase elevations in a proportion of patients. These elevations are usually mild, asymptomatic and self-limited and do not require dose modification. Phenelzine has also been associated with cases of acute, clinically apparent liver injury. The liver injury associated with MAO inhibitors typically arises 1 to 3 months after starting therapy and presents with a hepatocellular pattern of serum enzyme elevations. The acute hepatitis-like syndrome can be severe and even fatal. Cholestatic liver injury due to phenelzine has also been described (Case 1). Immunoallergic features (rash, fever, eosinophilia) are uncommon as is autoantibody formation. While few cases of phenelzine liver injury have been published, instances of severe jaundice and fatalities due to liver injury have been reported to the FDA and the sponsor.
Likelihood score: C (probable rare cause of clinically apparent liver injury).

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Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Because of the lack of data on use during breastfeeding, other antidepressants are preferred during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Phenelzine can elevate serum prolactin in some patients and has caused galactorrhea in nonpregnant, nonnursing patients. The clinical relevance of these findings in nursing mothers is not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

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Protein Binding
Unchanged phenelzine presents a high protein binding which reduced its bioavailability.

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Interactions
MAO inhibitors, including Nardil, are contraindicated in patients receiving guanethidine.
Patients taking Nardil should not undergo elective surgery requiring general anesthesia. Also, they should not be given cocaine or local anesthesia containing sympathomimetic vasoconstrictors. The possible combined hypotensive effects of Nardil and spinal anesthesia should be kept in mind. Nardil should be discontinued at least 10 days prior to elective surgery.
The concurrent administration of an MAO inhibitor and bupropion hydrochloride is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with bupropion hydrochloride. /MAO inhibitors/
The combination of MAO inhibitors and tryptophan has been reported to cause behavioral and neurologic syndromes including disorientation, confusion, amnesia, delirium, agitation, hypomanic signs, ataxia, myoclonus, hyperreflexia, shivering, ocular oscillations, and Babinski signs. /MAO inhibitors/
For more Interactions (Complete) data for Phenelzine (9 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Mouse iv 160 mg/kg body weight
LD50 Mouse oral 160 mg/kg body weight
LD50 Mouse ip 135 mg/kg body weight
LD50 Rat oral 210 mg/kg body weight

[1]. Phenelzine reduces the oxidative damage induced by peroxynitrite in plasma lipids and proteins. Arch Physiol Biochem. 2018 Dec;124(5):418-423.
[2]. Phenelzine, a small organic compound mimicking the functions of cell adhesion molecule L1, promotes functional recovery after mouse spinal cord injury. Restor Neurol Neurosci . 2018;36(4):469-483.

Therapeutic Uses
Antidepressive Agents, Monoamine Oxidase Inhibitors
Phenelzine is used in the treatment of major depressive disorder. /Included in US product label/
Phenelzine has been used with some success in the management of bulimia nervosa. /NOT included in US product label/
Nardil should rarely be the first antidepressant drug used. Rather, it is more suitable for use with patients who have failed to respond to the drugs more commonly used for these conditions.
Nardil has been found to be effective in depressed patients clinically characterized as "atypical," "nonendogenous," or "neurotic." These patients often have mixed anxiety and depression and phobic or hypochondriacal features. There is less conclusive evidence of its usefulness with severely depressed patients with endogenous features.

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Drug Warnings
/BOXED WARNING/ Suicidality and Antidepressant Drugs: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of Nardil or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Nardil is not approved for use in pediatric patients.
Safety and efficacy of phenelzine in pediatric patients have not been established. The US Food and Drug Administration (FDA) has determined that antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with major depressive disorder and other psychiatric disorders. However, FDA also states that depression and certain other psychiatric disorders are themselves associated with an increased risk of suicide. Anyone considering the use of phenelzine in a child or adolescent for any clinical use must balance the potential risk of therapy with the clinical need.
Phenelzine shares the toxic potentials of other MAO inhibitors, and the usual precautions and contraindications associated with these drugs should be observed. Patients should be fully advised about the risks, especially hypertensive crisis and suicidal thinking and behavior (suicidality), associated with MAO inhibitor therapy.
Nardil should not be used in patients who are hypersensitive to the drug or its ingredients, with pheochromocytoma, congestive heart failure, severe renal impairment or renal disease, a history of liver disease, or abnormal liver function tests.
For more Drug Warnings (Complete) data for Phenelzine (19 total), please visit the HSDB record page.

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Pharmacodynamics
The elimination of monoamine oxidase by phenelzine results in the elevation of brain amines such as 2-phenylethylamine which is a metabolite of phenelzine. These amines have then marked effects on the uptake and release of catecholamines and serotonin in nerve endings. Phenelzine is shown to elevate brain levels of the gamma-aminobutyric acid (GABA) and alanine (ALA) as well as to inhibit the activity of the transaminases that normally metabolize these amino acids. In preclinical studies, it has been shown to be neuroprotective in cerebral ischemia.

C8H12N2

136.20

136.1

C, 70.55; H, 8.88; N, 20.57

51-71-8

51-71-8; 156-51-4 (sulfate);

3675

Liquid

1.0±0.1 g/cm3

281.4±19.0 °C at 760 mmHg

157-161ºC
Crystals; mp: 174 °C /Phenelzine hydrochloride/
< 25 °C

143.7±25.1 °C

0.0±0.6 mmHg at 25°C

1.550

1.14

38.05

2

2

3

10

77.3

0

NNCCC1=CC=CC=C1

RMUCZJUITONUFY-UHFFFAOYSA-N

InChI=1S/C8H12N2/c9-10-7-6-8-4-2-1-3-5-8/h1-5,10H,6-7,9H2

Hydrazine, (2-phenylethyl)-

Phenelzine; 51-71-8; Phenethylhydrazine; 2-Phenylethylhydrazine; Nardil; Fenelzyne; Hydrazine, (2-phenylethyl)-; Fenelzyna;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。