African Journal of
Microbiology Research

  • Abbreviation: Afr. J. Microbiol. Res.
  • Language: English
  • ISSN: 1996-0808
  • DOI: 10.5897/AJMR
  • Start Year: 2007
  • Published Articles: 5232

Review

Drug resistance in African animal trypanosomes: A review

Solomon Assefa
  • Solomon Assefa
  • Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
  • Google Scholar
Workineh Shibeshi
  • Workineh Shibeshi
  • Department of Pharmacology and Clinical Pharmacy, College of Health Sciences, Addis Ababa University, Addis Ababa, Ethiopia.
  • Google Scholar


  •  Received: 01 November 2017
  •  Accepted: 30 January 2018
  •  Published: 07 May 2018

 ABSTRACT

Animal African trypanosmiasis (AAT) is the most important factor contributing to the sub potential performance of livestock. AAT is caused by Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei. Chemotherapy and chemoprophylaxis are the major means of combating the disease. An estimated 17 million cattle are treated with trypanocides annually. The emergence of drug-resistant trypanosome strains is considered a serious problem in trypanosomiasis control particularly for the resource-poor, at-risk populations and farmers in Africa. Trypanocidal drug resistance is the decreased or absence of sensitivity of trypanosome strains to standard quality trypanocidal drugs at the dose recommended in a good veterinary practice. Different resistance mechanisms are acquired independently through exposure to different drugs. A good example for this is cross resistance for diminazene and isometamidium. Trypanosomiasis drug resistance has been officially reported in 21 African countries. Moreover, certain African countries reported the presence of multi drug resistance. Safeguarding the available trypanocidal drugs is mandatory to reduce the devastating impact of the disease.

Key words: Resistance, trypanosome, African animal trypanosomiasis.


 INTRODUCTION

African trypanosomes cause human African trypanosomiasis (HAT) and African animal trypanosomiasis (AAT), a debilitating disease of humans and domestic animals in the humid and sub-humid zones of Africa, respectively (Muhanguzi et al., 2015). Most African trypanosomes are transmitted by tsetse flies (Glossinidae), which inhabit in many parts of the continent (Kebede and Animur, 2009). AAT is the most important factor contributing to the sub potential  performance of livestock (Chanie et al., 2013). AAT is caused by Trypanosoma congolense, Trypanosoma vivax and Trypanosoma brucei species. Trypanosoma evansi causes ‘Surra’ in camels (Camelus dromedarieus) (Mbaya et al., 2010). Concurrent infections can occur with more than one species of trypanosome (IICAB, 2009). Even though the name of the disease is called as African trypanosmiasis, T. vivax and T. evansi by virtue of their transmission by haematophagous biting flies also occur in Asia, Central and North and Southern America (Hoare, 1966). The occurrence of animal trypanosomiasis coincides with the distribution of tsetse fly vectors which includes the regions between latitudes 14°N and 29°S (OIE, 2013). AAT causes a great economic loss in the livestock industry with an estimated 3 million cattle death annually. Estimated direct production losses in cattle to African farmers are between 1 and 4 billion US dollars per year (Swallow, 2000; Abebe and Jobre, 1996). Infection of cattle by one or more of the three species results in sub-acute, acute or chronic disease. The cardinal clinical sign observed in AAT is anemia, within a week of infection with T. congolense and T. vivax. Moreover, there is a pronounced decrease in packed cell volume (PCV), hemoglobin and red blood cell count. These manifestations are observed in goats experimentally infected with T. vivax (Osman et al., 2012). Chemotherapy and chemoprophylaxis are the major means of combating the disease. An estimated 17 million cattle are treated with trypanocides annually (Kristjanson et al., 1999). However, effectiveness of these drugs is limited by factors such as parasite resistance (Afework et al., 2000; Melaku and Birrasa, 2013) and unacceptable toxicity (Onyekwelu, 1999). The emergence of drug-resistant trypanosome strains is considered a serious problem in trypanosomiasis control particularly for the resource-poor, at-risk populations and farmers in Africa (Kagira and Maina, 2007). The presence of indiscriminate drug utilization practices and subsequent complaints over the efficacy of the available trypanocidal drugs supplemented the presence of resistant strains (Fiarcloug, 1963).

