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245ISSN 0372-5480Printed in Croatia

VETERINARSKI ARHIV 88 (2), 245-270, 2018

Chemotherapeutic control of trypanosomosis - a review of past Chemotherapeutic control of trypanosomosis - a review of past measures, current status and future trends measures, current status and future trends

Kingsley I. Eghianruwa*, and Olayinka A. OridupaKingsley I. Eghianruwa*, and Olayinka A. Oridupa

Department of Veterinary Physiology, Biochemistry and Pharmacology, University of Ibadan, NigeriaDepartment of Veterinary Physiology, Biochemistry and Pharmacology, University of Ibadan, Nigeria________________________________________________________________________________________________________________________________________________________________________________EGHIANRUWA, K. I., O. A. ORIDUPA: EGHIANRUWA, K. I., O. A. ORIDUPA: Chemotherapeutic control of Chemotherapeutic control of trypanosomosis - a review of past measures, current status and future trends. Vet. trypanosomosis - a review of past measures, current status and future trends. Vet. arhiv 88, 245-270, 2018.arhiv 88, 245-270, 2018.

ABSTRACTABSTRACTAfrican trypanosomosis is a major parasitic disease which affects both humans and animals in the Africa African trypanosomosis is a major parasitic disease which affects both humans and animals in the Africa

continent, south of the Sahara desert. It is caused by infection with various species of trypanosome that are continent, south of the Sahara desert. It is caused by infection with various species of trypanosome that are transmitted to the host through the bite of an infected vector, the tsetse fl y. Efforts to control the disease have transmitted to the host through the bite of an infected vector, the tsetse fl y. Efforts to control the disease have involved attempts to reduce the vector population by use of traps, insecticide application, the sterile male involved attempts to reduce the vector population by use of traps, insecticide application, the sterile male technique as well as treatment and prophylaxis of overt cases with chemotherapeutic drugs, consisting mainly technique as well as treatment and prophylaxis of overt cases with chemotherapeutic drugs, consisting mainly of isometamidium, homidium, quinapyramine and diminazene. These drugs have been in use for over 50 years of isometamidium, homidium, quinapyramine and diminazene. These drugs have been in use for over 50 years and are associated with severe toxicity and parasite resistance. Over the years, efforts in several laboratories and are associated with severe toxicity and parasite resistance. Over the years, efforts in several laboratories to formulate new treatment profi les through pharmacokinetic studies of the trypanocides, combination to formulate new treatment profi les through pharmacokinetic studies of the trypanocides, combination therapy, use of medicinal plants and application of antioxidants, have not succeeded in eradicating the threat therapy, use of medicinal plants and application of antioxidants, have not succeeded in eradicating the threat of the disease. The development of an effective vaccine has also not been successful due to the antigenic of the disease. The development of an effective vaccine has also not been successful due to the antigenic variation of the trypanosome surface coat, a condition that has stifl ed progress, if not totally halted vaccine variation of the trypanosome surface coat, a condition that has stifl ed progress, if not totally halted vaccine development. However, more recent studies suggest the trypanosomal microtubulin could be a viable antigen development. However, more recent studies suggest the trypanosomal microtubulin could be a viable antigen for vaccine development. This review focuses on measures that have been undertaken to control Animal African for vaccine development. This review focuses on measures that have been undertaken to control Animal African Trypanosomosis by chemotherapy, and discusses future measures and prospects since the measures adopted so Trypanosomosis by chemotherapy, and discusses future measures and prospects since the measures adopted so far have not successfully controlled the disease. far have not successfully controlled the disease.

Key words: Key words: chemotherapy; trypanosomosis; control measures; sanative pair; combination therapy; chemotherapy; trypanosomosis; control measures; sanative pair; combination therapy; medicinal plants; antigenic variation; tubulin antigenmedicinal plants; antigenic variation; tubulin antigen________________________________________________________________________________________________________________________________________________________________________________

Introduction Introduction

PreamblePreambleAfrican trypanosomosis is a disease complex of both humans and animals in the African trypanosomosis is a disease complex of both humans and animals in the

African continent, south of the Sahara. It is caused by infection with various species African continent, south of the Sahara. It is caused by infection with various species *Corresponding author:Kingsley I. Eghianruwa, Department of Veterinary Physiology, Biochemistry and Pharmacology, University of Ibadan, Nigeria, Phone: +234 80 2122 9722; E-mail: [email protected]

DOI: DOI: 10.24099/vet.arhiv.161115a

246 Vet. arhiv 88 (2), 245-270, 2018

K. I. Eghianruwa et al.: Chemotherapeutic control of trypanosomosis - a review of past measures, current status and future trends

