A.A. ILEMOBADE
Introduction
Drugs currently in use
Strengths of chemotherapy
Limitations of chemotherapy
Conclusion
References
The field control of African animal trypanosomiasis has, over the years, relied on two broad strategies: using chemotherapeutic agents on infected animals and vector control. In general, however, the chemotherapeutic approach is used much more widely than vector control because it is easier to kill the trypanosomes than the flies. This paper examines the strengths and limitations of the chemotherapeutic approach.
Drug control of animal trypanosomiasis relies essentially on three drugs, namely: Homidium (Homidium chloride - Novidium; and Homidium bromide - Ethidium), Diminazine aceturate (Berenil) and Isometamidium chloride (Samorin, Trypamidium). Indications for their use and toxic effects are given in Table 1. Recently, however, Quinapyramine sulphate (Antrycide) has been reintroduced because of the need to especially combat camel trypanosomiasis. After the introduction of isometamidium in 1961 (Berg et al., 1961) the development of new trypanocidal drugs has made little progress. It is estimated that in Africa 25-30 million doses of trypanocidal drugs are used annually in the treatment of animal trypanosomiasis, but the population of animals at risk indicated that ten times this figure were necessary. The former figures are based on single-dose treatment. Although restrictive, the single dose treatment requirement is particularly suited to the nomadic situation in the field.
Table 1. Drugs available for treatment of African animal trypanosomiasis (adapted from Finelle, 1973).
|
Drug |
Trade Name |
Activity |
Toxic Effect |
Treatment of Relapses |
|||
|
Highly affective on |
Less effective on |
Good Tolerance |
Possible local Reaction |
Possible General Reaction |
|||
|
Homidium chloride
|
Novidium
|
T vivax |
|
Cattle |
Horses |
Horses |
Diminazine |
|
T congolense
|
|
Goats |
|
|
Isometamidium |
||
|
|
Sheep |
|
|
|
|||
|
Homidium
|
Ethidium
|
T vivax |
|
Cattle |
|
|
|
|
T congolense
|
|
Goats |
|
|
Isometamidium |
||
|
|
Sheep |
|
|
|
|||
|
Diminazine aceturate
|
|
T congolense |
T brucei |
Cattle |
Horses |
Horses |
Homidium |
|
Berenil
|
T vivax
|
T evansi |
Goats |
|
Camels |
Isometamidium |
|
|
|
Sheep |
|
|
|
|||
|
Isometamidium chloride
|
Samorin |
T vivax |
T brucei |
Cattle |
Cattle |
Cattle |
Diminazine |
|
Trypamidium
|
T congolense
|
|
Goats |
|
|
|
|
|
|
Sheep |
|
|
|
|||
|
|
Camel |
|
|
|
|||
|
Quinapyramine Sulphate
|
Antrycide
|
T congolense |
|
Cattle |
Horses |
Cattle |
Homidium |
|
T vivax |
|
Goat, |
|
|
Isometamidium |
||
|
T brucei |
|
Sheep |
|
|
Diminazine |
||
|
T evansi |
|
Camel |
|
|
|
||
When properly applied, chemotherapy has been found useful under the following situations.
Temporary or permanent livestock raising
Seasonal movement of stock into areas infested by tsetse flies, by livestock owners wanting to take advantage of pasture and water, requires that animals be protected if severe stock losses are to be averted. Such protection is often achieved by chemotherapy which can make the difference between small losses that allow a reasonable productivity and severe losses which can be crippling. If stock are to be kept permanently in such areas, however, chemotherapy as a strategy will succeed or fail depending on whether the tsetse in the area are the riverine or savanna species. It has been shown by MacLennan (1970) that the trypanosome infection rate of riverine tsetse is low (between 1 and 10%) and that the trypanosomiasis transmitted by riverine tsetse is usually less pathogenic than that transmitted by savanna tsetse. Furthermore, the density of riverine tsetse, for example Glossina palpalis palpalis, is usually of a low order and is confined to riverine courses and in vegetation along streams. However savanna tsetse, for example Glossina morsitans submorsitans, usually has a high density and is widely distributed in the savanna zone within specific belts. Thus, the chemotherapeutic approach is more successful in those areas infested by riverine tsetse than in those infested by savanna tsetse. As early as 1956 Professor Hill, then at the University of Ibadan, showed that zebu cattle can be maintained under light to moderate trypanosomiasis risk for an extended period without ill effects by careful monitoring and treatment of affected animals (Hill, 1956). A similar result is being obtained with our herd of zebu cattle in Akure.
