MAOI

モノアミン酸化酵素阻害薬

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/02/06 17:59:27」(JST)

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モノアミン酸化酵素阻害薬（-さんかこうそそがいやく）は抗パーキンソン薬の分類の1つで、モノアミン酸化酵素（MAO）の働きを阻害することによって、脳内のドーパミンなどの物質を増やす作用をする薬剤の総称。MAO阻害剤（MAOI）と呼ばれる。昔はうつ病の治療薬として使われていたが、その激しい副作用と扱いの難しさから、現在ではパーキンソン病の治療にのみ使われているが、アメリカ合衆国などでは現在もうつ病の治療薬として認可されており使用されることもある。

概要

ノルアドレナリン神経におけるMAO酸化酵素阻害薬の作用機序。

主な薬理作用は脳内のモノアミン酸化酵素の働きを阻害するものである。（結果的に脳内のモノアミン神経伝達物質の量を増やす）本来、脳内のモノアミン酸化酵素はドーパミンやセロトニンを分解するが、その働きを強力に阻害することによって、結果的に脳内にドーパミンなどの物質が蓄積され、濃度があがる。これにより、パーキンソン病の症状や抑うつ状態が改善されるとされる。 ただし、この薬の作用は一般的に非可逆的であるので、使用には注意を要する。

近年、改良品としてRIMA（例:オーロリックス（欧州）、マネリックス（カナダ））という、可逆的MAO-A阻害剤が開発された。 これらの治験が終了し認可されれば副作用の少ない新しい、難治性のパーキンソン病やうつ病の治療薬としての期待が見込まれる。

代表的なMAOIとして、セレギリンはMAO-Bを選択的に阻害し、RIMAはMAO-Aを阻害する。 RIMAを服用する場合、セレギリンとの併用は絶対にしてはいけない。

また、かつて日本国内では抗うつ薬として「デプレニル（錠）」の名でセレギリンが認可されていたことがあるが、現在はパーキンソンにのみ認可されている。 かつてサフラジンと呼ばれた非選択的MAOI「サフラ（錠）」という薬剤がうつ病に対して処方されていたこともあった。

副作用

従来のMAOIでは、MAO-Aの受容体が阻害されることで、チラミンを摂取したとき、致命的な高血圧が生じたり、肝障害があらわれていた。RIMAでは副作用が緩和されているものの依然としてチラミンの大量摂取には気をつけねばならない。

主にMAO-Aの働きが阻害されると、不安、イライラ、視覚障害、知覚障害、胃腸不調などの症状があらわれる。 またMAO-Bの働きが阻害されるとジスキネジア等の症状があらわれやすくなる可能性が高くなる。

飲み合わせ

この種の薬剤には併用に関して十分に注意を払わなければならないものがいくつかある。（相互作用）

• SSRIとの併用はセロトニン症候群を引き起こす恐れがある。
• エフェドリン類、アンフェタミン誘導体などドーパミンの放出を促進する薬物との併用で、ドパミン濃度の異常を引き起こす。悪性症候群。
• 各種のパーキンソン治療薬や、それ以外の薬品（インフルエンザの治療にも用いられるアマンタジンなど）にも相互作用を引き起こすものが多くあるため、これらと併用する場合は事前に注意を払う必要がある。（主にドパミンアゴニスト）

離脱

MAOIを含めて、一部の抗うつ薬はいくらかの依存性をもたらし、最も著名なのは離脱症候群である。とりわけMAOIを突然中断したり急速に断薬した場合は深刻である。しかしながら、MAOIや抗うつ薬の依存ポテンシャルは一般的にベンゾジアゼピンほど強烈ではない。たとえば抗うつ薬はベンゾジアゼピンほどの著名な薬物乱用ポテンシャルは見られない。 離脱症候群は、週や月単位のゆっくりとした減薬で最小化することができる。

MAOIはその他の抗うつ薬と同様に、障害のコースを変更しないので、断薬によって患者を治療前の状態に戻すことができる。

MAOIとSSRIの間で投与を切り替えるときは十分な配慮が必要である。それは以前の薬から完全に作用機構が切り替わるためである。もし片方の投与を徐々に減らした場合、抑うつの患者は薬物無しの間薬の力を借りることなくうつに立ち向かわなければならない。これは２つの薬の相互作用を減らすために取られるかもしれないが、結果は簡単なものでは無いだろう。

用法

通常はパーキンソン病の治療過程において、L-ドパ製剤などがあまり効かず、良い効果が得られない場合に追加して使用する。国内で使用するものには、塩酸セレギリン（選択的MAO-B阻害剤）がある。

関連項目

• 抗うつ薬
• 抗パーキンソン薬
• モノアミン神経伝達物質
• ドーパミン
• セロトニン

出典

wiki en

[Wiki en表示]

"MAOI" redirects here. For the Easter Island statues, see Moai.

