Método de análisis de costo-beneficio. (Cost Benefit Analysis Method,

A wide range of substituted phenols has been used for treatment of liver flukes and tapeworms in animals. Most drugs within this group have a low safety index

FIG. 4.6 Chemical structures of commonly used substituted phenols.

and, thus, have been largely superseded by less toxic and more effective drugs.

Nevertheless, a range of substituted phenols including nitroxynil, dichlorophen, hexachlorophen, niclofolan, and bithionol are still used as anthelminthics (Fig.

4.6).

Nitroxynil is one of the few injectable flukicides available and possesses activity not only against adult flukes but also against flukes of more than 4 weeks of age. Nitroxynil also displays a stunting effect against early immature larvae and, hence, reduces pasture contamination by suppressing egg output. It is used in cattle and sheep subcutaneously at a dosage of 10 mg/kg bw, but is contraindi-cated for use in lactating cows. It is also administered orally although with less success, because its nitro group is reduced to an inactive metabolite by the rumen microorganisms (32).

Nitroxynil is well absorbed after oral administration, with peak plasma levels being achieved within 5 h after dosing. In cows, sheep, and rabbits, ni-troxynil is highly bound to plasma proteins. In all species, residues in plasma are higher than in tissues and consist almost entirely of the unchanged drug. Ni-troxynil is extensively metabolized, 4-cyano-2-nitrophenol and 3-iodo-4-hyroxy-aminobenzamide being identified as the metabolites of the greatest concern.

Studies on the composition of nitroxynil-related residues in calves and sheep after subcutaneous treatment showed that the unchanged nitroxynil was the major component of the residues in calf kidney, muscle, and fat, accounting for around 56%, 69%, and 78% of the total residues, respectively. The

4-cyano-2-nitrophenol was the major component of the residues in calf liver with unmetab-olized nitroxynil composing only 2% of the residues. In sheep, nitroxynil was the major component of the residues in kidney, muscle, and fat, accounting for 45–56%, 90–100%, and 64–100% of the extractable residues, respectively, at 5-day withdrawal. In sheep liver, most of the residues were in the form of 3-iodo-4-hydroxy-aminobenzamide, while 4% was unchanged nitroxynil.

Nitroxynil has a tendency to bind strongly to proteins and therefore is retained in animal tissues and milk for long periods after its administration (8).

Residue depletion studies in cattle subcutaneously treated with nitroxynil showed that kidney contained 252, 107, and 90 ppb, muscle 149–587, 89–131, and 50, and the injection site 90–504, 90–207, and 90 ppb of the parent drug at 30, 45, and 60 days, respectively, after withdrawal of the treatment. In sheep, residues of nitroxynil in kidney were 382, 208, and 102 ppb, and at the injection site 161–508, 102–189, and 90 ppb at 30, 45, and 60 days, respectively, after withdrawal of treatment.

Dichlorophen is a safe, narrow-spectrum drug that, in addition to its bacte-ricidal and fungicidal properties, has been used as a teniacide in veterinary medi-cine for many years. It is administered to sheep as a tablet or suspension at a dosage of 0.5g/2.5 kg bw. The insolubility of dichlorophen in water limits its absorption from the gastrointestinal tract and probably accounts for its low toxic-ity. Worms are killed in the gut where they disintegrate prior to expulsion in the feces.

Hexachlorophen is a very efficient drug against mature flukes in sheep and cattle, but is not effective in removing immature flukes from the liver paren-chyma. This is due, at least in part, to the protein-binding tendency of the drug in blood and the consequent reduced availability to the immature flukes, which are bathed in blood.

Hexachlorophen is excreted into the animal bile in the form of its glucuron-ide metabolite, which has high activity against the adult flukes occupying the bile ducts (6). Although the principal anthelminthic use of hexachlorophen is for liver flukes in sheep and cattle, it has also limited use as an anticestodal drug in these species and in poultry. The main anticestodal use of hexachlorophen in the United States has been for the control of chicken tapeworms, when administered at an oral dosage of 30–60 mg/kg bw.

Niclofolan is a nitrosubstituted analogue of hexachlorophen. It is highly effective against adult flukes in sheep, cattle, and swine at dosages of 3–5 mg/

kg bw. Toxicity can occur at two times the recommended dosage rate. Although niclofolan can be administered subcutaneously in sheep, it is usually administered orally as a drench or in bolus forms.

Following its oral administration, niclofolan is metabolized to some degree in the rumen of cattle (45). Niclofolan passes into the milk of cattle at

concentra-tions not exceeding 100 ppb and remains at detectable levels for up to 5–8 days posttreatment.

Bithionol is used for the treatment of tapeworm infections in poultry, and tapeworm and rumen fluke infections in sheep, cattle, and goats. An oral dose of approximately 200 mg/kg bw is used in sheep and goats, whereas two treat-ments, 4 days apart, of 200 mg/kg bw are used for chickens. The drug is adminis-tered to poultry with the feed, whereas to other animals it is adminisadminis-tered in the form of gelatin capsules, tablets, or boluses.

Bithionol is absorbed to a limited degree from the digestive tract of the host and is detected in blood and particularly in the bile. Peak concentrations of bithionol are found in the bile within 2 h following treatment. Blood concentra-tions of the drug are significantly lower than those found in bile (6).