Sporadic trypanosomiasis
Chemotherapy is very effective in the control of sporadic trypanosomiasis due to mechanical transmission, seasonal fly dispersal and scattered tsetse foci. In 1971 an unusual outbreak of trypanosomiasis occurred on the Shika (now National Animal Production Research Institute [NAPRI]) livestock farm (Leeflang and Ilemobade, 1971). The trypanosomiasis was believed to have been transmitted by dispersed flies and maintained by mechanical transmission. Although only a small percentage of cattle on the farm was proved infected, it was believed that, trypanosomiasis being an occult disease, many more animals were also infected. Trypanocidal treatment of all animals resulted in the eradication of trypanosomiasis on the farm.
Introduction of livestock into tsetse reclamation schemes
Raising livestock in reclamation areas is akin to the situation where the density of the flies is sufficiently low to allow livestock to be raised under a regime of chemotherapy. This has led to better land utilization.
In combination with anti-tsetse measures
As noted earlier, chemotherapy tends to be less successful in areas of savanna tsetse. But when combined with anti-tsetse measures, (discriminate tsetse control by insecticide-impregnated traps and screens), chemotherapy has been found to be effective in the control of animal trypanosomiasis.
Protection of animals passing through fly belts
Cattle passing through fly belts can often be protected by chemotherapeutic means. Also, animals returning from the dry-season grazing areas infested with tsetse to tsetse-free wet-season grazing zones often perform better when they are treated against possible trypanosome infection.
Liability to reinfection
The usefulness of chemotherapy is limited in the field because cattle in contact with tsetse flies are liable to re-infection.
In areas of savanna tsetse
As noted earlier, because of the high vectorial capacity of savanna tsetse and the virulence of the trypanosomes they transmit, chemotherapy is less successful in areas infested by savanna tsetse, unless combined with anti-tsetse measures.
Need for regular monitoring
If chemotherapy is to be successful, the need for regular monitorings of the trypanosomiasis risk cannot be overemphasized. It is essential to know at which point drug intervention would be appropriate, which species of trypanosome is prevalent and its drug sensitivities. The degree to which these can be determined will depend on the sensitivity of the diagnostic techniques used and the trained manpower available.
Chemotherapy on a wide scale requires a thorough knowledge of the prevalent trypanosomes and their sensitivity to drugs. In Nigeria, for instance, T. vivax is generally more susceptible to Berenil than is T. congolense. Consequently, the use of either Homidium or Berenil is dictated by which of the two species predominates in a given area or season. In order, therefore, to determine the prevalence of trypanosomes, a sensitive diagnostic tool is a essential. Unfortunately, the diagnostic tools available are limited in their sensitivity to detect trypanosomes. Hence the absence of trypanosomes, therefore, may not necessarily imply that an animal is not infected.
Drug resistance
It would appear, from field observations, that whatever trypanocidal drugs are used on a regular basis, sooner or later strains of trypanosomes resistant to these drugs are bound to arise. That drug resistance is a major impediment to the effective control of trypanosomiasis and thus to improved livestock production in Africa, has long been recognized. Recent reports have shown that, at least in three countries (Nigeria, Kenya and Uganda), drug resistance has assumed some significance (Table 2), and in Central Africa, indications of reduced drug sensitivity by trypanosomes have been reported (Pinder and Authie, 1984). The situation throughout Nigeria, for instance, has been particularly troubling because resistant strains of the major species of trypanosomes of ruminants (. congolense and T. vivax) have been isolated. These strains do not respond to curative doses of Homidium chloride (Novidium) Homidium bromide (Ethidium) and Diminazine aceturate (Berenil). Indeed, it is becoming increasingly difficult to isolate either T. congolense or T. vivax that are not resistant to the recommended curative doses of these trypanocides.