 


 TRYPANOCIDAL DRUG RESISTANCE

Drug resistance also called drug fastness (Uilenberg, 1998) is the heritable loss of sensitivity of a micro-organism to a drug to which it was sensitive (Sinyangwe et al., 2004). Similarly, trypanocidal drug resistance is defined as the decreased or absence of sensitivity of trypanosome strains to standard quality trypanocidal drugs at the dose recommended by the manufacturer and administered according to the good veterinary practice (Peregrine et al., 1996; Uilenberg, 1998). Information on the extent and significance of the problem of drug resistance is scant (Sinyangwe et al., 2004). Over the last decades there has been a dramatic slowdown in the development of new antimicrobials, which increases the need to preserve existing antimicrobials (Grace, 2015). Due to this, only small group of chemoprophylactic and chemotherapeutic trypanocidal compounds are currently in use and new compounds are unlikely to be available (Barret, 2004). This is also the major limitation of trypanosomiasis treatment, because there is unwillingness of pharmaceutical companies to invest in development of drugs against trypanosomiasis (Geerts et al., 2010). Therefore, the exiting trypanocidal drug should be safeguarded. Moreover, it is clear that medicinal plants play a prominent role against various human and animal diseases. A variety of medicinal plants and plants extracts have been reported for their significant anti-trypanosomal activity (Assefa, 2017). Practically, treatment is mainly carried out by the livestock owners themselves without any supervision by veterinary personnel (Geerts et al., 2010). Consequently, treatment given by livestock owners is not without serious drawbacks because most farmers do not have adequate knowledge on diagnosis and the appropriate drug to use even in areas of high prevalence of trypanosomiasis. Since trypanocides are frequently used in the absence of diagnosis or used to treat conditions of which they are not effective, emergency of resistance is apparent (Holmes et al., 2004). When the trypanosome is resistant to more than one drug, it is considered as multidrug resistant. In this case, different resistance mechanisms are selected independently through exposure to different drugs. A good example for this is cross resistance for dimenazene and isometamidium (Black et al., 2001).  Different factors could affect the development of resistance against trypanocidal drugs; some of the major factors are as shown in Figure 1.

 

 

MECHANISMS AND GENETICS OF RESISTANCE TO TRYPANOCIDES

Diminazene

Diminazene was introduced onto the market as trypanocide for domestic livestock in 1955. But, in initial experiments, the compound was shown to be highly active against both trypanosome and Babesia species. It is the only trypanocidal drug used against Babesia spp. It is one of the most commonly used trypanocide drug (Geerts and Holmes, 1998). This might be due to its higher therapeutic index than other trypanocides in most livestock, low incidence of toxicity (Peregrine and Mamman, 1993) and being active against trypanosomes that are resistant to other trypanocides used in cattle (Williamson, 1970). Even though it has low incidence of resistance, some trypanosomes might have innate resistance subsequent to the first usage of diminazene aceturate in the field. Population of T. congolense and T.vivax were described in Nigeria that appeared to be innately resistant to diminazene (Jones-Davies, 1968). Furthermore, Wiliamson (1960) suggested that west african popluation of T. vivax express a higher level of natural resistance to diminazene than T. congolense. However, whether such resistance is a result of cross-resistnace induced by other drugs such as quinapyramine or natural is not clear (Gray and Roberts, 1971). The accumulation of diminazene has been shown to be markedly reduced in arsenical-resistant T. brucei, T. evansi and T. equiperdum owing to alterations in the P2-type purine transport system (Carter and Fairlamb, 1993; Carter et al., 1995). It is also suspected that diminazene resistance is multi-factorial (Delespaux et al., 2006). The TeDR40 gene, which is a novel gene encoding protein that appeared to have a ubiquitous cellular localization (Witola et al., 2004), might be a contributing factor to resistance linked to the alteration of the gene coding for the P2-type purine transporters. It is probable that diminazene resistance is the result of the cumulative effect of these two distinct resistance mechanisms (TeDR40 and P2-type purine transporter) (Delespaux et al., 2006). It has been urged that diminazene will not promote the development of resistant trypanosome strains even if sub-therapeutic doses are administered. But, resistance development as a result of the use of sub-therapeutic doses of diminazene and/or intensive use of the drug in the strain of T. congolense was reported. Further field studies confirmed the possibility of resistance in sub-therapeutic dose (Mbwambo et al., 1988).

