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Diethylcarbamazine
General information
Diethylcarbamazine is an antihelminthic drug used in the treatment of filarial infections, in particular for Loa Loa infections and lymphatic filariasis caused by Wuchereria bancrofti and Brugia malayi . With some infecting species it is effective in both the adult and microfilarial stages, whilst with others it is active only against the microfilarial stages and does not eradicate the infection. It can be associated with significant systemic adverse effects, which can compromise adherence to therapy. It is commonly believed that adverse reactions to diethylcarbamazine result from proinflammatory responses to antigens released from killed microfilariae rather than by direct drug or metabolite toxicity.
Pharmacokinetics
Diethylcarbamazine is extensively metabolized, the half-life being 6–12 hours; the remainder enters the urine within 48 hours. Over the initial period the dosage should be increased slowly to avoid or reduce allergic responses as a result of destruction of parasites and liberation of antigen, and then maintained at 3 mg/kg tds for 34 weeks. Not all of its adverse effects are necessarily due to destruction of the parasite; weakness, lethargy, anorexia, and nausea can be due to the drug itself.
The pharmacokinetics, safety, and tolerability of co-administered diethylcarbamazine and albendazole have been investigated in a double-blind, randomized, placebo-controlled trial in 42 subjects (aged 18–52 years, weighing 46–67 kg) living in a lymphatic filariasis endemic region but without detectable microfilariae [ ]. Three groups of 14 patients received diethylcarbamazine 6 mg/kg alone, albendazole 400 mg alone, or diethylcarbamazine 6 mg/kg plus albendazole 400 mg. Both diethylcarbamazine and albendazole were well tolerated alone and in combination. In contrast to a study in patients with lymphatic filariasis [ ], there were no adverse events in amicrofilaremic individuals. In all three treatment groups the drugs were rapidly absorbed from the gastrointestinal tract, although there was marked interindividual variation. The pharmacokinetics of diethylcarbamazine, albendazole, and albendazole sulfoxide were similar.
General adverse effects and adverse reactions
Adverse reactions to treatment with diethylcarbamazine vary with the infecting filarial species and are most severe in onchocerciasis. Minor reactions include malaise, nausea, and headache, but diethylcarbamazine also depresses the central nervous system in some individuals, resulting in dizziness and somnolence; reversible coma has been reported in patients in poor physical condition. Nicotine-like properties can produce autonomic effects. A degree of eosinophilia during treatment is usual.
Although over 120 million individuals have lymphatic filariasis, it may be eradicable. Newer strategies for the elimination of lymphatic filariasis aim at transmission control through the use of annual doses of combinations of ivermectin, diethylcarbamazine, or albendazole, and disease control through individual patient management. Mass chemotherapy appears to be essential in the control of lymphatic filariasis. However, drug availability and the co-endemicity of onchocerciasis and loiasis play crucial roles. Although a single annual dose of diethylcarbamazine may be an effective approach toward long-term suppression of brugian and bancroftian microfilaremia, repeated multidrug chemotherapy is the preferred approach for control of lymphatic filariasis, as in other chronic infections, such as tuberculosis and leprosy. In addition, combining diethylcarbamazine with albendazole has the advantage of controlling intestinal parasites.
The Mazzotti reaction
Presentation
The Mazzotti reaction, first described in 1948 [ ], was originally described after treatment of onchocerciasis with diethylcarbamazine. It is characterized by fever, urticaria, swollen tender lymph nodes, tachycardia, hypotension, arthralgia, edema, and abdominal pain within 7 days of treatment of microfilariasis. The Mazzotti reaction to diethylcarbamazine in onchocerciasis is so common that it is the basis of a skin patch test used to confirm the diagnosis [ , ]. The drug patch is placed on the skin, and if the patient is infected with the microfilaria of Onchocerca volvulus , localized pruritus and urticaria occur at the site of application. Intense pruritus is most marked where microfilariae are concentrated. Hypotension, fever, adenitis, pruritus, and peripheral blood eosinopenia and neutrophilia all correlate with the intensity of the infection [ ].
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A 13-year-old Liberian boy was given ivermectin, praziquantel, and albendazole for intestinal parasitosis and 6 days later began to have mid-epigastric pain, vomiting, and urticaria [ ]. He was treated with intravenous hydration and diphenhydramine and improved. However, on the next day his symptoms returned with the additional features of fever, generalized myalgia, swelling of his face, feet, and penis, and intense pruritus. His temperature was 38.6 °C, pulse 120/minute, respiratory rate 22/minute, and blood pressure 100/60 mmHg. There was a generalized urticarial was on the arms, legs, and trunk, bulbar and palpebral conjunctival injection, and angioedema of his face. He was given intravenous methylprednisolone (2 mg/kg bolus followed by 2 mg/kg/day) and diphenhydramine (1 mg/kg every 6 hours as needed for itching) and all his symptoms resolved completely in 12 hours.
The Mazzotti reaction in this case was ascribed to the presence of undiagnosed onchocerciasis or Wuchereria bancrofti infection.
Occurrence
The incidence of the Mazzotti reaction during treatment of onchocerciasis with ivermectin is low, at about 10% [ ], and about 25% of patients have only fever or pruritus. Albendazole has not been reported to cause Mazzotti-like reactions. Praziquantel is associated with rare adverse effects in schistosomiasis, including fever, abdominal pain, and urticaria, as the following case shows, but it does not cause the typical Mazzotti reaction.
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An 11-year-old African refugee was given praziquantel for intestinal schistosomiasis and 2 hours after the first dose developed abdominal pain, high fever, and an intensely pruritic, urticarial rash on the arms and trunk. He looked unwell, was wheezy, but had no peripheral edema. He had tender hepatosplenomegaly, confirmed by ultrasonography. His stool was positive for Schistosoma mansoni . He had fluctuating high fevers and wheeze during the next 3 days but his symptoms improved with conservative management. His brother had a similar, although less severe, reaction to praziquantel.
Pathogenesis
The Mazzotti reaction is generally ascribed to an inflammatory response, associated with eosinophil migration to the skin and degranulation [ ]. It is precipitated by abrupt release of parasite-specific antigens during cell death. Wolbachia bacteria, free-living endosymbionts of Onchocerca volvulus , form degenerating parasites, which may contribute to the pathogenesis of severe Mazzotti reactions, as occur in patients with high microfilarial loads.
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A 29-year-old New Zealand woman travelling to Asia was exposed to Bancroftian filariasis and took ivermectin (200 micrograms/kg) [ ]. She had transient pruritus ani, especially at night, and took mebendazole for presumed Enterobius vermicularis infestation.
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