Monoamine oxidase

Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.^{[citation needed]}

Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed. A transdermal patch form of the MAOI selegiline, called Emsam, was approved for use by the Food and Drug Administration in the United States on February 28, 2006.

New research into MAOIs indicate that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite proven effectiveness of this class of drugs, it is underutilized and misunderstood in the medical profession. New research also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research.

Indications

In the past, MAOIs were prescribed for those resistant to tricyclic antidepressant therapy.^{[citation needed]} Newer MAOIs such as selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy. However, these substances are not always as effective as their predecessors.^{[citation needed]}

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder. There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.

MAOIs can also be used in the treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons), as well as providing an alternative for migraine prophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety.

MAOIs appear to be particularly indicated for outpatients with "neurotic depression" complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected.

Mechanism of action

MAOIs act by inhibiting the activity of monoamine oxidase, thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenylethylamine and trace amines. Dopamine is equally deaminated by both types.

Reversibility

The early MAOIs inhibited monoamine oxidase irreversibly. When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about two weeks. A few newer MAOIs, a notable one being moclobemide, are reversible, meaning that they are able to detach from the enzyme to facilitate usual catabolism of the substrate. The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI.

Harmaline found in Peganum harmala, as well as the Ayahausca vine, Banisteriopsis caapi, and Passiflora incarnata is a reversible inhibitor of MAO-A (RIMA).

Selectivity

In addition to reversibility, MAOIs differ by their selectivity of the MAO receptor. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed to target one over the other.

MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B. Agents that act on serotonin if taken with another serotonin-enhancing agent may result in a potentially fatal interaction called serotonin syndrome or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. Tyramine is broken down by MAO-A and MAO-B, therefore inhibiting this action may result in excessive build-up of it, so diet must be monitored for tyramine intake.

MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine so there are no dietary restrictions associated with this. MAO-B would also metabolize tyramine, as the only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine. Two MAO-Bi drugs, selegiline and rasagiline have been approved by the FDA without dietary restrictions, except in high-dosage treatment, wherein they lose their selectivity.

Dangers

When ingested orally, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese effect"), the individual may suffer from hypertensive crisis. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual, and depends on the degree of inhibition, which in turn depends on dosage and selectivity.

The exact mechanism by which tyramine causes a hypertensive reaction is not well-understood, but it is assumed that tyramine displaces norepinephrine from the storage vesicles. This may trigger a cascade in which excessive amounts of norepinephrine can lead to a hypertensive crisis. Another theory suggests that proliferation and accumulation of catecholamines causes hypertensive crisis

Tyrosine, not tyramine, is the precursor to catecholamines. Tyramine is a breakdown product of tyrosine. In the gut and during fermentation, tyrosine, an amino acid, is decarboxylated to tyramine. Under ordinary circumstances, tyramine is deaminated in the liver to an inactive metabolite, but, when the hepatic MAO (primarily MAO-A) is inhibited, the "first-pass" clearance of tyramine is blocked and circulating tyramine levels can climb. Elevated tyramine competes with tyrosine for transport across the blood–brain barrier (via aromatic amino acid transport) where it can then enter adrenergic nerve terminals. Once in the cytoplasmic space, tyramine will be transported via the vesicular monoamine transporter (VMAT) into synaptic vesicles, thereby displacing norepinephrine. The mass transfer of norepinephrine from its vesicular storage space into the extracellular space via mass action can precipitate the hypertensive crisis. Hypertensive crises can sometimes result in stroke or cardiac arrhythmia if not treated. In general, this risk is not present with RIMAs. Both kinds of intestinal MAO inhibition can cause hyperpyrexia, nausea, and psychosis if foods high in levodopa are consumed.

Examples of foods and drinks with potentially high levels of tyramine include liver and fermented substances, such as alcoholic beverages and aged cheeses. (See a List of foods containing tyramine). Examples of levodopa-containing foods include broad beans. These diet restrictions are not necessary for those taking selective MAO-B inhibitors, unless these are being taken in high dosages, as mentioned above.

It deserves separate mention that some meat extracts and yeast extracts (Bovril, Marmite, Vegemite) contain extremely high levels of tyramine, and should not be used with these medications.

When MAOIs were first introduced, these risks were not known, and, over the following four decades, fewer than 100 people have died from hypertensive crisis.^{[citation needed]} Presumed due to the sudden onset and violent appearance of the reaction, MAOIs gained a reputation for being so dangerous that, for a while, they were taken off the market in America entirely. However, it is now believed that, used as directed under the care of a qualified psychiatrist, this class of drugs is a viable alternative treatment for intermediate- to long-term use.