Isometamidium

The amphiphilic cationic phenanthridine, isometamidium chloride, has been used in the field for several decades prophylactically or therapeutically for livestock suffering from trypanosomiasis. It is mainly used against infections with T. congolense and other Trypanosoma species (Leach and Roberts, 1981).  The first case of resistance to homidium and cross-resistance between homidium and isometamidium was reported in 1967 (Delespaux and De Koning, 2007). Decreased levels of drug accumulation have been observed in drug resistant populations of T. congolense (Sutherland et al., 1991). Experimental studies have demonstrated the occurrence of drug resistant trypanosomes to isometamidium (Schonefeld et al., 1987). This has been confirmed and reported by several authors (Codjia et al., 1993; Sinyangwe et al., 2004; Mulugeta et al., 1997). The transport of isometamidium was known to be energy dependent, as it was reduced in the presence of metabolic inhibitors such as SHAM/glycerol (Sutherland and Holmes, 1993). In T. brucei, the P2 adenosine transporter may be responsible for part of the isometamidium uptake as the drug inhibits P2-mediated adenosine uptake (De Koning et al., 2005). The mechanism of resistance to isometamidium chloride, however, is less clear despite certain suggested mechanisms from experimental finding results. Decreased levels of drug accumulation have been observed in drug resistant populations of T. congolense (Sutherland et al., 1991) and later work found indirect evidence of an increased efflux of drug from resistant trypanosomes (Sutherland and Holmes, 1993). Resistance to isometamidium is mostly associated with cross-resistance to homidium (Peregrine et al., 1997), and it could be speculated that these structurally related compounds might share the same uptake mechanism albeit that their distributions within the trypanosome are slightly different. Isometamidium is mainly concentrated in the kinetoplast, whereas homidium spread much more diffuse throughout the trypanosome (Boibessot et al., 2002).

Homidium

Homidium, which were introduced during 1950s, is active against T. congolense and T. vivax infections in cattle. Homidium salts are the main therapeutic drugs used in the management of clinical trypanosomiasis in animals (Holmes et al., 2004). It was widely used during the 1960s but due to the spread of resistance and its mutagenic activity, its use has greatly decreased (Holmes et al., 2004). The first report on the resistance of the drug was reported during 1960s (Jones-Davies, 1968). The resistance mechanism to this drug is still unknown even if some studies suggested that it is similar to isometamidium (Shiferaw et al., 2015). Isometamidium differs from homidium by an additional moiety of m-amidinophenyl-azo-amine. The resistance mechanism thus seems to be specific for the homidium moiety, not the m-amidinophenyl-azo-amine functional group common to diminazene (Wragg et al., 1958).

Quinapyramine

Liao and Shen (2010) tried to look for physical changes, including proteins and genes, involved in the quinapyramine-resistance. Based on the confirmation made by other authors regarding the involvement of some enzymes in the production of drug-resistance in trypanosomes (Venegas and Solari, 1995; Iten et al., 1997), Liao and Shen (2010) detected for some isoenzymes. The enzymes analyzed were isoenzyme bands of hexokinase, glucose-6-phosphate dehydrogenase, alanine transaminase and aspartate aminotransferase, but they showed that the four isoenzymes were not involved in the quinapyramine resistance. And the soluble proteins of the 7 T. evansi lines was studied, their study implied that the two protein bands of 15.79 kDa in the lines, R1, R2, R4, R6 and R7, and 19.76 kDa in the three lines with higher levels of the antrycide resistance.

THE IMPACT OF RESISTANCE

The impact of drug resistant trypanosomes on livestock productivity has been assessed by fewer studies. But, it is imperative to assess not only the distribution of the problem, but also the constraints it encounters on  effective control of the disease and economic impact (Melaku and Birrasa, 2013). Increasing drug resistance increased trypanosome prevalence in cattle three-fold and in tsetse two-fold at a treatment frequency of once-a-month. The benefits of increased trypanocide treatment frequency diminish rapidly with increasing resistance (McDermott et al., 2000). Previous study showed that trypanocidal drug resistance had no significant impact on the PCV and body weight losses of goats infected by T. vivax except for a few highly virulent strains. This conclusion contradicts the general believe that the development of resistance against trypanocides would leave farmers helpless in trypanosome infested areas (Vitouley et al., 2012). A study to assess the impact of drug-resistant trypanosomes on the productivity of the local cattle was carried out by Codjia et al. (1993) in the Ghibe valley, Ethiopia. The area had a high prevalence of multiple drug resistance. In their study, the authors indicated that calf mortality was rather high, incidence of abortion was increased and the financial and economic returns were also affected.