While, the problems of drug resistance have encouraged much research into alternative methods of disease control, for example immunological approaches and the use of trypanotolerant animals, it is becoming increasingly evident that such methods, to be successful, will have to be used in conjunction with chemotherapy. Thus, it is important that efforts should continue to be made to improve control of trypanosomiasis in the field using trypanocidal drugs.
Table 2 Spread of Drug Resistance In Africa.
|
Subregion |
Country |
Trypanocides in current use to which parasite resistance has developed |
Manufacturers recommended dose (mg/kg) |
Species of trypanosomes |
References |
|
West Africa
|
Nigeria
|
Diminazine Aceturate |
3.5 |
T congolense |
MacLennan 6 Jones-Davies (1967) |
|
(Berenil)
|
|
T vivax
|
Jones-Davies (1967) |
||
|
MacLennan 6 Na-Isa. (1970) |
|||||
|
Leeflang et al (1977) |
|||||
|
Ilemobade (1979) |
|||||
|
Homidium Chloride (Novidium)
|
0.1
|
T congolense
|
Jones-Davies 6 |
||
|
Folkers (1966) |
|||||
|
Jones-Davies (1968) |
|||||
|
Folkers et al (1958) |
|||||
|
T vivax
|
Ilemobade & Buys (1970) |
||||
|
Gray 6 Roberts (1971) |
|||||
|
Leeflang et al (1977) |
|||||
|
Ilemobade (1979) |
|||||
|
Isometamidium Chloride |
0.5
|
T congolense |
Na-Isa (1967) |
||
|
(Samorin) |
T vivax. |
Ilemobade (1979) |
|||
|
East Africa
|
Kenya
|
Diminazine-Aceturate
|
3.5
|
T congolense
|
Whiteside (1363)) |
|
Gitatha (1979) |
|||||
|
Uganda
|
Homidium Chloride |
1.0 |
T. vivax |
Rottcher & Schililnger (1984) |
|
|
Isometamidium Chloride
|
0.5
|
T vivax |
Mwambu & Mayende (1971) |
||
|
T vivax |
|
||||
|
Southern Africa
|
Zimbabwe
|
Isometamidium Chloride
|
0.5
|
T congolense
|
Boyt (1971) |
|
Lewis 6 Thomson (1974) |
Measures aimed at combating drug resistance in the field
The following measures are aimed at combating drug resistance in trypanosomes in the field.
Change of drugs
When drug resistance became a problem following wide-spread use of antrycide in the early 1950s, the obvious thing to do was to change drugs especially since the phenanthridinium compounds had arrived on the market. This was the case in Nigeria (Grover, 1965) and in Kenya (Whiteside, 1960), where homidium compounds were introduced and used extensively. In Nigeria for instance, the homidium compounds were used widely between 1954 and 1965 and were then withdrawn from general use for two years following widespread drug resistance by T. congolense (Jones-Davies and Folkers, 1966; Na-Isa, 1967; Folkers et al., 1968) and replaced by Berenil which had been introduced into the market by 1955. A similar fate soon befell Berenil in Nigeria (MacLennan and Jones-Davies, 1967; Jones-Davies, 1968). The extent to which a change of drugs can be effected, however, will depend on the drugs available on the market. The last drug to be introduced to the market was isometamidium (Samorin) and it was introduced in 1961 for prophylaxis. This, therefore, called for the evolution of a new treatment strategy. In the meantime, Whiteside (1962) had introduced the concept of sanative treatment.
Sanative treatment
The concept of sanative treatment prescribes the use of a pair of trypanocides (e.g. Berenil and Homidium) which are chemically unrelated and, therefore, are unlikely to induce cross-resistance. One of the pair is used until resistant strains of trypanosomes appear and then the second is substituted and used until the resistant strains have disappeared from cattle and tsetse (Whiteside, 1962). In Nigeria, while this technique was not used, a similar approach was adopted in 1965 when widespread resistance of T. congolense to homidium compounds dictated a change. Initially Berenil was used for two years, but strains of T. vivax resistant to Berenil soon appeared in the field, thus requiring a change. The evidence was that T. vivax was uniformly susceptible to Homidium treatment while T. congolense was not and that T. vivax was less sensitive to Berenil treatment than was T. congolense. It was therefore decided that Homidium be used when T. vivax was the prevalent trypanosome and Berenil used when T. congolense predominated.