of blood and tissue dwelling protozoan parasites of the genus Trypanosoma, that are of blood and tissue dwelling protozoan parasites of the genus Trypanosoma, that are transmitted by multiple species of the tsetse fl y (Glossina spp.) which inhabit about half transmitted by multiple species of the tsetse fl y (Glossina spp.) which inhabit about half the non-desert area of Africa. Animal species vary in their susceptibility to the different the non-desert area of Africa. Animal species vary in their susceptibility to the different species of trypanosomes. Cattle, sheep and goats are most commonly infected by species of trypanosomes. Cattle, sheep and goats are most commonly infected by T. T. congolensecongolense (GROOTENHUIS et al., 1990; SAMDI et al., 2011), (GROOTENHUIS et al., 1990; SAMDI et al., 2011), T. vivaxT. vivax (WELLDE (WELLDE et al., 1989; KIMETO et al., 1990), and et al., 1989; KIMETO et al., 1990), and T. brucei bruceiT. brucei brucei (WELLDE et al., 1989). (WELLDE et al., 1989). Trypanosoma simiaeTrypanosoma simiae is the major cause of infection in pigs (ONAH, 1991). Horses are is the major cause of infection in pigs (ONAH, 1991). Horses are infected by infected by T. equiperdumT. equiperdum (SNOW et al., 1996; FAYE et al., 2001), causing a form of (SNOW et al., 1996; FAYE et al., 2001), causing a form of the disease called “dourine” which is sexually transmitted. Horses have been observed to the disease called “dourine” which is sexually transmitted. Horses have been observed to be infected by be infected by T. congolenseT. congolense, , T. b. bruceiT. b. brucei and and T. vivaxT. vivax with an infection rate of 31% for with an infection rate of 31% for T. congolenseT. congolense, 87% for , 87% for T. vivaxT. vivax and 18% for and 18% for T. bruceiT. brucei sp. (SNOW et al., 1996; FAYE et sp. (SNOW et al., 1996; FAYE et al., 2001; DHOLLANDER et al., 2006; PINCHBECK et al., 2008). al., 2001; DHOLLANDER et al., 2006; PINCHBECK et al., 2008). Trypanosoma evansiTrypanosoma evansi causes surra in a wide variety of wild and domestic animals, including equines, camels, causes surra in a wide variety of wild and domestic animals, including equines, camels, goats, sheep, cattle, buffaloes, pigs, dogs, tigers and elephants (GUTIERREZ et algoats, sheep, cattle, buffaloes, pigs, dogs, tigers and elephants (GUTIERREZ et al.., 2008; , 2008; RATHORE et al., 2016). RATHORE et al., 2016). Trypanosoma evansiTrypanosoma evansi is mechanically transmitted by blood- is mechanically transmitted by blood-sucking fl ies, such as Tabanus and Stomoxys species, and its ability to infect human sucking fl ies, such as Tabanus and Stomoxys species, and its ability to infect human beings has been reported (RATHORE et albeings has been reported (RATHORE et al.,., 2016). Chickens are naturally resistant to the 2016). Chickens are naturally resistant to the disease (JOSHUA, 1982). In humans, disease (JOSHUA, 1982). In humans, T. brucei rhodesienseT. brucei rhodesiense is responsible for an acute is responsible for an acute form of trypanosomosis in Eastern and Southern Africa (FEVRE et al., 2005), while form of trypanosomosis in Eastern and Southern Africa (FEVRE et al., 2005), while T. T. b. gambienseb. gambiense causes a chronic form in West and Central Africa (SMITH et al., 1998; causes a chronic form in West and Central Africa (SMITH et al., 1998; MAUDLIN, 2006). Sporadic reports have appeared of other trypanosome species causing MAUDLIN, 2006). Sporadic reports have appeared of other trypanosome species causing the disease in humans. These include the disease in humans. These include T. congolenseT. congolense (TRUC et al., 1998) and (TRUC et al., 1998) and T. evansiT. evansi (JOSHI et al(JOSHI et al.,., 2005; WABALE et al., 2015; CHAU et al., 2016). 2005; WABALE et al., 2015; CHAU et al., 2016). Trypanosoma barrettoiTrypanosoma barrettoi has been isolated from the blood of fi sh (LOPES et al., 1990). Animal reservoirs play an has been isolated from the blood of fi sh (LOPES et al., 1990). Animal reservoirs play an important role in the epidemiology of both animal and human trypanosomosis (NJIOKOU important role in the epidemiology of both animal and human trypanosomosis (NJIOKOU et alet al.,., 2006; SIMO et al., 2006). Wild animals can also suffer from trypanosomosis, 2006; SIMO et al., 2006). Wild animals can also suffer from trypanosomosis, although they generally have greater tolerance to the disease than domestic animals. although they generally have greater tolerance to the disease than domestic animals.

Animal African trypanosomosis has been a major constraint to agricultural production Animal African trypanosomosis has been a major constraint to agricultural production in about 10 million Kmin about 10 million Km22 of sub-Saharan Africa (LUCKINS, 1992; ILRI, 1996). Over 40 of sub-Saharan Africa (LUCKINS, 1992; ILRI, 1996). Over 40 million head of Africa’s cattle population are kept in tsetse infested areas (BUDD, 1999)million head of Africa’s cattle population are kept in tsetse infested areas (BUDD, 1999).. Cattle living in areas where trypanosomosis is endemic are 20% less productive in terms Cattle living in areas where trypanosomosis is endemic are 20% less productive in terms of meat and milk production than herds living in tsetse and trypanosomosis-free areas of meat and milk production than herds living in tsetse and trypanosomosis-free areas (BUDD, 1999). It has been estimated that direct losses due to trypanosomosis, in the areas (BUDD, 1999). It has been estimated that direct losses due to trypanosomosis, in the areas of meat, milk, traction power, and control programs, amount to US$ 500 million and indirect of meat, milk, traction power, and control programs, amount to US$ 500 million and indirect losses resulting from the inability to keep livestock and grow food because of poor human losses resulting from the inability to keep livestock and grow food because of poor human health, amount to US$ 5 billion per annum (ILRI, 1997). health, amount to US$ 5 billion per annum (ILRI, 1997).

Concerted efforts to control trypanosomosis have been going on over the past century Concerted efforts to control trypanosomosis have been going on over the past century (DREWS, 2004). Numerous methods of control have been developed, yet the disease has (DREWS, 2004). Numerous methods of control have been developed, yet the disease has