DISTRIBUTION OF TRYPANOCIDAL DRUG RESISTANCE

The problem of drug resistance in animal trypanosomes is highly spreading geographically to many regions in which trypanosomiasis occurs (Grace et al., 2009; Geerts and Holmes, 1998). Decades after first case of drug resistance in trypanosomes, Clausen et al. (1988) confirmed multiple resistance trypanosomes isolates in the pastoral area of Samorogouan in Burkina Faso. Moreover, resistance developed by trypanosomes to trypanocidal drug, has been reported from East Africa (Mulugeta et al., 1997). There is a report on a five-fold increase in the prevalence of dimenazene resistance over a seven year period in the Eastern Province of Zambia, suggesting, there might be a worsening of the problem. Trypanosomiasis drug resistance has been officially reported in 17 African countries (Burkina Faso, Chad, Ivory coast, Ethiopia, Kenya, Mali, Somalia, Sudan, Tanzania, Uganda, Zimbabwe, Zambia, Mozambique, Cameroon, Nigeria, Guinea, and Central African Republic) (Delespaux et al., 2008). But recently, this number is increased to 21 African countries (Tsegaye et al., 2015). In addition, in 10 African countries including Ethiopia (Tsegaye et al., 2015), Sudan (Mohammed-Ahmed et al., 1992), Nigeria and Kenya, multiple drug resistance trypanosomes that decreased sensitivity to the common trypanocidal drugs (dimenazene, isometamidium and homidium) have been reported (Mulugeta et al., 1997; Delespaux et al., 2008). As it is suggested by Delespaux et al. (2008), it is suspected that in several other African countries, resistance is present but is yet to be demonstrated, because in several countries surveys for resistance have not yet been carried out or cases of resistance have not been published (Melaku and Birrasa, 2013). Eze et al. (2015) conducted a study on trypanocidal resistance in trypanosomes isolated from animals to diminazene and isometamidium, in sub humid tropical zone of Southeastern Nigeria.

Their results of the sensitivity tests showed that out of the ten isolates tested, nine were resistant to diminazene aceturate at the dose of 7.0 mg/kg out of which four were slightly resistant whereas all the isolates were sensitive to diminazene at 28 mg/kg. On the other hand, only two isolates were resistant to isometamidium chloride at the dose of 1 mg/kg out of which one was slightly resistant.  Clausen et al. (1988) and Grace et al. (2009) reported for the presence of multiple drug resistant T. congolense in tsetse infested areas of Burkina Faso. Trypanocidal drug resistance appears to be widespread in the Adamaoua, Cameroon. Apparently, the problem is more serious in T. congolense than in T. brucei, which is unfortunate because the former is more pathogenic to cattle than the latter. Qadeer et al. (2015) tested the sensitivity of trypanosome isolates from Nigeria in experimentally induced trypanosomiasis, and their result showed the presence of resistant T. vivax strains to a particular dosage of 3.5 mg/kg diminazene aceturate and to all dosages of isometamidium. Some reports on resistant trypanosomes are shown in Table 1. The two important drugs (dimenazene and isometamidium) have been used for more than 40 years in Ethiopia (Dagnachew et al., 2015). Some studies conducted on the few isolates of T congolense in Ethiopia have shown the prevalence of drug resistance that might pose a higher risk for the tsetse infested areas of the countries (Abebe and Jobre, 1996). Moreover, Afework et al. (2000) and Tewelde et al. (2004) have conducted a large scale survey demonstrating area-wide resistance in at least one region of the country.  The magnitude of drug resistant trypanosomes across Ethiopia is not well documented (Chaka and Abebe, 2003). The dynamic nature of the epidemiology of drug resistant infection in the Ghibe valley, which was reported to be 6% in 1986 and i1989, is increased to 14% (Rowlands et al., 1993). In addition, Mulugeta et al. (1997) indicated a long-term occurrence of T. congolense resistant to diminazene, isometamidium and homidium in cattle of Ghibe, Ethiopia.

 

 

Afework et al. (2000) detected for the presence of resistance in mice using clones of T. congolense which were obtained from the isolates collected from relapsed chattels treated with ismetamidium, in northern western Ethiopia. Those clones found were resistant to both diminazene and isometamidium.In Tigray, Ethiopia, T. vivax has developed resistance to dimenazene and iseomtamidum (Wlyohannes et al., 2010). According to the study, relapse occurred to diminazene aceturate and isomethamidum chloride at 3.5 and 0.25 mg/kg of body weight, respectively.  Different authors have reported the development of drug resistance trypanosomes in Gibhe valley (Codjia et al., 1993; Shimelis et al., 2008). The four isolates of T. congolense from Ghibe, Bedelle, Sodo and Arbaminch regions of Ethiopia were found to be resistant to the curative action of diminazene (in mice and cattle) and isometamidium (in cattle) at a dose rate of 3.5 and 0.5 mg/kg body weight, respectively (Chaka and Abebe, 2003).  Recently, Hagos et al. (2014) tested sensitivity of T. congolense field isolates to isomethamidium and diminazene in Konso district, Southern Ethiopia. The demonstration of resistance to diminazene was about 33% from their study, which also could be to isometamidium. Current T. congolense isolates resistance was unsurprisingly an expected outcome. Dagnachew et al. (2015) also conducted in vivo testing of two isolates of T. vivax from tsetse infested and non-infested areas of Ethiopia. The authors concluded that for the presence of drug resistance T. vivax (more than 20 percent) against recommended doses of both the available trypanocidal drugs.

