ジエチルカルバマジン

解説

ジエチルカルバマジン．N-メチルピペラジンにジエチルカルバモイルクロリドを縮合させると得られる．融点47～49 ℃，沸点108～111 ℃(0.4 kPa)．クエン酸塩(白色の結晶．融点140～142 ℃．水に可溶，エタノールに微溶)はフィラリア症に対して高い治療効果をもつ抗原虫薬であり，回虫に対しても有効である．LD50 2073 mg/kg(マウス，経口)．駆虫剤の一つ。ピペラジン誘導体である。おもにフィラリア幼虫に作用し，末梢血流中の幼虫を消失させる。そのほか回虫，蟯虫などの線虫類に有効である。毒性は低く，安全域が大きいが，白血球増加症を起すことがある。また，静脈注射により血圧が一過性に上昇し，次いで下降する。中毒量を投与すれば嘔吐，振戦，けいれんをきたす。

効能

駆虫薬

説明

Discovered in the 1940s, diethylcarbamazine (DEC) has proven to be especially effective as a filaricidal agent. The incidence of filariasis among American troops during World War II necessitated a search for drugs with an antifalarial spectrum of activity. The once-popular piperazine also was discovered during these initial screenings. Although chemically similar, the activity again helminths is quite different. Piperazine is active against nematodes, whereas DEC is active against falaria and microfalaria.

適応症

Diethylcarbamazine citrate (Hetrazan) is active against several microfilaria and adult filarial worms. It interferes with the metabolism of arachidonic acid and blocks the production of prostaglandins, resulting in capillary vasoconstriction and impairment of the passage of the microfilaria. Diethylcarbamazine also increases the adherence of microfilariae to the vascular wall, platelets, and granulocytes.
Diethylcarbamazine is absorbed from the gastrointestinal tract, and peak blood levels are obtained in 4 hours; the drug disappears from the blood within 48 hours. The intact drug and its metabolites are excreted in the urine.
Diethylcarbamazine is the drug of choice for certain filarial infections, such as Wuchereria bancrofti, Brugia malayi and Loa loa. Since diethylcarbamazine is not universally active against filarial infections, a specific diagnosis based on blood smears, biopsy samples, and a geographic history is important. Dosage should be adjusted in patients with renal impairment.
Caution is necessary when using this agent, particularly when treating onchocerciasis.The sudden death of the microfilariae can produce mild to severe reactions within hours of drug administration. These are manifested by fever, lymphadenopathy, cutaneous swelling, leukocytosis, and intensification of any preexisting eosinophilia, edema, rashes, tachycardia, and headache. If microfilariae are present in the eye, further ocular damage may result. Other side effects are relatively mild and range from malaise, headache, and arthralgias to gastrointestinal symptoms.

抗菌性

Useful activity is restricted to filarial worms. It is adulticidal and microfilaricidal against Loa loa. Against Wuchereria bancrofti and Brugia malayi it is predominantly microfilaricidal, but slowly kills adult worms. It kills microfilariae, but not adults, of Onchocerca volvulus.

応用例（製薬）

A carbamyl derivative of piperazine formulated as the citrate. It is readily soluble in water and slightly hygroscopic.

作用機序

Although studied extensively, the mechanism of action of DEC remains unknown. Diethylcarbamazine appears to be the active form of the drug, with a very rapid onset of action (within minutes), but of interest is the fact that the drug is inactive in vitro, suggesting that activation of a cellular component is essential to the filaricidal action. Three mechanisms have been suggested. The first is involvement of blood platelets triggered by the action of filarial excretory antigens. A complex reaction is thought to occur between the drug, the antigen, and platelets. Although these authors were unable to show a direct action of the drug on the microfalaria, a more recent study showed that DEC produced morphological damage to the microfalaria. The damage consisted of the loss of the cellular sheath, exposing antigenic determinants to immune defense mechanisms. Severe damage then occurred to microfalaria organelles, leading to death. The second is inhibition of microtubule polymerization and disruption of preformed microtubules. The third is interference with arachidonic acid metabolism. Diethylcarbamazine is known to have anti-inflammatory action, which appears to involve blockage at cyclooxygenase and leukotriene A4 synthase (leukotriene synthesis). This action appears to alter vascular and cellular adhesiveness and cell activation. This latter action would suggest a possible relationship between the first and third mechanism.

薬物動態学

Oral absorption: >90%
C_max 200 mg: 1.5–2 mg/L after 2 h
Plasma half-life: c. 6–12 h
Volume of distribution: 107–371 L
Plasma protein binding: Very low
Like piperazine (to which it is related), diethylcarbamazine is rapidly and completely absorbed. About half the dose is excreted unchanged in the urine; the rest is metabolized and eliminated by renal and extrarenal routes.

臨床応用

Filariasis
It has also been used for visceral larva migrans, but experience is limited and there is little evidence of its efficacy.

副作用

In uninfected people, diethylcarbamazine has virtually no side effects, but in those with various forms of filariasis it has unpleasant effects primarily due to the death of bloodor skin-dwelling microfilariae. Severe reactions (‘Mazzotti reactions’), most frequently of the skin, occur in patients with onchocerciasis and may also be systemic with fever, headache, prostration, nausea, joint and muscle pain, vertigo, tachycardia, cough and respiratory distress, hypotension and ocular signs. In patients with L. loa who harbor very large numbers of microfilariae in their blood, neurological problems may be very severe. Cardiological damage has also been reported. In patients with W. bancrofti and B. malayi high fever occurs in the first few days after treatment. Reversible proteinuria may occur.

安全性プロファイル

Poison by intraperitoneal route. Human systemic effects by ingestion: allergc dermatitis. An experimental teratogen. Mutation data reported. When heated to decomposition it emits toxic fumes of NOx and HCl. An additive permitted in the food and drinking water of animals and/or for the treatment of food-producing animals.

代謝

The metabolism of DEC leads to the compounds shown in Figure 39.18 plus trace amounts of methylpiperazine and piperazine. Nearly all of the metabolites appear in the urine. As much as 10 to 20% of the drug is excreted unchanged. As indicated by the rapid action of the drug, it would appear that none of the metabolites are involved in the therapeutic action of DEC.