メラルソプロール

危険有害性情報のコード(GHS)

• 絵表示(GHS)

  

• 注意喚起語

  Danger

• 危険有害性情報

  H301：飲み込むと有毒

  H331：吸入すると有毒

  H410：長期的影響により水生生物に非常に強い毒性

• 注意書き

  P261：粉じん/煙/ガス/ミスト/蒸気/スプレーの吸入を避ける こと。

  P264：取扱い後は皮膚をよく洗うこと。

  P264：取扱い後は手や顔をよく洗うこと。

  P270：この製品を使用する時に、飲食または喫煙をしないこ と。

  P271：屋外または換気の良い場所でのみ使用すること。

  P273：環境への放出を避けること。

  P301+P310：飲み込んだ場合：直ちに医師に連絡すること。

  P304+P340：吸入した場合：空気の新鮮な場所に移し、呼吸しやすい 姿勢で休息させること。

  P311：医師に連絡すること。

  P321：特別な処置が必要である（このラベルの．．． を見よ）。

  P330：口をすすぐこと。

  P391：漏出物を回収すること。

  P403+P233：換気の良い場所で保管すること。容器を密閉 しておくこと。

  P405：施錠して保管すること。

  P501：内容物/容器を．．．に廃棄すること。

メラルソプロール 化学特性,用途語,生産方法

• 効能

  抗原虫薬

• 説明

  Knowingly or unknowingly, arsenic-containing drugs have been used for treatment of parasitic conditions for thousands of years. In the late 1800s and early 1900s, Paul Ehrlich introduced the use of trivalent arsenicals. Melarsoprol, an organoarsenical, came into use in the late 1940s, and it remains the first-choice drug in the treatment of trypanosomiasis. Until 1990, it also was the only treatment for late-stage sleeping sickness.

• 使用

  Melarsoprol is a drug used for the treatment of African trypanosomes, a sleeping sickness in humans, a disease that is typically fatal without chemotherapy.

• 抗菌性

  It is highly and rapidly active against Trypanosoma brucei gambiense and T. brucei rhodesiense in vitro at submicromolar concentrations. It is much less active against the trypanosomes that infect domestic animals, T. congolense and T. vivax. Co-administration with eflornithine is effective against central nervous system (CNS) infection with T. brucei in rodent models, but clinical studies have found the combination less effective than nifurtimox–eflornithine.

• 獲得抵抗性

  Up to 25% of cases of T. brucei gambiense in Central Africa relapse. Patients infected with T. brucei rhodesiense normally respond to a second course of the drug, but those with T. brucei gambiense do not. In laboratory-generated resistant strains, decreased sensitivity results from reduced uptake of the drug by bloodstream trypomastigotes that either lack an adenine/adenosine transporter (TbAT1) or contain a transporter gene with point mutations. There is conflicting evidence about the role of this mechanism of resistance in isolates from patients unresponsive to treatment.

• 健康ハザード

  Melarsoprol (4, Mel B, Arsobal C12H15AsN6OS2) is applied for T. b. gambiense or T. b. rhodesiense. The drug, administered intravenously, is a solution containing a combination of BAL (2,3-dimercaptopropanol) and the trivalent arsenic compound, melarsen oxide. Not only can the drug cause serious side effects such as intense dermal irritation, myocarditis, and renal and hepatic damage, but it is also responsible for death in 5% of patients.

• 応用例（製薬）

  Mel B. A derivative of trivalent melarsen oxide and dimercaprol (BAL), possessing a melaminyl moiety. Formulated in 3.6% propylene glycol for intravenous administration. It is almost insoluble in water.

• 作用機序

  It generally is accepted that the enzyme with which melarsoprol reacts is an enzyme involved in glycolysis, and as a result, inhibition of pyruvate kinase occurs. It is argued, however, that the inhibition may not occur at pyruvate kinase but, rather, at a step before the pyruvate kinase. Blockage of glycolysis would be expected to lead to loss of motility and cell lysis. More recently, Fairlamb et al. have proposed a mechanism of action that results in the inhibition of trypanothione reductase through the formation of a stable complex between melaroprol and trypanothione. Melarsoprol reacts with the cysteine sulfhydryl of trypanothione to form the stable adduct shown in Figure 39.10. Supportive of this mechanism is the synergistic action of melarsoprol with eflornithine (DMFO). Two drugs that produce sequential blockage of the synthesis of trypanothione.

• 薬物動態学

  Serum levels of 2–4 mg/L were achieved 24 h after administration of 3.6 mg/kg, falling to 0.1 mg/L at 120 h after the fourth daily injection. Elimination was biphasic with a half-life of 35 h. The volume of distribution was 100 L. It is rapidly metabolized by microsomal enzymes to melarsen oxide, reaching maximum plasma concentration by 15 min and eliminated with a half-life of 3.9 h. This metabolite can cross the blood–brain barrier and effect a CNS cure in mice. Levels of melarsoprol in the cerebrospinal fluid (CSF) reached around 300 μg/L, about 50 times lower than serum levels.

• 臨床応用

  2-p-(4,6-Diamino-s-triazin-2-yl-amino)phenyl-4-hydroxymethyl-1,3,2-dithiarsoline (Mel B, Arsobal) is prepared byreduction of a corresponding pentavalent arsanilate to thetrivalent arsenoxide followed by reaction of the latter with2,3-dimercapto-1-propanol (British anti-Lewisite [BAL]). Ithas become the drug of choice for the treatment of thelater stages of both forms of African trypanosomiasis.Melarsoprol has the advantage of excellent penetration intothe CNS and, therefore, is effective against meningoencephaliticforms of T. gambiense and T. rhodesiense.Trivalent arsenicals tend to be more toxic to the host (as wellas the parasites) than the corresponding pentavalent compounds.The bonding of arsenic with sulfur atoms tends toreduce host toxicity, increase chemical stability (to oxidation),and improve distribution of the compound to the arsenoxide.Melarsoprol shares the toxic properties of other arsenicals, however, so its use must be monitored for signsof arsenic toxicity.

• 副作用

  The propylene glycol formulation can cause tissue trauma and long-term damage to veins. Drug-induced reactions include fever on first administration, abdominal colic pain, dermatitis and arthralgia. Polyneuropathy has been reported in about 10% of patients. Reactive arsenical encephalopathy is a serious side effect that occurs in around 10% of those treated, with death in 1–3% of cases. The frequency of encephalopathy increases with a rise in the white cell count or the presence of trypanosomes in the CSF. The causes of the immunological responses involved in the encephalopathy and the possible existence of two forms (reactive and hemorrhagic) are not completely resolved. Studies to identify antiinflammatory approaches to reduce reactive encephalopathy in late-stage T. brucei gambiense infection have produced limited results.

• 代謝

  Melarsoprol is administered IV in multiple doses and multiple sessions. Its major metabolite in humans is the lipophilic melarsen oxide, which can penetrate into the CNS. This metabolite apparently is responsible for the protein-binding characteristic for melarsoprol.

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