247Vet. arhiv 88 (2), 245-270, 2018


proved very diffi cult to eradicate. Ironically, trypanosomes were among the fi rst organisms proved very diffi cult to eradicate. Ironically, trypanosomes were among the fi rst organisms to be targeted by synthetic drugs. Paul Ehrlich, ‘the father of chemotherapy’, chose these to be targeted by synthetic drugs. Paul Ehrlich, ‘the father of chemotherapy’, chose these organisms as a model on which to test his ideas (DREWS, 2004). Chemotherapy has organisms as a model on which to test his ideas (DREWS, 2004). Chemotherapy has been a major component in the control of trypanosomosis but no new trypanocide has been a major component in the control of trypanosomosis but no new trypanocide has been introduced into the fi eld since the early 1960s (ONYIAH, 1997). This is partly been introduced into the fi eld since the early 1960s (ONYIAH, 1997). This is partly because of the prohibitive cost of discovering, developing and introducing new drugs because of the prohibitive cost of discovering, developing and introducing new drugs onto the market (GEERTS et al., 2001; LINARES et alonto the market (GEERTS et al., 2001; LINARES et al.,., 2006). For instance, in 1975, 2006). For instance, in 1975, the $1 billion spent on drug research and development in the USA yielded only seven the $1 billion spent on drug research and development in the USA yielded only seven drug entities, in sharp contrast to the situation in the 1950s in which about forty new drug entities, in sharp contrast to the situation in the 1950s in which about forty new drug entities were introduced yearly, with a total annual research and expenditure of drug entities were introduced yearly, with a total annual research and expenditure of less than $100 million (TROUILLER and OLLIARO, 1999). This situation is partly due less than $100 million (TROUILLER and OLLIARO, 1999). This situation is partly due to the scope of testing required by the regulatory bodies, with the consequent increase to the scope of testing required by the regulatory bodies, with the consequent increase in expenditure. The huge capital required by the developed economies to develop new in expenditure. The huge capital required by the developed economies to develop new trypanocides is regarded as hardly worth it because the political and economic situations trypanocides is regarded as hardly worth it because the political and economic situations in the countries where trypanocides are required are not encouraging (MURGOLO et in the countries where trypanocides are required are not encouraging (MURGOLO et al., 1989; GEERTS et al., 2001). Human African trypanosomiasis (HAT) has thus been al., 1989; GEERTS et al., 2001). Human African trypanosomiasis (HAT) has thus been classifi ed as a neglected disease (REMME et al., 2002). BARRETT et alclassifi ed as a neglected disease (REMME et al., 2002). BARRETT et al.., (2007) defi ne , (2007) defi ne neglected diseases as those ailments which affect people from among the world’s poorest neglected diseases as those ailments which affect people from among the world’s poorest populations, for which satisfactory treatment does not exist, but for which the investment populations, for which satisfactory treatment does not exist, but for which the investment required to bring new compounds to the market has proven a major disincentive to drug required to bring new compounds to the market has proven a major disincentive to drug development. development.

Chemotherapy of trypanosomosisChemotherapy of trypanosomosisChemotherapy and chemoprophylaxis of animal trypanosomosis rely on the use of Chemotherapy and chemoprophylaxis of animal trypanosomosis rely on the use of

trypanocidal drugs. They are the mainstay of trypanosomosis control measures (ONYIAH, trypanocidal drugs. They are the mainstay of trypanosomosis control measures (ONYIAH, 1997; BARRETT et al., 2007) and will probably remain so for a long time, in spite of the 1997; BARRETT et al., 2007) and will probably remain so for a long time, in spite of the problems of drug resistance and toxicity (ROSS and TAYLOR, 1990; GEERTS et al., 2001; problems of drug resistance and toxicity (ROSS and TAYLOR, 1990; GEERTS et al., 2001; BALDISSERA et al., 2016a) because drugs are the only method of control readily available BALDISSERA et al., 2016a) because drugs are the only method of control readily available to individual farmers. to individual farmers.

The drugs currently in use in animal trypanosomosis include: diminazene aceturate The drugs currently in use in animal trypanosomosis include: diminazene aceturate (Berenil(Berenil), isometamidium chloride (Samorin), isometamidium chloride (Samorin), homidium chloride (Novidium), homidium chloride (Novidium), homidium ), homidium bromide (Ethidiumbromide (Ethidium), quinapyramine methylsulfate (Antrycide), quinapyramine methylsulfate (Antrycide), and quinapyramine ), and quinapyramine methylsulfate/chloride (Antrycide prosaltmethylsulfate/chloride (Antrycide prosalt). Of these, only Berenil and Samorin are ). Of these, only Berenil and Samorin are commonly available. Berenil is used exclusively as a therapeutic agent, while Samorin has commonly available. Berenil is used exclusively as a therapeutic agent, while Samorin has both prophylactic and curative properties. Homidium has limited prophylactic properties. both prophylactic and curative properties. Homidium has limited prophylactic properties. Table 1 shows the list of drugs that have been used in the treatment of Animal African Table 1 shows the list of drugs that have been used in the treatment of Animal African Trypanosomosis (AAT). These trypanocides have been in use for over 50 years. Today, Trypanosomosis (AAT). These trypanocides have been in use for over 50 years. Today,

248 Vet. arhiv 88 (2), 245-270, 2018


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249Vet. arhiv 88 (2), 245-270, 2018


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250 Vet. arhiv 88 (2), 245-270, 2018


parasite resistance to these drugs is widely reported (AFEWERK et al., 2000; ANENE et al., parasite resistance to these drugs is widely reported (AFEWERK et al., 2000; ANENE et al., 2001; KAGIRA and MAINA, 2007; SHIFERAW et al., 2015). 2001; KAGIRA and MAINA, 2007; SHIFERAW et al., 2015).