This treatment regime eventually became the trypanosomiasis drug policy of the then Northern Region of Nigeria. This arrangement was found to be more suitable than the Whiteside sanative-pair concept because it has been demonstrated that the resistant nature of trypanosomes was unaffected by passage through tsetse (Gray and Roberts, 1968) or wildlife (Gray and Roberts, 1971). The drug policy prescribed that each of the two curative drugs be used for six months of the year when a species of trypanosomes sensitive to the drug was predominant. For example, T. vivax was found to be generally susceptible to homidium compounds and was the predominant species in cattle when they were withdrawn to the wet-season grazing areas; whereas T. congolense was geneally susceptible to Berenil and was the predominant species in cattle during the dry season when cattle were moved to pastureland in the tsetse belts of the south. This treatment regime was effective for almost ten years before isolates of T. congolense and T. vivax with multiple resistance to curative trypanocides were isolated and subsequently found to be widespread (Ilemobade, 1979). Since there was no drug to fall back upon, the only recourse was to increase the dose of the available trypanocides.
Increased dosage
When trypanocides were first introduced in the market there was some question as to whether sufficient laboratory and field trials had been carried out to justify increased dosages of the drugs recommended for field use by manufacturers. Obviously, because of competition and the pressure for new drugs, manufacturers could not, in the absence of strict registration requirements, wait for extensive trials before launching new trypanocides. That this could be an important consideration was underlined by Davey (1957). However, the recommended increased dosage of trypanocides did not appear to offer a solution as shown by MacLennan and Na-Isa (1970), Leeflang et al. (1977) and Ilemobade (1979).
Repetitive treatments
Repeated treatments of drug-resistant isolates of trypanosomes (T. vivax and T. congolense) have been tried. While they were found to be effective, field applications appeared impractical because of the need for effective monitoring to ensure that animals were treated soon after relapse (Leeflang, 1978; Ilemobade and Na-Isa, 1981).
Use of complexes
The use of complexes was tried with isometamidium chloride-dextran complex, based on the early work of Williamson (1957). A complex can be used at a high enough dosage without the attendant toxic reactions, to cure resistant strains. Initial results have, however, been disappointing (Aliu and Sannusi, 1980).
The foregoing has shown that efforts directed at combating drug resistance have only provided temporary relief. Some of the reasons for this may be attributed to:
(a) only a small number of trypanocides are available on the market for treatment and prophylaxis and several of them share some cross-resistance characteristics (for instance since isometamidium was introduced in 1961, (Berg et al, 1961), no new drug has been introduced into the market);(b) the basic mechanism of drug resistance in trypanosomes is not fully understood and it is only recently that the pharmaco-kinetics are being studies;
(c) certain species of trypanosomes seem to possess some intrinsic resistance to drugs, e.g. T. congolense to Homidium (this may in fact be due to a recent finding which showed that a number of congolense-like trypanosomes found in cattle were in fact T. simian, a trypanosome that responds poorly to drugs); and
(d) lack of effective veterinary supervision in the field during trypanosomiasis treatments leads to abuse and misuse of drugs.
It has been suggested that some of the reported field cases of drug resistance may not be due to drug resistance per se but to the ineffectiveness of the drug during the chronic stage of the infection (Jennings et al., 1977). It was hypothesized that drug failure in T. brucei infection was due to inaccessibility of the drug to tissue stages of trypanosomes or to the insensitivity of some stages in the life-cycle of the trypanosome to the drug. While this may account for some cases of drug resistance reported from the field, it is unlikely to account for the majority of them. If this were so, drug failures would have been more prevalent following introduction of trypanocides than was the case, since most field cases of trypanosomiasis were chronic when presented for treatment. However, the matter of drug resistance in trypanosomiasis requires That we evolve a standardized protocol that can be used to test drug-resistant strains. New techniques which are now available, for example DNA probes, may prove helpful.
Drug resistance in trypanosomiasis is a serious problem. It will continue to remain a critical challenge to the control of the disease until the basic mechanism of resistance is known. In the meantime, the judicious use of trypanocides must be insisted upon so as to limit the spread of resistance. While chemotherapy has a place in the short- and medium-term control of animal trypanosomiasis, greater success will be achieved when it is combined with anti-tsetse measures.
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