The most significant risk associated with the use of MAOIs is the potential for interactions with over-the-counter and prescription medicines, illicit drugs or medications, and some supplements (e.g., St. John's Wort). It is vital that a doctor supervise such combinations to avoid adverse reactions. For this reason, many users carry an MAOI-card, which lets emergency medical personnel know what drugs to avoid. (E.g., adrenaline dosage should be reduced by 75%, and duration is extended.) The risk of the interaction of MAOI medications with other drugs or certain foods is particularly dangerous because those on the medication who would have to restrict their diets often are depressed patients who "don't care if they live or die."

MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine, tramadol, and dextromethorphan^{[citation needed]}. Agents with actions on epinephrine, norepinephrine, or dopamine must be administered at much lower doses due to potentiation and prolonged effect.

Nicotine, a substance frequently implicated in tobacco addiction, has been shown to have "relatively weak" addictive properties when administered alone. The addictive potential increases dramatically after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally-occurring MAOI compounds in addition to the nicotine.

Withdrawal

Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a withdrawal syndrome, which may be severe especially if MAOIs are discontinued abruptly or over-rapidly. However, the dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. For example, antidepressants have significantly less abuse potential than benzodiazepines. Withdrawal symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimize or prevent withdrawal symptoms.

MAOIs, as with any antidepressant medications, do not alter the course of the disorder, so it is possible that discontinuation can return the patient to the pre-treatment state.

This consideration greatly complicates switching a patient between a MAOI and a SSRI, because it is necessary to clear the system completely of one drug before starting another. If one also tapers dosage gradually, the result is that for weeks a depressed patient will have to bear the depression without chemical help during the drug-free interval. This may be preferable to risking the effects of an interaction between the two drugs, but it is often not easy for the patient^{[citation needed]}.

Interactions

The MAOIs are infamous for their numerous drug interactions. Unless the interaction is desired, any drug that falls within the following classifications should be avoided:

• Substances that are metabolized by monoamine oxidase, as they can be boosted by up to several-fold.
• Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.

Such substances include:

• Phenethylamines: 2C-B, Mescaline, Phenethylamine (PEA), etc.
  • Amphetamines: Amphetamine, MDMA ("Ecstasy"), Dextroamphetamine, Methamphetamine, DOM, etc.
• Tryptamines: DMT, Psilocin/Psilocybin ("Magic Mushrooms"), etc.
  • Lysergamides: Ergolines/LSA, LSD ("Acid"), etc.
• Serotonin, Norepinephrine, and/or Dopamine Reuptake Inhibitors:
  • Selective Serotonin Reuptake Inhibitors (SSRIs): Citalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline.
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Desvenlafaxine, Duloxetine, Milnacipran, Venlafaxine.
  • Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs): Amineptine, Bupropion, Methylphenidate, Nomifensine.
  • Norepinephrine Reuptake Inhibitors (NRIs): Atomoxetine, Mazindol, Reboxetine.
  • Tricyclic Antidepressants (TCAs): Amitriptyline, Butriptyline, Clomipramine, Desipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Nortriptyline, Protriptyline, Trimipramine.
  • Tetracyclic Antidepressants (TeCAs): Amoxapine, Maprotiline.
  • Phenylpiperidine derivative Opioids: Meperidine/Pethidine, Tramadol, Methadone, Fentanyl, Dextropropoxyphene, Propoxyphene.
  • Others: Brompheniramine, Chlorpheniramine, Cocaine, Cyclobenzaprine, Dextromethorphan (DXM), Ketamine, MDPV, Nefazodone, Phencyclidine (PCP), Pheniramine, Sibutramine, Trazodone.
• Serotonin, Norepinephrine, and/or Dopamine Releasers: 4-Methylaminorex (4-MAR), Amphetamine, Benzphetamine, Cathine, Cathinone, Diethylcathinone, Ephedrine, Levmetamfetamine, Lisdexamfetamine, MDMA ("Ecstasy"), Methamphetamine, Pemoline, Phendimetrazine, Phenethylamine (PEA), Phentermine, Propylhexedrine, Pseudoephedrine, Phenylephrine, Tyramine.
• Serotonin, Norepinephrine, and/or Dopamine Supplemental Precursors: 5-HTP, L-DOPA, L-Phenylalanine, L-Tryptophan, L-Tyrosine.
• Local and General anesthetic in surgery and dentistry in particular those containing Epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as Phenelzine and it is, therefore, vital to inform all clinicians especially dentists of the potential effect of MAOIs and Local Anesthesia. In preparation for dental work, withdrawal from Phenelzine is specifically advised, however since this takes two weeks it is not always a desirable or practical option. Dentists using Local Anesthesia are advised to use a non-epinephrine anesthetic such as Carbocaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure and the level of the anesthetic should be regularly and appropriately topped up since non-epinephrine anestetics take longer to come into effect and wear off faster. Patients taking Phenelzine are advised to notify their Psychiatrist prior to any dental treatment.
• Certain Other Supplements: Hypericum perforatum ("St John's Wort"), Inositol, Rhodiola rosea, S-Adenosyl-L-Methionine (SAMe), L-Theanine.
• Other Monoamine Oxidase Inhibitors.