 

 

 


 CONCLUSION

Treatment of trypanosomiasis is currently facing a number of problems including toxicity of trypanocidal drugs and development of resistance by the parasites. These limitations have prompted the search for alternative active substances (such as of natural origin). Different factors can lead to the development of trypanocidal resistance including the sub-curative dose utilization and mutagenic ability of some of the drugs .Calf mortality can be high, with increased incidence of abortion and the financial and economic returns were also affected due to the prevalence drug resistant strains of trypanosomes. Safeguarding of the currently available drugs is mandatory to preserve the effectiveness of the drugs.

 


 CONFLICT OF INTERESTS

The authors have not declared any conflict of interests.

 



 REFERENCES

Abebe G, Jobre Y (1996). Trypanosomosis: A threat to cattle production in Ethiopia. Rev. Med. Vet. 147:897-902.

 

Afework Y, Clausen PH, Abebe G, Tilahun G, Mahaltiz D (2000). Multiple drug-resistant Trypanosoma congolense populations in village bovine of Metekel district, Northwest Ethiopia. Acta. Trop. 76:231-238.
Crossref

 
 

Assefa S (2017). Potential anti-trypanosomal plants against African animal trypanosomiasis. J. Pharmacogn. Phytochem. 6(5):77-85.

 
 

Barret MP (2004). Future prospects in chemotherapy for trypanosomiaisis in I maudin ph holmes and MA Miles editors, the trypanosomiasis, CABI publishing pp. 445-458.

 
 

Black SJ, Seed JR, Murphy NB (2001). Innate and acquired resistance to African trypanosomiasis. J. Parasitol. 87(1):1-9.
Crossref

 
 

Boibessot I, Turner CM, Watson DG, Goldie E, Connel G, McIntosh A, et al (2002). Metabolism and distribution of phenanthridine trypanocides in Trypanosoma brucei. Acta Trop. 84:219-228.
Crossref

 
 

Carter NS, Fairlamb AH (1993) Arsenical resistant trypanosomes lack an unusual adenosine transporter. Nature 361:173-176.
Crossref0

 
 

Carter NS, Berger BJ, Fairlamb AH (1995). Uptake of diamidine drugs by the P2 nucleoside transporter in melarsen-sensitive and -resistant Trypanosoma brucei brucei. J. Biol. Chem. 270:28153-28157.
Crossref

 
 

Chaka H, Abebe G (2003). Drug resistant trypanosomes: a threat to cattle production in the Southwest of Ethiopia. Revue Élev. Méd vét Pays trop 56(1-2):33-36.
Crossref

 
 

Chanie M, Adula D, Bogale B (2013). Socio-economic assessment of the impacts of trypanosomiasis on cattle in Girja district, Southern Oromia Region, Southern Ethiopia. Acta Parasitologica Globalis 4:80-85.

 
 

Chitanga S, Marcotty T, Namangala B, Van den Bossche P, Van Den Abbeele J (2011). High prevalence of drug resistance in animal trypanosomes without a history of drug exposure. PLoS Negl. Trop. Dis. 5(12):e1454.
Crossref

 
 

Clausen PH, Wiemann A, Patzelt R, Kakaire D, Poetzsch C, Mehlitz D (1988). Use of a PCR assay for the specific and sensitive detection of Trypanosoma spp. in naturally infected dairy cattle in peri-urban Kampala, Uganda. Ann N Y Acad Sci 849:21-31.
Crossref

 
 

Clausen PH, Bauer B, Zessin KH, Diall O, Bocoum Z, Sidibe I, Affognon H, Waibel H, Grace D, Randolph T (2010). Preventing and containing trypanocide resistance in the cotton zone of West Africa. Transbound Emerg Dis 57:28-32.
Crossref

 
 

Codjia V, Mulatu W, Majiwa PA, Leak SG, Rowlands GJ, Authie E, d'Ieteren GDM, Peregrine AS (1993). Epidemiology of bovine trypanosomosis in the Ghibe valley, Southwest Ethiopia. Occurrence of populations of Trypanosoma congolense resistant to diminazene, isometamidium and homidium. Acta Trop 53:151-163.
Crossref

 
 

Dagnachew S, Terefe G, Abebe G, barry D, Mcculloch R, Goddeeris B (2015). In vivo experimental drug resistance study in Trypanosoma vivax isolates from tsetse infested and non-tsetse infested areas of Northwest Ethiopia. Acta Trop. 146:95-100.
Crossref

