Anthelmintic Action

Microfilarial forms of susceptible species are most affected by diethylcarbamazine, which elicits rapid disappearance from blood for W. bancrofti, B. malayi, and L. loa. The drug kills microfilariae of O. volvulus in skin but not in nodules that contain the adult (female) worms. It does not affect the microfilariae of W. bancrofti in a hydrocele. Diethylcarbamazine appears to exert a direct toxic effect on W. bancrofti microfilariae; it also kills worms of adult L. loa and probably adult W. bancrofti and B. malayi. Diethylcarbamazine may impair intracellular processing and transport of certain macromolecules to the helminth plasma membrane. The drug also may affect specific immune responses of the host.

ABSORPTION, FATE, AND EXCRETION Diethylcarbamazine is absorbed rapidly from the GI tract. Peak plasma levels occur within 1-2 hours, and the plasma t1/2 varies from 2 to 10 hours, depending on urinary pH. Metabolism is rapid and extensive. A major metabolite, diethylcarbamazine-N-oxide, is bioactive. Diethylcarbamazine is excreted by both urinary and extraurinary routes. Alkalinizing the urine can elevate plasma levels, prolong the plasma t1/2, and increase both therapeutic effect and toxicity of diethylcarbamazine. Dosage reduction may be required in people with renal dysfunction or sustained alkaline urine.

THERAPEUTIC USES Recommended regimens for filarial infections differ according to whether the drug is used for population-based chemotherapy, control of filarial disease, or prophylaxis against infection.

W. Bancrofti, B. Malayi, and B. Timori The standard regimen for LF has been a 12-day, 72-mg/kg (6 mg/kg/day) course of diethylcarbamazine. A single dose of 6 mg/kg had comparable macrofilaricidal and microfilaricidal efficacy to previous regimens. Single-dose therapy may be repeated every 6-12 months, as necessary.

Although diethylcarbamazine does not usually reverse existing lymphatic damage, early treatment of asymptomatic individuals may prevent progression. Repeat treatment sometimes is recommended if microfilariae remain in the circulation or adult worms are seen on ultrasound. During acute episodes of lymphangitis, diethylcarbamazine is not recommended until acute symptoms subside. Supportive treatment is critical, including prevention of secondary bacterial infections by attention to hygiene, wearing shoes to prevent foot injury, and avoidance of lymphostasis by exercise and limb elevation.

For mass treatment programs, the introduction of diethylcarbamazine into table salt (0.2-0.4% by weight of the base) has markedly reduced the prevalence, severity, and transmission of lymphatic filariasis in many endemic areas. Diethylcarbamazine given annually as a single oral dose of 6 mg/kg is most effective in reducing microfilaremia when coadministered with either albendazole (400 mg) or ivermectin (0.2-0.4 mg/kg). Adverse reactions to microfilarial destruction usually are well tolerated. However, mass chemotherapy with diethylcarbamazine should not be used in regions where onchocerciasis or loiasis coexist because it may induce severe reactions related to parasite burden in these infections.

O. Volvulus and L. Loa Diethylcarbamazine is contraindicated for onchocerciasis because it causes severe reactions related to microfilarial destruction, including worsening ocular lesions. For purposes of LF control, ivermectin is preferred in areas where onchocerciasis is endemic. Diethyl-carbamazine remains the best drug for therapy of loiasis. Treatment is initiated with test doses of 50 mg (1 mg/kg in children) daily for 2-3 days, escalating as tolerated to daily doses of 9 mg/kg in three doses for a total of 2-3 weeks.

Low test doses are used, often with glucocorticoid or antihistamine pretreatment to minimize reactions to dying microfilariae and adult worms. Repeated courses of diethylcarbamazine treatment, separated by 3-4 weeks, may be required. Ivermectin is not a good alternative for treatment of loiasis, but albendazole may prove to be useful in patients who either fail therapy with diethyl-carbamazine or who cannot tolerate the drug.

TOXICITY AND SIDE EFFECTS At <8-10 mg/kg/day, direct toxic reactions to diethyl-carbamazine, including anorexia, nausea, headache, and vomiting, are rarely severe and usually disappear within a few days despite continued therapy. Major adverse effects result from host response to destruction of parasites, primarily microfilariae.