It is recommended by the FDA to contact a physician or pharmacist before taking any drug while on an MAOI.

History

The older MAOIs' heyday was mostly between the years 1957 and 1970. The initial popularity of the 'classic' non-selective irreversible MAO inhibitors began to wane due to their serious interactions with sympathomimetic drugs and tyramine-containing foods that could lead to dangerous hypertensive emergencies. As a result, the use by medical practitioners of these older MAOIs declined. When scientists discovered that there are two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, (for example, selegiline, which is used for Parkinson's disease), to reduce the side-effects and serious interactions. Further improvement occurred with the development of compounds (moclobemide and toloxatone) that not only are selective but cause reversible MAO-A inhibition and a reduction in dietary and drug interactions.

Irreversible MAOIs were the first antidepressants to be discovered, but they fell out of favour with the advent of the discovery of safer antidepressants; these newer antidepressant drug classes have fewer adverse effects, especially the dangerous irreversible MAOI food interaction with tyramine, sometimes referred to as the 'cheese syndrome', which leads to dangerous hypertension. However, reversible MAOIs lack these hypertensive adverse effects. Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice; its reversible inhibitory features give it a number of advantages over the older irreversible MAO inhibitors.

List of MAOIs

• Herbal Drugs
  • Selective MAO-A Inhibitors
    • Harmala alkaloids (found in Coffee, Syrian rue,
    • Resveratrol (found in Japanese knotweed and skin of red grapes)
  • Nonselective MAO-A/MAO-B Inhibitors
    • Curcumin (found in Turmeric)
    • Rhodiola rosea (active constituent(s) unknown)
    • Ruta graveolens (active constituent(s) unknown)
    • Ginkgo biloba
    • Anthocyanins
    • Proanthocyanidin
  • Selective MAO-B inhibitors
    • Epicatechin
    • Emodin (found in Fo-Ti)
    • Gentiana lutea (active constituent(s) unknown)

• Pharmaceutical Drugs
  • Nonselective MAO-A/MAO-B Inhibitors
    • Hydrazines
      • Benmoxin (Nerusil, Neuralex)
      • Hydralazine (Apresoline)
      • Iproclozide (Sursum)
      • Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida)
      • Isocarboxazid (Marplan)
      • Isoniazid (Laniazid, Nydrazid)
      • Mebanazine (Actomol)
      • Nialamide (Niamid)
      • Octamoxin (Ximaol, Nimaol)
      • Phenelzine (Nardil, Nardelzine)
      • Pheniprazine (Catron)
      • Phenoxypropazine (Drazine)
      • Pivalylbenzhydrazine (Tersavid)
      • Procarbazine (Matulane, Natulan, Indicarb)
      • Safrazine (Safra)
    • Non-Hydrazines
      • Caroxazone (Surodil, Timostenil)
      • Echinopsidine (Adepren)
      • Furazolidone (Furoxone, Dependal-M)
      • Linezolid (Zyvox, Zyvoxam, Zyvoxid)
      • Tranylcypromine (Parnate, Jatrosom)
  • Selective MAO-A Inhibitors
    • Brofaromine (Consonar)
    • Metralindole (Inkazan)
    • Minaprine (Cantor)
    • Moclobemide (Aurorix, Manerix)
    • Pirlindole (Pirazidol)
    • Toloxatone (Humoryl)
  • Selective MAO-B Inhibitors
    • Lazabemide (Pakio, Tempium)
    • Pargyline (Eutonyl)
    • Rasagiline (Azilect)
    • Selegiline (Deprenyl, Eldepryl, Emsam)

• Research Compounds
  • Nonselective MAO-A/MAO-B Inhibitors
    • Hydrazines
      • Metfendrazine
  • Selective MAO-A Inhibitors
    • Amiflamine
    • Bazinaprine
    • Befloxatone
    • Cimoxatone
    • Clorgyline
    • Esuprone
    • Eprobemide (Befol)
    • Methylene Blue
    • Pirlindole
    • Sercloremine
    • Tetrindole
    • Thesputiaint
    • CX157 (Tyrima)
  • Selective MAO-B Inhibitors
    • D-Deprenyl
    • Ladostigil
    • Milacemide
    • Mofegiline

• Antiparasitic
  • Invertebrate MAO Inhibitors
    • Amitraz antiparasitic used in animals for ticks, mites (sarcoptes, demodex) and lice. Used on plants as an insecticide against mites, aphids, etc.