A relatively new, water-soluble trivalent arsenical agent, melarsamine hydrochloride, A relatively new, water-soluble trivalent arsenical agent, melarsamine hydrochloride, has been evaluated as a trypanocide. Melarsamine hydrochloride is a melaminophenylarsine has been evaluated as a trypanocide. Melarsamine hydrochloride is a melaminophenylarsine compound made by conjugation of one equivalent of melarsen oxide and two equivalents of compound made by conjugation of one equivalent of melarsen oxide and two equivalents of cysteamine. It was patented in 1985 under the trade name Cymelarsan (Rhone Merieux, cysteamine. It was patented in 1985 under the trade name Cymelarsan (Rhone Merieux, France). It has been shown to be very effective against France). It has been shown to be very effective against T. brucei brucei, T. evansiT. brucei brucei, T. evansi, and , and T. equiperdumT. equiperdum in camels, buffalo, goats, and pigs (LUN et al., 1991; OTSULYA et al., in camels, buffalo, goats, and pigs (LUN et al., 1991; OTSULYA et al., 1992; ZWEYGARTH et al., 1992). YOUSSIF et al. (2008) reported that cymelarsan was 1992; ZWEYGARTH et al., 1992). YOUSSIF et al. (2008) reported that cymelarsan was effective at a single dose of 0.25-0.625 mg/kg in Nubian goats infected with effective at a single dose of 0.25-0.625 mg/kg in Nubian goats infected with T. evansiT. evansi. . The authors also observed that the single dosage of 1.25 mg/kg and the multiple dosages The authors also observed that the single dosage of 1.25 mg/kg and the multiple dosages were toxic and fatal, and that the drug has an accumulative effect. Cymelarsan was also were toxic and fatal, and that the drug has an accumulative effect. Cymelarsan was also found to be effective against diminazene aceturate-resistant found to be effective against diminazene aceturate-resistant T. brucei brucei and T. evansiT. brucei brucei and T. evansi (ZHANG et al., 1992). ANENE et al(ZHANG et al., 1992). ANENE et al.. (1999) evaluated the effi cacy of Cymelarsan, (1999) evaluated the effi cacy of Cymelarsan, against against T. bruceiT. brucei infection in mice and dogs, and observed improvements in their clinical infection in mice and dogs, and observed improvements in their clinical condition as well as weight gains in treated dogs. On the basis of the results from the condition as well as weight gains in treated dogs. On the basis of the results from the evaluation experiments, MelCy was licensed for use against trypanosomosis in animals. evaluation experiments, MelCy was licensed for use against trypanosomosis in animals. Recently, HAGOS et al. (2010) also found Cymelarsan to be quite effective in curing Recently, HAGOS et al. (2010) also found Cymelarsan to be quite effective in curing horses with the acute as well as the chronic form of dourine. horses with the acute as well as the chronic form of dourine.

Attempts at improving the effi cacy of trypanocidal drugsAttempts at improving the effi cacy of trypanocidal drugsIn the absence of new drugs, it was deemed necessary by several researchers to In the absence of new drugs, it was deemed necessary by several researchers to

formulate new treatment protocols to improve the effi cacy of the existing drugs. The goals formulate new treatment protocols to improve the effi cacy of the existing drugs. The goals have been to elucidate the pharmacokinetics of trypanocides; formulate an inexpensive, have been to elucidate the pharmacokinetics of trypanocides; formulate an inexpensive, non-toxic, easy to administer chemotherapeutic drug, or to create a medium that would non-toxic, easy to administer chemotherapeutic drug, or to create a medium that would enhance the effi cacy of the existing trypanocides. Some of the foci of research included:enhance the effi cacy of the existing trypanocides. Some of the foci of research included:

Pharmacokinetic studies on available trypanocides to improve our understanding and Pharmacokinetic studies on available trypanocides to improve our understanding and enable a reassessment of the dosages and treatment protocol.enable a reassessment of the dosages and treatment protocol.

Complexation of trypanocides with adjuvants.Complexation of trypanocides with adjuvants.The use of a sanative pair. The use of a sanative pair. The use of hyperosmolar agents to enhance drug distribution and penetration into the The use of hyperosmolar agents to enhance drug distribution and penetration into the

brain.brain.The use of combination therapy involving trypanocides, antioxidants and natural The use of combination therapy involving trypanocides, antioxidants and natural

products. products.

Pharmacokinetic studies Pharmacokinetic studies In line with the objective of a better understanding of the pharmacokinetics of In line with the objective of a better understanding of the pharmacokinetics of

trypanocides, and reassessment of dosages and treatment protocols, the pharmacokinetic trypanocides, and reassessment of dosages and treatment protocols, the pharmacokinetic profi le of diminazene aceturate (DMA) was intensively studied in several animal profi le of diminazene aceturate (DMA) was intensively studied in several animal

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species, including rabbits (GILBERT, 1983), monkeys (RAETHER et al., 1974), cattle species, including rabbits (GILBERT, 1983), monkeys (RAETHER et al., 1974), cattle (MAMMAN et al., 1993; ALIU et al., 1993), dogs (ONYEYILI and ANIKA, 1989, 1991), (MAMMAN et al., 1993; ALIU et al., 1993), dogs (ONYEYILI and ANIKA, 1989, 1991), goats (ALIU et algoats (ALIU et al.,., 1984; ONYEYILI et al., 2002), sheep (ALIU and ǾDEGAARD, 1984; ONYEYILI et al., 2002), sheep (ALIU and ǾDEGAARD, 1985), and rats (ODIKA et al., 1995). Absorption of diminazene aceturate through the 1985), and rats (ODIKA et al., 1995). Absorption of diminazene aceturate through the oral route has been recorded in some animal species, including rats (RAETHER et al., oral route has been recorded in some animal species, including rats (RAETHER et al., 1974; KELLNER et al., 1985) and monkeys (RAETHER et al., 1974).1974; KELLNER et al., 1985) and monkeys (RAETHER et al., 1974).

It was observed that DMA (3.5 mg/kg) administered intravenously to mongrel It was observed that DMA (3.5 mg/kg) administered intravenously to mongrel dogs after infection with dogs after infection with T. congolenseT. congolense was rapidly distributed in the body. However, was rapidly distributed in the body. However, the infection had no marked infl uence on the urinary excretion of the drug, whereas the infection had no marked infl uence on the urinary excretion of the drug, whereas intravenous administration of DMA 3.5 mg/kg in intravenous administration of DMA 3.5 mg/kg in T. b. bruceiT. b. brucei infected mongrel dogs infected mongrel dogs signifi cantly altered the kinetic disposition of DMA (ONYEYILI and ANIKA, 1989). signifi cantly altered the kinetic disposition of DMA (ONYEYILI and ANIKA, 1989). The distribution half-life of the drug was markedly decreased and there was a prolonged The distribution half-life of the drug was markedly decreased and there was a prolonged elimination half-life, with a decreased total body clearance in the infected animals. These elimination half-life, with a decreased total body clearance in the infected animals. These observations were attributed to the pathological changes in the cardiovascular system observations were attributed to the pathological changes in the cardiovascular system induced by trypanosomal infection. The tissue distribution and residue profi le of DMA induced by trypanosomal infection. The tissue distribution and residue profi le of DMA (3.5 mg/kg) was also investigated in healthy dogs, and in dogs infected with (3.5 mg/kg) was also investigated in healthy dogs, and in dogs infected with T. congolenseT. congolense and and T. b. bruceiT. b. brucei treated intramuscularly (ONYEYILI and ANIKA, 1991). Diminazene treated intramuscularly (ONYEYILI and ANIKA, 1991). Diminazene was observed to be distributed to various organs and tissues of the body, with the highest was observed to be distributed to various organs and tissues of the body, with the highest concentrations occurring in the liver and kidneys. Higher drug levels were found in the concentrations occurring in the liver and kidneys. Higher drug levels were found in the tissues of healthy dogs when compared with those of trypanosome infected animals, tissues of healthy dogs when compared with those of trypanosome infected animals, except in the brain. Drug residues were still detectable in the tissues of the animals 10 except in the brain. Drug residues were still detectable in the tissues of the animals 10 days after drug administration (ONYEYILI and ANIKA, 1991). days after drug administration (ONYEYILI and ANIKA, 1991).