Reactions typically are most severe in patients heavily infected with O. volvulus, less serious in B. malayi or L. loa infections, and mild in bancroftian filariasis, but the drug occasionally induces retinal hemorrhages and severe encephalopathy in patients heavily infected with L. loa. In patients with onchocerciasis, reactions typically occur within a few hours after the first dose and include intense itching, tender lymphadenitis, and sometimes a papular rash, fever, tachycardia, arthralgias, and headache. This reaction persists for 3—7 days and then subsides, after which high doses sometimes can be tolerated. Ocular complications include limbitis, keratitis, uveitis, and atrophy of the retinal pigment epithelium. In patients with bancroftian or brugian filariasis, nodular swellings may occur along the course of the lymphatics, often with an accompanying lymphadenitis that also subsides within a few days. Almost all patients receiving therapy exhibit a leukocytosis Reversible proteinuria may occur, and the eosinophilia so frequently observed in patients with filariasis can be intensified by diethylcarbamazine. Delayed reactions include lymphangitis, swelling and lymphoid abscesses in bancroftian and brugian filariasis, and small skin wheals in loiasis. Diethylcarbamazine appears to be safe during pregnancy.

PRECAUTIONS AND CONTRAINDICATIONS Population-based therapy with diethyl-carbamazine should be avoided in areas where onchocerciasis or loiasis is endemic, although the drug can be used to protect foreign travelers from these infections. Pretreatment with glucocorti-coids and antihistamines often is given to minimize indirect reactions to diethylcarbamazine that result from dying microfilariae.

Ivermectin

The avermectins are a novel class of 16-membered lactones. Ivermectin (mectizan; stromectol; 22,23-dihydroavermectin B1a) is FDA-approved for treatment of onchocerciasis and for therapy of intestinal strongyloidiasis. Ivermectin taken as a single oral dose every 6-12 months continues to serve as the mainstay of major programs to control onchocerciasis. In addition, annual oral doses of ivermectin, either taken alone or combined with annual oral doses of albendazole, markedly reduce microfilaremia in lymphatic filariasis due to W. bancrofti or B. malayi. Current recommendations advocate diethylcar-bamazine (6 mg/kg) plus albendazole (400 mg). The two-drug regimen is preferred in regions where LF coexists with either onchocerciasis or loiasis. Ivermectin is the drug of choice against intestinal strongy-loidiasis and is effective against several other human infections caused by intestinal nematodes.

IVERMECTIN (R = CH3 or C2H5) ANTIPARASITIC ACTIVITY AND RESISTANCE

Ivermectin is effective and highly potent against at least some stages of many parasitic nematodes that affect animals and humans. Avermectins affect a group of glutamate-gated Ct channels found in nematode nerve or muscle cells, causing hyperpolarization and paralysis by increasing Ct permeability of the cell membrane. Alterations in genes encoding P-glycoprotein transporters that bind aver-mectins and in those encoding components of the glutamate-gated Ct channel have been associated with the development of resistance. Avermectins also interact with g-aminobutyric acid (GABA) receptors in mammalian brain, but their affinity for invertebrate receptors is ~100-fold higher.

In humans infected with O. volvulus, ivermectin causes a rapid, marked decrease in microfi-larial counts in the skin and ocular tissues that lasts for 6—12 months. The drug has little discernible effect on adult parasites, even at doses as high as 800 ^g/kg, but affects developing larvae and blocks egress of microfilariae from the uterus of adult female worms. Regular treatment with ivermectin also may act prophylactically against the development of Onchocerca infection.

Ivermectin also is effective against microfilaria but not adult worms of W. bancrofti, B. malayi, L. loa, and M. ozzardi. It exhibits excellent efficacy against A. lumbricoides, S. sterco-ralis, and cutaneous larva migrans.

ABSORPTION, FATE, AND EXCRETION Peak plasma levels of ivermectin are achieved within 4-5 hours after oral administration. The long terminal t1/2 of ~57 hours primarily reflects a low systemic clearance and a large apparent volume of distribution. Ivermectin is ~93% bound to plasma proteins. The drug is extensively converted by hepatic CYP3A4 to at least 10 metabolites, mostly hydroxylated and demethylated derivatives. Virtually no ivermectin appears in human urine in either unchanged or conjugated form. Highest tissue concentrations occur in liver and fat. Extremely low levels are found in brain; a P-glycoprotein efflux pump in the blood-brain barrier prevents ivermectin from entering the central nervous system (CNS).

Naturally Cure Your Headaches

Naturally Cure Your Headaches

Are Headaches Taking Your Life Hostage and Preventing You From Living to Your Fullest Potential? Are you tired of being given the run around by doctors who tell you that your headaches or migraines are psychological or that they have no cause that can be treated? Are you sick of calling in sick because you woke up with a headache so bad that you can barely think or see straight?

Get My Free Ebook


Post a comment