Various tryptamine and phenethylamine/amphetamine derivatives such as αET, αMT, amphetamine (itself), methamphetamine, MDMA, 4-MTA, PMA, 2C-T-7, and 2C-T-21 may also have weak to strong MAOI effects at high doses. Many other unlisted hydrazines like hydrazine (itself), monomethylhydrazine, and phenylhydrazine have some MAOI properties as well.

Cultural references

• In the episode "The Late Shaft" of the TV detective drama Castle, Bobby Mann was taking an MAO inhibitor. His killer used this fact to trigger a negative interaction with the drug, leading to Bobby's death through what seemed to be a normal heart attack.

• In the episode "Cut" of Law & Order, a surgeon prescribes painkillers that interact with an MAOI a patient was taking, leading to her death.

• The pilot episode of Law and Order was similar to an actual event. Journalist Sidney Zion questioned the sudden death of his daughter Libby Zion at an ER room in Manhattan on Oct 4, 1984. The cause of death was attributed to "mysterious infection". The father convinced authorities to launch a criminal investigation when it was discovered that several medications, including Demerol, were administered to his daughter, reacting with her Nardil medications. The DA sought charges of murder against a doctor, which approved use of restraints and narcotics when Libby became increasingly agitated. The case prompted many reforms in graduate medical education and limiting number of hours staff can work. Drug abuse was successfully argued as a major factor leading to her death.

See also

• Reversible inhibitor of MAO-A (RIMA)
• Hydrazine (antidepressant)
• MAO, MAO-A, MAO-B

References

UpToDate Contents

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• 1. 成人におけるうつ病治療としてのモノアミン酸化酵素阻害剤（MAOI） monoamine oxidase inhibitors maois for treating depressed adults
• 2. パーキンソン病の薬理学的治療 pharmacologic treatment of parkinson disease
• 3. Switching antidepressant medications in adults
• 4. メチシリン耐性黄色ブドウ球菌およびバンコマイシン耐性腸球菌の治療のための抗菌薬の薬理学 pharmacology of antimicrobial agents for treatment of methicillin resistant staphylococcus aureus and vancomycin resistant enterococcus
• 5. 成人における単極性うつ病：難治性うつ病の治療 unipolar depression in adults treatment of resistant depression

English Journal

• Phenolic compounds from Jacaranda caroba (Vell.) A. DC.: Approaches to neurodegenerative disorders.

• Ferreres F, Grosso C, Gil-Izquierdo A, Valentão P, Andrade PB.SourceResearch Group on Quality, Safety and Bioactivity of Plant Foods, Department of Food Science and Technology, CEBAS (CSIC), P.O. Box 164, 30100 Campus University Espinardo, Murcia, Spain. Electronic address: federico@cebas.csic.es.
• Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association.Food Chem Toxicol.2013 Jul;57:91-8. doi: 10.1016/j.fct.2013.03.012. Epub 2013 Mar 21.
• Diseases affecting the central nervous system are spread throughout the world. As so, more efficient and safe neuroprotective drugs are required. The present study describes, for the first time, the phenolic composition and bioactivity of Jacaranda caroba (Vell.) A. DC, a species whose infusion is c
• PMID 23524314

• The antinociceptive effect of reversible monoamine oxidase-A inhibitors in a mouse neuropathic pain model.

• Villarinho JG, Pinheiro Kde V, Pinheiro Fde V, Oliveira SM, Machado P, Martins MA, Bonacorso HG, Zanatta N, Fachinetto R, Ferreira J.SourcePrograma de Pós-graduação em Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, 97105-900, Santa Maria, RS, Brazil.
• Progress in neuro-psychopharmacology & biological psychiatry.Prog Neuropsychopharmacol Biol Psychiatry.2013 Jul;44:136-42. doi: 10.1016/j.pnpbp.2013.02.005. Epub 2013 Feb 15.
• Neuropathic pain is a debilitating condition that is often resistant to common analgesics, such as opioids, but is sensitive to some antidepressants, an effect that seems to be mediated by spinal cord 5-HT3 receptors. Because the analgesic potential of monoamine oxidase-A (MAO-A) inhibitors is under
• PMID 23419243