In another study, the effect of chlorpromazine (CPZ) on the tissue distribution of In another study, the effect of chlorpromazine (CPZ) on the tissue distribution of DMA was also investigated in rabbits. There was a delay in the attainment of peak DMA was also investigated in rabbits. There was a delay in the attainment of peak concentration in the rabbits treated with DMA (7mg/kg, intramuscular) and CPZ (5mg/kg, concentration in the rabbits treated with DMA (7mg/kg, intramuscular) and CPZ (5mg/kg, intramuscular). High levels of DMA occurred in the brain of rabbits given a combination intramuscular). High levels of DMA occurred in the brain of rabbits given a combination of CPZ and DMA compared to the level obtained in the rabbits given DMA alone. This of CPZ and DMA compared to the level obtained in the rabbits given DMA alone. This indicates the greater penetration of DMA into the central nervous system of the rabbits indicates the greater penetration of DMA into the central nervous system of the rabbits that received a combination of CPZ and DMA (ONYEYILI et althat received a combination of CPZ and DMA (ONYEYILI et al.., 1992)., 1992).

With regards to isometamidium (ISMD), BRAIDE and EGHIANRUWA (1980) With regards to isometamidium (ISMD), BRAIDE and EGHIANRUWA (1980) reported that drug levels were detected in goat plasma 24 hours after intramuscular reported that drug levels were detected in goat plasma 24 hours after intramuscular injection, but not after intravenous injection. These authors attributed this observation to its injection, but not after intravenous injection. These authors attributed this observation to its rapid distribution from the systemic circulation. ISMD concentrations were also detected rapid distribution from the systemic circulation. ISMD concentrations were also detected in appreciable levels in the liver and kidneys, 12 weeks after intravenous administration. in appreciable levels in the liver and kidneys, 12 weeks after intravenous administration. No drug concentration was detected in the muscles, except at the intramuscular site of No drug concentration was detected in the muscles, except at the intramuscular site of injection. The authors attributed the prophylactic action of the drug to this intramuscular injection. The authors attributed the prophylactic action of the drug to this intramuscular depot, which becomes limited following encapsulation resulting from local tissue depot, which becomes limited following encapsulation resulting from local tissue reaction (ALIU and CHINEME, 1980). As a result of the known tissue reaction of ISMD reaction (ALIU and CHINEME, 1980). As a result of the known tissue reaction of ISMD

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at the intramuscular site of injection, OGUN and EGHIANRUWA, (1993) evaluated at the intramuscular site of injection, OGUN and EGHIANRUWA, (1993) evaluated the absorption rate of ISMD from the stomach and intestine of rats, and reported that the absorption rate of ISMD from the stomach and intestine of rats, and reported that ISMD was appreciably absorbed from the stomach and not from the intestine. In a ISMD was appreciably absorbed from the stomach and not from the intestine. In a comparative effi cacy study of ISMD following intramuscular and oral administrations, comparative effi cacy study of ISMD following intramuscular and oral administrations, the intramuscular route was found to be clearly superior (EGHIANRUWA et al., 2004).the intramuscular route was found to be clearly superior (EGHIANRUWA et al., 2004).

Complexation of trypanocidesComplexation of trypanocidesComplexes of ISMD with adjuvants have also been produced to alter the kinetic profi le Complexes of ISMD with adjuvants have also been produced to alter the kinetic profi le

of ISMD. Studies involving the Isometamidium-dextran complex and isometamidium-of ISMD. Studies involving the Isometamidium-dextran complex and isometamidium-suramin complex were undertaken in the late seventies and early eighties (JAMES, 1978; suramin complex were undertaken in the late seventies and early eighties (JAMES, 1978; ALIU and SANNUSI, 1979; ALIU and CHINEME, 1980), following the suggestion that ALIU and SANNUSI, 1979; ALIU and CHINEME, 1980), following the suggestion that complexation would alter the kinetics of absorption and lengthen the prophylactic period. complexation would alter the kinetics of absorption and lengthen the prophylactic period. The results of the studies showed that the amount of isometamidium-dextran complex The results of the studies showed that the amount of isometamidium-dextran complex containing an equivalent of the therapeutic dose of uncomplexed drug extended the containing an equivalent of the therapeutic dose of uncomplexed drug extended the period of effective prophylaxis by several months in both rats and mice (JAMES 1978). period of effective prophylaxis by several months in both rats and mice (JAMES 1978). Following studies on the isometamidium-dextran complex, ALIU and SANNUSI, (1979) Following studies on the isometamidium-dextran complex, ALIU and SANNUSI, (1979) concluded that the complex, at a 1 or 2 mg/kg subcutaneous injection, could be expected concluded that the complex, at a 1 or 2 mg/kg subcutaneous injection, could be expected to protect cattle against trypanosomosis and still yield good carcass and hide grading. to protect cattle against trypanosomosis and still yield good carcass and hide grading. The therapeutic index of the isometamidium-dextran complex was four times that of The therapeutic index of the isometamidium-dextran complex was four times that of isometamidium alone (ALIU and CHINEME (1980). The subcutaneous site of injection isometamidium alone (ALIU and CHINEME (1980). The subcutaneous site of injection of the complex tolerated a higher dose of isometamidium, with a resultant increase in the of the complex tolerated a higher dose of isometamidium, with a resultant increase in the prophylactic period (ALIU and SANNUSI, 1979; ALIU and CHINEME, 1980).prophylactic period (ALIU and SANNUSI, 1979; ALIU and CHINEME, 1980).