 
 

De Koning HP, Bridges DJ, Burchmore RJS (2005). Purine and pyrimidine transport in pathogenic protozoa: From biology to therapy. FEMS Microbiol. Rev. 29:987-1020.
Crossref

 
 

Delespaux V, Chitanga S, Geysen D, Goethals A, Van den Bossche P, Geerts S (2006). SSCP analysis of the P2 purine transporter TcoAT1 gene of Trypanosoma congolense leads to a simple PCR-RFLP test allowing the rapid identification of diminazene resistant stocks. Acta Trop 100:96-102.
Crossref

 
 

Delespaux V, De Koning HP (2007) Drugs and drug resistance in African trypanosomiasis. Drug Resist. Updat. 10(1-2):30-50.
Crossref

 
 

Delespaux V, Geysen D, Van den Bossche P, Geerts S (2008). Molecular tools for the rapid detection of drug resistance in animal trypanosomes. Trends Parasitol. 24:236-242.
Crossref

 
 

Eze JI, Ejimonye CC, Ezeh IO (2015). Prevalence and drug sensitivity of trypanosome isolates from slaughter animals to diminazene and isometamidium in sub humid tropical zone of Southeastern Nigeria. Global Veterinaria 14(2):282-286.

 
 

Fiarcloug R (1963). Observation on the use of bernil against trypanosomiasis of cattle in Kenya. Vet. Rec. 75:107.

 
 

Geerts S, Holmes PH (1998). Drug management and parasite resistance in animal trypanosomiasis in Africa. Position Paper-Programme Against African Trypanosomiasis (PAAT), Technical series, FAO, Rome, Italy. P 22.

 
 

Geerts S, Delespaux V, Van den Bossche P (2010). Drug Resistance in Trypanosomes of Livestock: A Worrying Issue. Bull. Séanc. Acad R Sci Outre-MerMeded 55:177-184.

 
 

Grace D (2015). Review of evidence on antimicrobial resistance and animal agriculture in developing countries. UK: Evidence on Demand.
Crossref

 
 

Grace D, Randolph, Affognon H, Dramane D, Diall O, Clausen PH (2009). Characterisation and validation of farmers' knowledge and practice of cattle trypanosomosis management in the cotton zone of West Africa. Acta Trop. 111:137-143.
Crossref

 
 

Gray AR, Roberts CJ (1971). The cyclical transmission of strains of trypanosome congolense and t. vivax resistant to normal therapeutid doses of trypnocidal drugs. Parsitol 63:67-81.
Crossref

 
 

Gray MA, Kimarua RW, Peregrine AS, Stevenson P (1993). Drug sensitivity screening in vitro of populations of Trypanosoma congolense originating from cattle and tsetse flies at Nguruman, Kenya. Acta Trop. 55:1-9.
Crossref

 
 

Hagos A, Gewado A. and Yacob HT (2014). Sensitivity of Trypanosoma congolense field isolates in experimentally infected calves in Konso district, Southern Ethiopia to isomethamidium and diminazen. J. Vet. Med Anim. Health 6(1):44-47.
Crossref

 
 

Hoare CA (1966). The classification of mammalian trypanosomes. Ergeb Mikrobiol Immunitatsforsch Exp. Ther. 39:43-57.
Crossref

 
 

Holmes PH, Eisler MC, Geerts S (2004) Current Chemotherapy of Animal Trypanosomiasis. In: Ian Maudlin, Peter H. Holmes and Michael A. Miles (eds.). The Trypanosomiasis. CABI International. Wallingford, UK. pp. 431-444.
Crossref

 
 

Institute for international cooperation in animal biologics (IICAB) (2009). 

View. accesed on March 3 2016

 
 

Iten M, Mett H, Evans A, Enyaru JC, Brun R, Kaminsky R (1997). Alterations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodesiense to d, l-alpha-difluoromethylornithine. Antimicrob Agents Chemother 41:1922-1925.

 
 

Jamal S, Sigauque I, Macuamule C, Neves L, Penzhorn BL, Marcotty T, Van Den Bossche P (2005). The susceptibility of T. congolense isolated in Zambézia Province, Mozambique, to isometamidium chloride, diminazene aceturate and homidium chloride. J. Vet. Res. 72:333-338.
Crossref

 
 

Jones-Davies WJ (1968). Berenil resistance in naturally occurring Trypanosoma congolense. Bull Epizoot Dis. Afr. 16(2):213-216.

