Filarial worms

Diethylcarbama2iae (9) (orally administered) has been successful for decades in the treatment of filariasis, eg, elephantiasis (32). It kills microfilariae in the blood of the filarial worms Wuchereria bancrofti Brugia malaji and lj)a loa. 

Diethylcarbama2iae has limited antimicrofilarial activity against Onchocerca volvulus. Adults of W. bancrofti the filarial worm causiag elephantiasis, coil in the lymph system. Here females can attain a length of 10 cm. Over the years, tissue reactions result in obstmction to lymph return. Lymph nodes, lymph vessels, and the spleen become enlarged. The condition of elephantiasis is a late and unusual complication of filariasis, where the lower extremities of the body become edematous, enlarge, and over a period of time harden with a rough nodular skin. 

Antibiotic curing experiments provide a powerful approach in investigating endosymbiont effects on host biology and have been widely used in work on arthropod Wolbachia. A number of such experiments have been inadvertently conducted on filarial worms, in the course of testing... 

Bandi, C., McCall, J.W., Genchi, C., Corona, S., Venco, L. and Sacchi, L. (1999) Effects of tetracycline on the filarial worms Brugia pahangi and Dirofilaria immitis and their bacterial endosymbionts Wolbachia. InternationalJournalfor Parasitology 29, 357-364. 

Sironi, M., Bandi, C., Sacchi, L., Di Sacco, B., Damiani, G. and Genchi, C. (1995) A close relative of the arthropod endosymbiont Wolbachia in a filarial worm. Molecular and Biochemical Parasitology 74, 223-227. 

Tobie, J.E. and Beye, H.K. (1960) Fluorescence of tetracycline in filarial worms. Proceedings of Society of Experimental Biology and Medicine 104, 137-140. 

The filarial worms differ from other nematodes in that they are threadlike and are found in blood and tissue. The infective larvae enter following the bite of an infected arthropod (fly or mosquito). They then enter the lymphatics and lymph nodes. Fever, lymphangitis, and lymphadenitis are associated with the early stage of the disease. Chronic infections may be characterized by elephantiasis as a result of lymphatic obstruction. Some species of filarial worms migrate in the subcutaneous tissues and produce nodules and blindness (onchocerciasis). 

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. 

Infestations with parasitic worms and flukes are widespread both in humans and in animals, and their treatment requires drugs that act in a different manner from antibacterial and antiprotozoal agents. It is desirable for worms to be expelled from the body intact since the presence of dead worms in the tissues can provoke severe reactions. Such reactions are seen when filarial worms which circulate in the blood and lymph are killed by diethylcar-bamazine (264). Intestinal worms may be expelled when they are paralyzed by neuromuscular blockers such as piperazine citrate or pyrantel (265), or their metabolism may be disrupted by the anthelmintic drugs tetramisole and thiabendazole (266) which inhibit fumarate reductase, or mebendazole (267) which prevents glucose uptake by the worms. The anthelmintic activity of tetramisole is due to its laevo isomer levamisole (186). The dextro isomer has antidepressant activity. 

The L. carinii model is routinely used for primary screening and provides a reliable indication of the in vivo action of a compound. It was first used by Culbertson and Rose [18] for antifilarial screening. This parasitic infection is generally transmitted [ 19-21 ] in 3 weeks by the rat mites Liponsyssus bacoti and requires 8 more weeks to mature in the next animal until microfilariae appear in the blood. The adult filarial worms are found in the pleural cavity. 

Chapter 4 surveys a new class of 5-substituted arylmethylbenzimidazole carbamates and increases the prospect that an orally active and powerful drug against the adult filarial worm may soon be discovered. The protective action offered by vitamin E against the damaging effects of hypoxia is discussed in Chapter 5, although this action is only one possible use for this vitamin in medicine. 

The guinea worm infection is a very old parasitic disease caused by Dracuncu-lus medinensis which are enlongated thread-like filarial worms living in the deep connective and subcutaneous tissues of man. The infection has been reported from different parts of Africa, South America and Asia however, it is endemic in Cameroon, Lake Chad, Sudan, Uganda and India. 

Polyamines regulate a number of biochemical functions in mammals as well in the parasites. The presence of these amines has been demonstrated in some helminths. Others, such as the buffalo filarial worm, Setaria cervi, which lack the enzymes essential for the biosynthesis of polyamines, depend on their host to meet the requirement of these amines [65a]. Consequently, the inhibition of the uptake of polyamines, their biosynthesis or metabolic functions also provide useful targets for design of potential anthelmintics [65a,b]. 

The biosynthesis of ecdysteroids in filarial worms has been studied [75]. It has been shown that D. immitis and Brugia pahangi can not synthesize ecdysteroids from cholesterol. Further, no evidence was available to support the conversion of ecdysone (14) to 20-hydroxyecdysone (15). Not withstanding the fact that the basic studies regarding endocrinology of female worms are still not elaborate, interference of ecdysteroid biosynthesis and function in female helminths may provide... 

The action of DEC on adult filarial worms is species dependent. The drug shows only poor or no activity on the macrofilariae of L.carinii and D. viteae in rodents and Dirofilaria immitis and D.repens in dogs. The adult worms of O. volvulus are also not susceptible to DEC. However, DEC has been found to kill the adult worms of Brugia pahangi, B.malayi, W.bancrofti, L loa, Dipetalonema streptocerca and Setaria digitata in different animals [7,62]. 

Animal models suggest that both genetic and environmental factors are important in co-morbidity, and of particular interest is the way in which environmental factors can modify genetic susceptibility. Thus, non-obese diabetic (NOD) mice develop thyroiditis and sialo-adenitis in addition to autoimmune diabetes (Skarstein et al., 1995). This expression of autoimmune disorders is modified by the degree of microbial contamination of the environment (Rossini et al., 1995) and by early life exposure to filarial worms (Imai et al., 2001). In both cases, early immune stimulation leads to lower incidence of diabetes, showing how genetic susceptibility to multiple autoimmune disorders may be disguised by environmental factors. 

Parasitic helminth (worm) infections are widespread and may be the most common disease in the world. Estimates by the WHO and others are that one type of schistosomiasis, the blood flukes, has 200 million people infected. Ascaris, a large roundworm, accounts for at least 650 million, hookworm 450 million, and the several filarial worm species add another 250 million victims to the total. The situation has improved little in the past decade. 

Pyrvinium (Table 7-10) is an unsymmetrical red cyanine dye whose amidinium ion system exhibits unusual resonance (Eq. 7.12). Its mechanism of action is not fully understood, nor has it recently been investigated. It was shown to interfere irreversibly with glucose absorption and has been effectively used in the treatment of pinworms and threadworms, which both reside in the low-oxygen environment of the human intestine. Under more aerobic conditions of filarial worms similar dye compounds have been found to inhibit oxygen consumption. 

Ivermectin has found wide use as a systemic antiparasitic agent against endo and ectoparasites of animals. Ivermectin is also used as a treatment for human filarial worm infections Onchocerca volvulus) [220]. The monosaccharides were 2 to 4 times less active than the disaccharide, and dihydroavermectin B1 aglycone was 30 times less potent [219]. 

Little work has been done on purine metabolism in other parasitic helminths. The dog heart worm, Dirofilaria immitis (73) and Brugia pahangi, a filarial worm of cats and primates, lack de novo purine biosynthesis (74). Thus the parasitic helminths is a group where purine metabolism is largely unexplored. 

Loaiasis Tropical eye disease caused by the filarial worm Loa loa. 

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