FLUCK and HOPKINS (1988), incorporated Diminazene, homidium and FLUCK and HOPKINS (1988), incorporated Diminazene, homidium and isometamidium into liposomal formulations, with a view to prolonging their activity isometamidium into liposomal formulations, with a view to prolonging their activity and improving tolerance. The authors observed no adverse effects after administration and improving tolerance. The authors observed no adverse effects after administration of the phospholipid complexes as multilamellar liposomes, but reported that the reaction of the phospholipid complexes as multilamellar liposomes, but reported that the reaction at the intramuscular injection site to liposomal isometamidium was markedly less than at the intramuscular injection site to liposomal isometamidium was markedly less than the reaction to a isometamidium solution, even though the liposomal preparations did not the reaction to a isometamidium solution, even though the liposomal preparations did not substantially enhance the duration of the prophylaxis of the three compounds.substantially enhance the duration of the prophylaxis of the three compounds.

The use of a sanative pairThe use of a sanative pairThis concept, which was fi rst suggested by WHITESIDE (1962), prescribes the This concept, which was fi rst suggested by WHITESIDE (1962), prescribes the

sequential use of a pair of chemically unrelated trypanocides (e.g. Berenil and Homidium). sequential use of a pair of chemically unrelated trypanocides (e.g. Berenil and Homidium). The concept entails the use of one of the sanative pair until resistant strains of trypanosomes The concept entails the use of one of the sanative pair until resistant strains of trypanosomes appear, following which the second is substituted and used until the resistant strains have appear, following which the second is substituted and used until the resistant strains have disappeared from cattle and tsetse. A modifi ed version of this concept ultimately became disappeared from cattle and tsetse. A modifi ed version of this concept ultimately became the trypanosomosis drug policy of the then Northern Region of Nigeria. The drug policy the trypanosomosis drug policy of the then Northern Region of Nigeria. The drug policy prescribed that each of the two curative drugs be used for six months of the year when a 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 (ILEMOBADE, 1979). species of trypanosomes sensitive to the drug was predominant (ILEMOBADE, 1979).

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For example, For example, T. vivaxT. vivax was found to be generally susceptible to homidium compounds was found to be generally susceptible to homidium compounds and was the predominant species in cattle when they were withdrawn to the wet-season and was the predominant species in cattle when they were withdrawn to the wet-season grazing areas; whereas grazing areas; whereas T. congolenseT. congolense was generally susceptible to berenil and was the was generally susceptible to berenil and was the predominant species in cattle during the dry season when cattle were moved to pastureland predominant species in cattle during the dry season when cattle were moved to pastureland in the tsetse belts of the south. However, this treatment regime was rather short lived, as in the tsetse belts of the south. However, this treatment regime was rather short lived, as isolates of isolates of T. congolenseT. congolense and and T. vivaxT. vivax with multiple resistance to curative trypanocides with multiple resistance to curative trypanocides were isolated and subsequently found to be widespread.were isolated and subsequently found to be widespread.

Hyperosmolar agents and relapse infectionsHyperosmolar agents and relapse infectionsPoor drug distribution to infected tissues, particularly the brain, is one of the host Poor drug distribution to infected tissues, particularly the brain, is one of the host

related factors associated with relapse of trypanosomosis infection (JENNINGS et al.related factors associated with relapse of trypanosomosis infection (JENNINGS et al.,, 1979). Diminazene aceturate, the routine drug for treating trypanosomosis in Nigeria, has 1979). Diminazene aceturate, the routine drug for treating trypanosomosis in Nigeria, has small molecular size but its charged nature prevents easy passage across the blood-brain-small molecular size but its charged nature prevents easy passage across the blood-brain-barrier (BBB), with the result that in cerebral trypanosomosis, the trypanosomes evade barrier (BBB), with the result that in cerebral trypanosomosis, the trypanosomes evade its trypanocidal action. In order to overcome this failure to reach the required therapeutic its trypanocidal action. In order to overcome this failure to reach the required therapeutic concentrations at the parasite location in the brain, hyperosmolar agents such as lithium concentrations at the parasite location in the brain, hyperosmolar agents such as lithium chloride (LiCl) and sucrose were used in combination with trypanocides, to achieve the chloride (LiCl) and sucrose were used in combination with trypanocides, to achieve the osmotic opening of the BBB and the resultant effective chemotherapy. Lithium chloride osmotic opening of the BBB and the resultant effective chemotherapy. Lithium chloride and sucrose are known to effectively open the BBB (SPATZ et aland sucrose are known to effectively open the BBB (SPATZ et al.., 1976)., 1976).

Intramuscular lithium chloride (10 mg/kg) caused a signifi cant increase in the brain Intramuscular lithium chloride (10 mg/kg) caused a signifi cant increase in the brain concentration of DMA (3.1 mg/kg im). The addition of sucrose (1.0 g/kg im) was not as concentration of DMA (3.1 mg/kg im). The addition of sucrose (1.0 g/kg im) was not as effective. The DMA levels were also signifi cantly higher in the organs (brains, kidney, effective. The DMA levels were also signifi cantly higher in the organs (brains, kidney, liver and spleen) of trypanosome infected rats compared to those uninfected (ODIKA et liver and spleen) of trypanosome infected rats compared to those uninfected (ODIKA et alal.,., 1995). Furthermore the concentration of DMA in the organs increased signifi cantly 1995). Furthermore the concentration of DMA in the organs increased signifi cantly (P<0.05) with increasing concentrations of LiCl (ODIKA(P<0.05) with increasing concentrations of LiCl (ODIKA et alet al.., 1995)., 1995).