 
 

Joshua RA, Obwolo M, Bwangamoi O, Mandebvu E (1995). Resistance to diminazine aceturate by Trypanosoma congolense from cattle in the Zambezi Valley of Zimbabwe. Vet. Parasitol. 60(1-2):1-6.
Crossref

 
 

Kagira JM, Maina N (2007). Occurrence of multiple drug resistance in Trypanosoma brucei rhodesiense isolated from sleeping sickness patients. Onderstepoort J. Vet. Res. 74:17-22.

 
 

Kazibwe AJN, Nerima B, de Koning HP, Mäser P, Barrett MP, Matovu E (2009) Genotypic Status of the TbAT1/P2 Adenosine Transporter of Trypanosoma brucei gambiense Isolates from Northwestern Uganda following Melarsoprol Withdrawal. PLoS Negl. Trop. Dis3(9):e523.
Crossref

 
 

Kebede N, Animur A (2009) trypanosomiais of cattle in selected districts of Awi zone, Northwestern Ethiopia. Trop. Anim. Health Prod. 41:1353-1356.
Crossref

 
 

Kristjanson PM, Swallow BM, Rowlands GJ, Kruska RL, de Leeuw PN (1999). Measuring the costs of African animal trypanosomosis, the potential benefits of control and returns to research. Agric. Syst. 59:79-98.
Crossref

 
 

Leach TM, Roberts CJ (1981). Present status of Chemotherapy and Chemoprophylaxis of Animal Trypanosomiasis in the eastern hemisphere. Pharmacol. Ther. 13:91-147.
Crossref

 
 

Liao D, Shen J (2010). Studies of quinapyramine-resistance of Trypanosoma brucei evansi in China. Acta Trop. 116(3):173-177.
Crossref

 
 

Mbaya AW, Ibrahim UI, Apagu ST (2010). Trypanosomiasis of the dromedary camel (Camelus dromedarius) and its vectors in the tsetse-free arid zone of Northeastern, Nigeria. Nig. Vet. J. 31(3):195-200.

 
 

Mbwambo HA, Mella PNP, Lekaki KA (1988). Berenil (diminazene aceturate)-resistant Trypanosoma congolense in cattle under natural tsetse challenge at Kibaha, Tanzania. Acta Trop. 45:239-44.

 
 

Melaku A, Birrasa B (2013). Drugs and drug resistance in African animal Trypanosomosis: A review. Eur. J. Appl. Sci. 5:84-91.

 
 

Mohammed-Ahmed MM, Rahman AHA, Karim EIA (1992) Multiple drug-resistant bovine trypanosomes in south Darfur Province Sudan. Trop. Anim. Health Prod. 24(3):179-181.
Crossref

 
 

Moti Y, Fikru R, Van Den Abbeele J, Büscher P, Van den Bossche P, Duchateau L, Delespaux V (2012). Ghibe river basin in Ethiopia: Present situation of trypanocidal drug resistance in Trypanosoma congolense using tests in mice and PCR-RFLP. Vet. Parasitol. 189:197-203.
Crossref

 
 

Muhanguzi D, Okello WO, Kabasa JD, Waiswa C, Welburn SC, Shaw APM (2015). Cost analysis of options for management of African animal Trypanosomiasis using interventions targeted at cattle in Tororo district; South-eastern Uganda. Parasit. Vectors 8:387.
Crossref

 
 

Mulugeta W, Wilkes J, Mulatu W, Majiwa PAO, Masake R, Peregrine AS (1997). Long-term occurrence of Trypanosoma congolense resistant to diminazene, isometamidium and homidium in cattle at Ghibe, Ethiopia. Acta Trop. 64:205-217.
Crossref

 
 

Mungube EO, Vitouley HS, Cudjoe EA, Diall O, Boucoum Z, Diarra B, Sanogo Y, Randolph T, Bauer B, Zessin KH, Clausen PH (2012). Detection of multiple drugresistant Trypanosoma congolense populations in village cattle of south-east Mali. Parasit. Vectors 5:155.
Crossref

 
 

Onyekwelu NA (1999). Toxicity of existing trypanocides. A review. West Afr. J. Pharmacol. Drug. Res. 15:1-6.

 
 

Osman NM, Fadl M, Rahman AH (2012). Hematological profile and parasitological diagnosis of Trypanosoma vivax infection in Sudanese Nubian goats. J. Vet. Med. Anim. Prod. 3(1):28-45.

 
 

Peregrine AS, Gray MA, Moloo SK (1997). Cross-resistance associated with development of resistance to isometamidium in a clone of Trypanosoma congolense. Antimicrob. Agents Chemother. 41:1604-1606.