Japanese Journal

• 東京医大を愛し続けた私の半生

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• 東京醫科大學雜誌 69(3), 298-306, 2011-07-30
• NAID 10029507734

• <原著論文>早期子宮頚癌患者(CIS/I期)のhigh risk HPV感染率は上昇し年令は若年化している

• 船越 真生,FUNAKOSHI Maoi
• 秋田医学 31(3-4), 195-200, 2004
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• NAID 110001052880

• 招聘講演 Selective Serotonin Reuptake Inhibitors (SSRIs) in Panic Disorder

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• 心身医学 40(4), 275-281, 2000-04-01
• … Initial evidence of the effectiveness of imipramine and the monoamine oxidase inhibitors(MAOI), phenelzine and tranylcypromine, was first observed in Europe and the United States in the early to mid-60s. …
• NAID 110001122619

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★リンクテーブル★

リンク元	「抗利尿ホルモン不適合分泌症候群」「デュロキセチン」「モノアミン酸化酵素阻害薬」「monoamine oxidase inhibitor」
関連記事	「MA」「MAOIs」「MAO」

「抗利尿ホルモン不適合分泌症候群」

　　[★]

英

syndrome of inappropriate secretion of antidiuretic hormone, (国試)SIADH

syndrome of inappropriate secretion of antidiuresis, SIAD

同

抗利尿ホルモン不適合分泌、ADH不適合分泌症候群 inappropriate antidiuretic hormone secretion inappropriate secretion of antidiuretic hormone syndrome inappropriate ADH syndrome IADHS、シュワルツ・バーター症候群 Schwartz-Bartter syndrome。抗利尿ホルモン分泌異常症。不適切ADH分泌症候群

syndrome of inappropriate ADH、syndrome of inappropriate ADH secretion、syndrome of inappropriate antidiuretic hormone、syndrome of inappropriate antidiuretic hormone secretion、syndrome of inappropriate diuresis、syndrome of inappropriate secretion of ADH、syndrome of inappropriate secretion of antidiuretic hormone

関

バソプレシン AVP

病因

• 抗利尿ホルモンの不適切な分泌。

• 1. 抗利尿ホルモンが分泌される血漿浸透圧の閾値が異常となっている　←　セットポイントの異常
• 2. 何らかの原因によって、恒常的に抗利尿ホルモンが分泌されている

HIM.2222改変

• 悪性腫瘍

• 癌腫：肺、十二指腸、膵臓、卵巣、膀胱・尿路系
• その他：胸腺腫、中皮腫、気管支腺腫、カルチノイド、gangliocytoma、ユーイング肉腫

• 頭部外傷
• 感染症
• 血管障害
• 神経疾患
• 先天奇形
• 代謝異常
• 薬剤性

• バソプレシン、デスモプレシン
• (高用量の)オキシトシン
• ニコチン
• クロフィブラート
• クロルプロパミド
• カルバマゼピン(抗てんかん薬)
• ビンクリスチン(抗悪性腫瘍薬、ビンカアルカロイド。微小管の重合を抑制)
• シクロホスファミド(抗悪性腫瘍薬、免疫抑制薬)
• モノアミンオキシダーゼ阻害薬 MAOI
• ハロペリドール(抗精神病薬ブチロフェノン系)
• クロルプロマジン(抗精神病薬フェノチアジン系)
• フェノチアジン(抗精神病薬フェノチアジン系)
• 三環系抗うつ薬(アミトリプチリン)
• 選択的セロトニン再取り込み阻害薬 SSRI(抗うつ薬、抗不安薬)

病態生理

なぜ、waterのreabsorptionが増えるにもかかわらず、血圧が上昇しないの？

HIM.2222

• 何らかの原因による不適切な抗利尿ホルモンの分泌　→　水の過剰な保持　→

1. →　細胞外液の増加　→　(1)糸球体濾過量の増加と心房性利尿ペプチドの分泌、(2)レニン活性の抑制(supresses plasma renin activity)、(3)尿ナトリウム排泄の増加

細胞外液の増加を相殺しているが、その代償としてナトリウムを喪失し、低ナトリウム血症の増悪に繋がっている。　←　このために血圧は正常で、浮腫も起きないし、体液量も増えないと。

2. →　低ナトリウム血症　→　脳を含めた全身の細胞内液の増加　→　頭蓋内圧が亢進　→　急性水中毒症状

2-3日で脳の組織から水が排除されて症状が寛解する。

上記メカニズムに追加。

3. 1.の通り、循環血漿量の増加を招き、RAA系抑制などが起こる　→　近位尿細管でのNa、水吸収低下(近位尿細管でのNa再吸収にはアンジオテンシンIIが関与)　→　尿酸の再吸収低下、尿排泄増加(近位尿細管での挙動はNa、水と同じ、らしい)　→　低尿酸血症

