Comparison of isometamidium chloride and homidium bromide as prophylactic drugs for trypanosomiasis in cattle at Nguruman, Kenya

doi:10.1016/0001-706X(94)00080-K

Acta Tropica

Volume 59, Issue 2, May 1995, Pages 77-84

https://doi.org/10.1016/0001-706X(94)00080-K Get rights and content

Abstract

The duration of prophylaxis provided by isometamidium chloride and homidium bromide, each at a dose rate of 1 mg kg⁻¹ bodyweight, was compared in a 12-month field trial involving groups of 30 zebu cattle in south-west Kenya. The trial took place between February 1990 and February 1991 and included several months of high trypanosome challenge. Cattle in the prophylaxis groups were retreated on a group basis when 10% of the group had become infected since the previous group treatment. On this basis the mean intervals between retreatment were 7.5 ± 1.9 and 4.6 ± 2.1 weeks for the isometamidium and homidium groups, respectively. Weight gains in the two groups were similar. In spite of the need for more frequent treatment in the homidium group as compared to the isometamidium group, total drug costs were lower in the former. There was evidence of Trypanosoma congolense resistant to homidium and some evidence of T. vivax resistant to isometamidium.

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Ethidium bromide (EtBr) is an intercalating agent commonly used as a fluorescent tag (nucleic acid stain) in molecular biology laboratories for techniques such as agarose gel electrophoresis (Stevenson et al., 1995).
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Drug therapies currently used for second stage Human African Trypanosomiasis (HAT) exhibit problems with toxicity, difficulty of administration, and resistance linked to the loss of transporter function. Key to the development of new drugs for HAT is a better understanding of the transport properties of candidate compounds. Standard methods for studying transport utilize radio-labelled permeant or HPLC–MS, however the natural fluorescence of many trypanocidal compounds can be exploited.
Here we present a fluorescence-based assay for measuring uptake, by trypanosomes, of CPD0801, a drug candidate for second stage HAT. Sample fluorescence is measured in a 96-well format using a benchtop fluorimeter. Our method is directly applicable to the study of other diamidines with similar fluorescent properties and readily adapted for use with other cell types or fluorescent molecules as we demonstrate for the veterinary trypanocide ethidium.
The effects of drug-sensitive and drug-resistant Trypanosoma congolense infections on the pharmacokinetics of homidium in Boran cattle
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Control of trypanosomosis in cattle, sheep and goats in endemic areas has depended largely on the use of chemotherapeutic or chemoprophylactic agents. One such agent is homidium which is generally classified mainly as a chemotherapeutic drug but has been reported to offer some prophylactic activity against trypanosome infections in the field (Mwambu, 1971; Dolan et al., 1990; Stevenson et al., 1995). Following its introduction, several studies were carried out to determine the minimum curative and maximum tolerated doses (Wilde and Robson, 1953; Wilson and Fairclough, 1953; Unsworth, 1954a,b).
Two groups of five Boran (Bos indicus) cattle were infected with one of two populations of Trypanosoma congolense; one drug-sensitive (IL1180), and one drug-resistant (IL3330). The animals were then treated intramuscularly with homidium bromide at a dose rate of 1.0 mg kg⁻¹ bodyweight 7 days after trypanosomes were detected in the peripheral blood of all the five animals in each group. Following treatment of cattle infected with drug-sensitive trypanosomes, parasites could no longer be detected in the bloodstream of four out of five cattle after 24 h, and after 48 h for the fifth animal. The animals remained aparasitaemic up to the end of the observation period of 90 days and serum drug concentrations determined by enzyme-linked immunosorbent assay (ELISA) remained above the detection limit of 0.1 ng ml⁻¹ for the entire period. Following treatment of cattle infected with drug-resistant trypanosomes, parasites did not disappear from the bloodstream in any of the five animals. The rate of drug elimination was greater in cattle infected with drug-resistant trypanosomes and the drug was no longer detectable approximately 3 weeks after treatment. Non-compartmental pharmacokinetic analysis showed that the values for t_$12$β of 75.5±16.9 h, the area under the curve (AUC_0−∞) of 1.33±0.156 μg h ml⁻¹ and the MRT_0−∞ of 32.8±4.45 h obtained in cattle infected with the drug-resistant trypanosome population were significantly lower than the values of 424±146 h for t_$12$β, 1.67±0.233 μg h ml⁻¹ for AUC_0−∞ and 297±159 h for MRT_0−∞ obtained in cattle infected with the drug-sensitive population. The persistence of drug-resistant infections in cattle following homidium treatment was associated with more rapid drug elimination than in those in which infections with drug-sensitive parasites were cleared by the drug.
Comparison of the isometamidium-based trypanocidal drugs Samorin® and Veridium® in cattle under field conditions at Nguruman, Kenya
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The observation, that breakthrough infections in isometamidium-treated cattle are predominantly T. vivax, concurs with previous reports. In an earlier trial, involving Samorin®, carried out in the same location as the present study, 90% of breakthrough infections were identified as being T. vivax (Stevenson et al., 1995) compared with 81% for Samorin® treated cattle and 76% for Veridium® treated cattle in the present trial. The dose rate of isometamidium used in this trial, 0.5 mg kg−1 bodyweight, is the lowest dose rate recommended by the manufacturers for prophylaxis.
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The Brazilian Pantanal is a 138 000 km² tropical seasonal wetland located in the center of South America bordering Bolivia and Paraguay. The Pantanal contains approximately 1100 cattle ranches, 3 million cattle, 49 000 horses and a unique diversity of wildlife. Cattle ranching is the most important economic activity in the Pantanal. This study explores the direct financial impacts of the adoption of seven treatment strategies for the control of Trypanosoma evansi in the Brazilian Pantanal. T. evansi adversely affects the health of the horse population in the region. Horses are indispensable to the cattle ranching industry in the Pantanal. Estimated costs include risk of infection, costs of diagnosis, alternative treatments, collecting animals for treatment, and costs of animal losses. The estimated total cost of T. evansi to the Pantanal region's cattle ranchers is about US$2.4 million and 6462 horses/yr. Results indicate that one preventive and two curative treatment strategies are financially justifiable. The best available technology for the treatment of T. evansi from an economic perspective is a curative treatment employed year-round. This treatment represents an annual net benefit of more than US$2 million or US$1845/ranch and spares about 5783 horses. It represents an annual net benefit of over US$200 000 and 600 horses relative to the currently most widely adopted strategy.

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Comparison of isometamidium chloride and homidium bromide as prophylactic drugs for trypanosomiasis in cattle at Nguruman, Kenya

Abstract

Acta Trop.

Acta Trop.

Trans. R. Soc. Trop. Med. Hyg.

Vet. Parasitol.