 
 

Peregrine AS, Mamman M (1993). Pharmacology of diminazene: A review. Acta Trop. 54:185-203.
Crossref

 
 

Qadeer MA, Adamu T, Gumel MA, Nganjiwa J (2015). Sensitivity of bovine Trypanosoma vivax isolate using three trypanocidal drugs in experimentally induced caprine trypanosomosis. Int. J. Sci. Res. 4(3):2343-2352.

 
 

Rowlands GJ, Mulatu W, Authie E, D'ieteren GDM, Leak SGA, Nagda SM, Peregrine AS (1993). Epidemiology of bovine trypanosomiasis in the Ghibe valley, southwest Ethiopia. 2. Factors associated with variations in trypanosome prevalence, incidence of new infections and prevalence recurrent infections. Acta trop 53:135-150.
Crossref

 
 

Schonefeld AR, Rottcher D, Moloo SK (1987). The sensitivity of trypanocidal drugs of Trypanosoma vivax isolated in Kenya and Somalia. Trop. Med. Parasitol. 38:177-180.

 
 

Shiferaw S, Muktar Y, Belina DA (2015). Review on trypanocidal drug resistance in Ethiopia. J. Parasitol. Vector Biol. 7(4):58-66.

 
 

Shimelis D, Arun KS, Getachew A (2008). Assessment of trypanocidal drug resistance in cattle of the Abay (Blue Nile) basin areas of Northwest Ethiopia. Ethiop. Vet. J. 12:45-59.

 
 

Sinyangwe L, Delespaux V, Brandt J, Geerts S, Mubanga J, Machila N, Holmes PH, Eisler MC (2004). Trypanocidal drug resistance in eastern province of Zambia. Vet. Parasitol. 119:125-135.
Crossref

 
 

Sow A, Sidibe I, Bengaly Z, Marcotty T, Sere M, Diallo A, Vitouley HS, Nebié RL, Ouédraogo M, Akoda GK, Van den Bossche P, Van Den Abbeele J, De Deken R, Delespaux V (2012). Field detection of resistance to isometamidium chloride and diminazene aceturate in Trypanosoma vivax from the region of the Boucle du Mouhoun in Burkina Faso. Vet. Parasitol. 187:105-111.
Crossref

 
 

Sutherland IA, Holmes PH (1993). Alterations in drug transport in resistant Trypanosoma congolense. Acta Trop. 54(3-4):271-278.
Crossref

 
 

Sutherland IA, Peregrine AS, Lonsdale-Eccles JD, Holmes PH (1991). Parasitol. 103:245-251.
Crossref

 
 

Tewelde N, Abebe G, Eisler MC, McDermott J, Greiner M, Afework Y, Kyule M., Münstermann S, Zessin K, Clausen P (2004). Application of field methods to assess isometamidium resistance of trypanosomes in cattle in Western Ethiopia. Acta Trop. 90:163-170.
Crossref

 
 

Tsegaye B, Dagnachew S, Terefe G (2015). Review on Drug Resistant Animal Trypanosomes in Africa and Overseas. Afr. J. Basic Appl. Sci. 7:73-83.

 
 

Uilenberg G (1998). A field guide for the diagnosis, treatment and prevention of African Animal Trypanosomosis. Food and Agriculture Organization of the United Nations, Rome. (ISBN 92-5-104238-1). 157p.

 
 

Venegas J, Solari A (1995). Purification and characterization of a beta-like DNA polymerase from Trypanosoma cruzi. Mol. Biochem. Parasitol. 73:53-62.
Crossref

 
 

Vitouley HS, Sidibe I, Bengaly Z, Marcotty T, Van Den Abbeele J, Delespaux V (2012). Is trypanocidal drug resistance a threat for livestock health and production in endemic areas? Food for thoughts from Sahelian goats infected by Trypanosoma vivax in Bobo Dioulasso (Burkina Faso). Vet Parasitol 190:349-354.
Crossref

 
 

W/yohannes D, Etsay K, Getachew A (2010). Study on the assessment of drug resistance on Trypanosoma vivax in Tselemti woreda, Tigray, Ethiopia. Ethiop. Vet. J. 14(1):15-30.

 
 

Williamson J (1970). Review of chemotherapeutic and chemoprophylactic agents. In: the African trypanosomiasis ed. Mulligan, H.w Allen and Unwin London. pp. 125-221.

 
 

Witola WH, Inoue N, Ohashi K, Onuma M (2004). RNA-interference silencing of the adenosine transporter-1 gene in Trypanosoma evansi confers resistance to diminazene aceturate. Exp. Parasitol. 107:47-57.
Crossref

 
 

Wragg WR, Washbourn K, Brown KN, Hill J (1958). Metamidium: A new trypanocidal drug. Nature 182:1005-1006.
Crossref

 

 




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