症状

低ナトリウム血症に基づくもの

尿量は変化がない　　←　　水の再吸収が亢進しているため？？

検査

• ナトリウム：低値
• 尿酸：低値
• クレアチニン：低値
• BUN：低値

診断基準

• 1．低ナトリウム血症：血清ナトリウム濃度は135mEq/Lを下回る。
• 2．血漿バゾプレシン値：血清ナトリウムが135mEq/L未満で、血漿バゾプレシソ値が測定感度以上である。
• 3．低浸透圧血症：血漿浸透圧は280mOsm/kgを下回る。　←　基準値：275-295 mOsmol/kg serum water(HIM.A)
• 4．高張尿：尿浸透圧は300mOsm/kgを上回る。　←　基準値：50-1200 mOsm/l (QB) , 500-800 mOsmol/kg water(HIM.A)
• 5．ナトリウム利尿の持続：尿中ナトリウム濃度は20mEq/L以上である。
• 6．腎機能正常：血清クレアチニンは1.2mg/dl以下である。
• 7．副腎皮質機能正常：早朝空腹時の血清コルチゾールは6μg/dl以上である。

鑑別診断

• 低ナトリウム血症を呈する疾患・病態を除外する

治療

参考1

• 1．根治療　　　：　原疾患の治療を行う。
• 2．水分摂取制限：　1日の総水分摂取量を体重1 kg当り15～20 mlに制限する。
• 3．Na摂取　　　：食塩を経口的または非経口的に1日200 mEq以上投与する。
• 4． 自由水排泄　：重症低ナトリウム血症(120 mEq/L以下)で中枢神経系症状を伴うなど速やかな治療を必要とする場合はフロセミドを随時10～20 mg静脈内に投与し、尿中ナトリウム排泄量に相当する3％食塩水を投与する。その際、橋中心髄鞘崩壊を防止するために1日の血清ナトリウム濃度上昇は10 mEq/L以下とする。
• 5．ADH拮抗阻害薬：異所性バゾプレシン産生腫瘍に原因し、既存の治療で効果不十分な場合に限り、成人にはモザバプタン塩酸塩錠(30 mg)を1日1回1錠食後に経口投与する。投与開始3日間で有効性が認められた場合に限り、引き続き7日間まで継続投与することができる。
• 6．ADH拮抗阻害薬：デメクロサイクリンを1日600～1,200 mg経口投与する。

注意：急速な低Na血症の補正は橋中心髄鞘崩壊 CPMをきたす。

ADH拮抗薬としては抗菌薬のデメクロサイクリン(レダマイシン)や抗てんかん薬のジフェニルヒダントイン(フェニトイン)が使われることがあった

参考

• 診療と治療の手引き

http://square.umin.ac.jp/endocrine/tebiki/001/001008.pdf

国試

• 104I032、102I021

同

不適切ADH分泌症候群

「デュロキセチン」

　　[★]

英

duloxetine

化

塩酸デュロキセチン duloxetine hydrochloride

商

サインバルタ Cymbalta, Yentreve

関

抗精神病薬、抗うつ薬、セロトニン・ノルアドレナリン再取り込み阻害薬 SNRI

適応

• うつ病・うつ状態
• 下記疾患に伴う疼痛：糖尿病性神経障害、線維筋痛症、慢性腰痛症、変形性関節症

用法・用量

• 通常、成人には1日1回朝食後、デュロキセチンとして40mgを経口投与する。投与は1日20mgより開始し、1週間以上の間隔を空けて1日用量として20mgずつ増量する。
• なお、効果不十分な場合には、1日60mgまで増量することができる。
• 減量する場合には1-2週で20mgずつ減量しする。20mgまで到達したら、隔日投与、2日おき投与、3日おき投与と投与間隔を長くしていく。離脱症状（身体症状：しびれ・耳鳴り・めまい・頭痛・吐き気・だるさ。精神症状：イライラ・ソワソワ感・不安・不眠。特徴的な症状：シャンピリ感・ビリビリする）に注意する。

禁忌

• 1.　本剤の成分に対し過敏症の既往歴のある患者
• 2.　モノアミン酸化酵素阻害剤(MAOI)を投与中あるいは投与中止後2週間以内の患者
• 3.　高度の肝障害のある患者［肝障害が悪化することがある。また、消失半減期が延長し、本剤の血中濃度が上昇することがある。
• 4.　高度の腎障害のある患者［本剤の血中濃度が上昇することがある。
• 5.　コントロール不良の閉塞隅角緑内障の患者［症状が悪化することがある。］