Combination therapyCombination therapyIt has been suggested that the low effi cacy of trypanocides may result from under-dosing, It has been suggested that the low effi cacy of trypanocides may result from under-dosing,

poor drug quality, rapid-infection with short-acting therapeutic agents (such as DMA) and poor drug quality, rapid-infection with short-acting therapeutic agents (such as DMA) and drug resistance. To exclude the possibilities of under-dosing and poor drug quality, samples of drug resistance. To exclude the possibilities of under-dosing and poor drug quality, samples of DMA and isomethamedium chloride obtained locally were analyzed, and the results showed DMA and isomethamedium chloride obtained locally were analyzed, and the results showed that the qualities were of acceptable standards. This result thus suggested the existence of that the qualities were of acceptable standards. This result thus suggested the existence of genuine drug resistance in the fi eld (ANENE et algenuine drug resistance in the fi eld (ANENE et al.., 1996)., 1996).

In order to address the problem of drug resistance, a study was conductedIn order to address the problem of drug resistance, a study was conducted in vitro in vitro to assess to assess the ability of calcium antagonists of several chemical classes (verapamil, cyproheptadine, the ability of calcium antagonists of several chemical classes (verapamil, cyproheptadine, desipramine and chlorpromazine) to reverse resistance of desipramine and chlorpromazine) to reverse resistance of Trypanosoma evansiTrypanosoma evansi to a range to a range of trypanocides including DMA, suramin and MelCy. The putative resistance modulators of trypanocides including DMA, suramin and MelCy. The putative resistance modulators were intrinsically antitrypanosomal, but were unable to reverse resistance to any of the were intrinsically antitrypanosomal, but were unable to reverse resistance to any of the trypanocides tested (ANENE et altrypanocides tested (ANENE et al.., 1996)., 1996).

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Again, because most of the available trypanocides in use were developed over 5 Again, because most of the available trypanocides in use were developed over 5 decades ago, it was perceived that their long usage and misuse may have encouraged the decades ago, it was perceived that their long usage and misuse may have encouraged the development of drug resistant parasites. A study was thus conducted to assess the effi cacy development of drug resistant parasites. A study was thus conducted to assess the effi cacy of Difl uoromethylornithine (DFMO, efl ornithine), a newly introduced human trypanocide of Difl uoromethylornithine (DFMO, efl ornithine), a newly introduced human trypanocide in the treatment of both primary and relapse infections of in the treatment of both primary and relapse infections of Trypanosoma bruceiTrypanosoma brucei in dogs. in dogs. Simultaneous administration of DFMO intravenously and single dose of diminazene Simultaneous administration of DFMO intravenously and single dose of diminazene (7mg/kg) in primary infections achieved a higher chemotherapeutic level compared to the (7mg/kg) in primary infections achieved a higher chemotherapeutic level compared to the monotherapy, as no relapses occurred (ANENE et almonotherapy, as no relapses occurred (ANENE et al.., 1997)., 1997).

The suggestions of some authors (IGBOKWE, et al., 1998; UMAR et alThe suggestions of some authors (IGBOKWE, et al., 1998; UMAR et al.,., 2000; 2000; IHEDIOHA and ANWA, 2002) of the possible involvement of Reactive Oxygen Species IHEDIOHA and ANWA, 2002) of the possible involvement of Reactive Oxygen Species (ROS) in the pathogenesis of trypanosomosis prompted the evaluation of the effi cacy (ROS) in the pathogenesis of trypanosomosis prompted the evaluation of the effi cacy of diminazene aceturate alone and in combinations with antioxidants (ascorbic acid, of diminazene aceturate alone and in combinations with antioxidants (ascorbic acid, dimethyl sulfoxide, tocopherol and selenium) in experimental murine dimethyl sulfoxide, tocopherol and selenium) in experimental murine T. brucei T. brucei andand T. T. congolensecongolense infections. Results from these studies were variable, with both the species of infections. Results from these studies were variable, with both the species of trypanosome and antioxidants. When considered in totality, antioxidant supplementation trypanosome and antioxidants. When considered in totality, antioxidant supplementation following diminazene injection showed superiority over diminazene alone in reversing following diminazene injection showed superiority over diminazene alone in reversing the pathological conditions caused by trypanosome infection (EGHIANRUWA et al., the pathological conditions caused by trypanosome infection (EGHIANRUWA et al., 2009, EGHIANRUWA and ANIKA, 2010, 2011, 2012; EGHIANRUWA and OBIDIKE, 2009, EGHIANRUWA and ANIKA, 2010, 2011, 2012; EGHIANRUWA and OBIDIKE, 2011; EGHIANRUWA, 2012). 2011; EGHIANRUWA, 2012).

An overview of the many efforts made to obtain better therapeutic results from drug An overview of the many efforts made to obtain better therapeutic results from drug treatment of overt trypanosomosis cases showed that these treatments relieved the animals treatment of overt trypanosomosis cases showed that these treatments relieved the animals temporarily of the parasitaemia. No treatment protocol had the desired prolonged and temporarily of the parasitaemia. No treatment protocol had the desired prolonged and lasting effect. Moreover, the issue of relapse and drug resistance could not be resolved.lasting effect. Moreover, the issue of relapse and drug resistance could not be resolved.

Future trends in the chemotherapy of trypanosomosisFuture trends in the chemotherapy of trypanosomosisDevelopment of new drugsDevelopment of new drugsOne of the most signifi cant problems faced in controlling the spread of trypanosomosis One of the most signifi cant problems faced in controlling the spread of trypanosomosis

is that there is little economic incentive to conduct research in these impoverished parts of is that there is little economic incentive to conduct research in these impoverished parts of the world that are endemic to the disease, and it is diffi cult to get expensive drugs to the the world that are endemic to the disease, and it is diffi cult to get expensive drugs to the people. The drug discovery scenario, however, is changing dramatically. Several potential people. The drug discovery scenario, however, is changing dramatically. Several potential drug targets and molecules have been recognized. drug targets and molecules have been recognized.