副作用

副作用等発現状況の概要

• うつ病・うつ状態の患者を対象とした国内臨床試験において、安全性評価対象例735例中、副作用（臨床検査値異常変動を含む）は663例（90.2％）に認められた。
• 主なものは、悪心269例（36.6％）、傾眠228例（31.0％）、口渇168例（22.9％）、頭痛154例（21.0％）、便秘102例（13.9％）、下痢87例（11.8％）、めまい80例（10.9％）、トリグリセリド上昇56例（7.6％）、腹部痛52例（7.0％）、ALT（GPT）上昇51例（6.9％）、不眠50例（6.8％）、倦怠感45例（6.1％）、AST（GOT）上昇38例（5.2％）、食欲減退38例（5.2％）であった。（承認時）

重大な副作用

• 1. セロトニン症候群（頻度不明※1）

• 不安、焦燥、興奮、錯乱、発汗、下痢、発熱、高血圧、固縮、頻脈、ミオクローヌス、自律神経不安定等があらわれることがある。セロトニン作用薬との併用時に発現する可能性が高くなるため、特に注意すること。異常が認められた場合には投与を中止し、体冷却、水分補給等の全身管理と共に適切な処置を行うこと。

• 2. 抗利尿ホルモン不適合分泌症候群（SIADH）（頻度不明※1）

• 低ナトリウム血症、低浸透圧血症、尿中ナトリウム排泄量の増加、高張尿、痙攣、意識障害等を伴う抗利尿ホルモン不適合分泌症候群（SIADH）があらわれることがあるので、異常が認められた場合には投与を中止し、水分摂取の制限等適切な処置を行うこと。

• 3. 痙攣（0.27％）、幻覚（頻度不明※1）

• 痙攣、幻覚があらわれることがあるので、異常が認められた場合には投与を中止し、適切な処置を行うこと。

• 4. 肝機能障害、肝炎、黄疸（頻度不明※1）

• AST（GOT）、ALT（GPT）、γ-GTP、総ビリルビン等の上昇を伴う肝機能障害、肝炎、黄疸があらわれることがあるので、適宜肝機能検査を行うとともに、患者の症状を十分に観察し、異常が認められた場合には、減量、休薬又は中止するなど適切な処置を行うこと。

• 5. 皮膚粘膜眼症候群（Stevens-Johnson症候群）（頻度不明※1）

• 皮膚粘膜眼症候群（Stevens-Johnson症候群）があらわれることがあるので、観察を十分に行い、異常が認められた場合には投与を中止し、適切な処置を行うこと。

• 6. アナフィラキシー反応（頻度不明※1）

• 呼吸困難、痙攣、血管浮腫、蕁麻疹等を伴うアナフィラキシー反応があらわれることがあるので、観察を十分に行い、異常が認められた場合には投与を中止し、適切な処置を行うこと。

• 7. 高血圧クリーゼ（頻度不明※1）

• 高血圧クリーゼがあらわれることがあるので、高血圧又は心疾患のある患者においては血圧の推移等に十分注意しながら投与すること。異常が認められた場合には投与を中止し、適切な処置を行うこと。

• 8. 尿閉（頻度不明※1）

• 尿閉があらわれることがあるので、症状があらわれた場合には投与を中止し、導尿を実施するなど適切な処置を行うこと。

添付文書

http://www.info.pmda.go.jp/go/pack/1179052M1022_2_03/

「モノアミン酸化酵素阻害薬」

　　[★]

英

monoamine oxidase inhibitor, MAOI

同

MAO阻害薬 MAO inhibitor、モノアミンオキシダーゼ阻害薬

副作用

• 起立性低血圧(once the body adapts to higher basal level of catecholamines, it is nolonger able to further vasoconstrict in response to stress), hepatotoxicity, and hypomania.
• MAO(特にA型)阻害薬使用時に、チラミン含有量の高い食物(ワイン、チーズ、チョコレートなど)を摂取すると、チラミンが分解されずに高血圧発作を起こす

「monoamine oxidase inhibitor」

　　[★] モノアミン酸化酵素阻害薬, MAOI

「MA」

　　[★]

• 僧帽弁閉鎖症 僧帽弁閉鎖 mitral atresia
• 僧帽弁輪 mitral annulus

　

「MAOIs」

　　[★]

関

Monoamine oxidase inhibitors

同

See Monoamine oxidase inhibitors MAOIs

「MAO」

　　[★] モノアミンオキシダーゼ monoamine oxidase