One of the drug targets identifi ed so far is related to an unusual enzyme, Trypanosome One of the drug targets identifi ed so far is related to an unusual enzyme, Trypanosome Alternative Oxidase (TAO) which Alternative Oxidase (TAO) which T. bruceiT. brucei uses in glycolysis. This enzyme is the uses in glycolysis. This enzyme is the terminal oxidase of the respiratory chain of long slender bloodstream forms of the African terminal oxidase of the respiratory chain of long slender bloodstream forms of the African trypanosome, and it is absent from the host (NIHEI et al., 2002; CHAUDHURI et al., trypanosome, and it is absent from the host (NIHEI et al., 2002; CHAUDHURI et al., 2006). The amino acid sequence of TAO in HAT-causing trypanosomes was observed 2006). The amino acid sequence of TAO in HAT-causing trypanosomes was observed to be identical to that in non-human infective to be identical to that in non-human infective T. b. bruceiT. b. brucei (NAKAMURA et al., 2010). (NAKAMURA et al., 2010). As an essential factor for trypanosome survival, TAO is a promising drug target in both As an essential factor for trypanosome survival, TAO is a promising drug target in both

255Vet. arhiv 88 (2), 245-270, 2018


human and animal Africa trypanosomes, due to the absence of alternative oxidases in human and animal Africa trypanosomes, due to the absence of alternative oxidases in the mammalian host. Ascofuranone, a compound isolated from the phytopathogenic the mammalian host. Ascofuranone, a compound isolated from the phytopathogenic fungus fungus Ascochyta visiae,Ascochyta visiae, has been shown to be the most potent inhibitor of TAO to date has been shown to be the most potent inhibitor of TAO to date (NIHEI et al., 2002). NAKAMURA et al. 2010 reported that ascofuranone, quickly (NIHEI et al., 2002). NAKAMURA et al. 2010 reported that ascofuranone, quickly kills trypanosomes in vitro and cures mice infected with kills trypanosomes in vitro and cures mice infected with T. b. bruceiT. b. brucei. The potential of . The potential of Cathepsin (CATL), a lysosomal cysteine peptidase, as an important potential drug target Cathepsin (CATL), a lysosomal cysteine peptidase, as an important potential drug target in trypanosomes has also been suggested (ALSFORD et al., 2014).in trypanosomes has also been suggested (ALSFORD et al., 2014).

KALIDAS and PHILIPS (2012) reported systematic analysis of approximately 200 KALIDAS and PHILIPS (2012) reported systematic analysis of approximately 200 genes coding for enzymes involved in different biochemical and signaling pathways, genes coding for enzymes involved in different biochemical and signaling pathways, by RNA interference (RNAi) knockdown or gene knockout. RNA interference is a by RNA interference (RNAi) knockdown or gene knockout. RNA interference is a phenomenon through which double stranded RNA (dsRNA) induces potent sequence-phenomenon through which double stranded RNA (dsRNA) induces potent sequence-specifi c degradation of homologous transcripts, and it has emerged as an invaluable tool specifi c degradation of homologous transcripts, and it has emerged as an invaluable tool for elucidation of gene function and drug target validation (VINCENT et al., 2008). for elucidation of gene function and drug target validation (VINCENT et al., 2008). Using a newly developed vector (pTrypRNAiGate), KALIDAS and PHILIPS 2012, have Using a newly developed vector (pTrypRNAiGate), KALIDAS and PHILIPS 2012, have knocked down seven aminoacyl tRNA synthetases (AARS), which have an important knocked down seven aminoacyl tRNA synthetases (AARS), which have an important role in protein translation. RNAi against fi ve AARS resulted in growth inhibition of the role in protein translation. RNAi against fi ve AARS resulted in growth inhibition of the T. bruceiT. brucei bloodstream forms in vitro. bloodstream forms in vitro.

It is well established that the bloodstream forms of trypanosomes in a patient have It is well established that the bloodstream forms of trypanosomes in a patient have a coat of variant surface glycoprotein (VSG) that shields them from the immune system a coat of variant surface glycoprotein (VSG) that shields them from the immune system (TAYLOR and RUDENKO, 2006). However, the procyclic forms, which are the fi rst (TAYLOR and RUDENKO, 2006). However, the procyclic forms, which are the fi rst life-cycle stage to develop in the tsetse fl y, replace the VSG coat by procyclins that do not life-cycle stage to develop in the tsetse fl y, replace the VSG coat by procyclins that do not protect the parasite from lysis by serum components. This process of differentiation from protect the parasite from lysis by serum components. This process of differentiation from bloodstream to procyclic forms is specifi c to the parasite and has been exploited by some bloodstream to procyclic forms is specifi c to the parasite and has been exploited by some workers to screen for potential drug candidates (WENZLER et al., 2016). workers to screen for potential drug candidates (WENZLER et al., 2016).

The prospects for exploiting differences between parasite and mammalian protein The prospects for exploiting differences between parasite and mammalian protein kinases to develop new trypanocides have been reported (NAULA et al., 2005). Protein kinases to develop new trypanocides have been reported (NAULA et al., 2005). Protein kinase regulates many different cellular processes, such as transcriptional control, cell kinase regulates many different cellular processes, such as transcriptional control, cell cycle progression and differentiation (WIESE et al., 2003; ELLIS et al., 2004) and its cycle progression and differentiation (WIESE et al., 2003; ELLIS et al., 2004) and its potential as drug targets is not restricted to trypanosomosis but also to a wide range of potential as drug targets is not restricted to trypanosomosis but also to a wide range of diseases and syndromes, such as cancer, cardiovascular disease and Alzheimer’s disease diseases and syndromes, such as cancer, cardiovascular disease and Alzheimer’s disease (SEBOLT-LEOPOLD and HERRARA, 2004; NAULA et al., 2005; STRUMBERG and (SEBOLT-LEOPOLD and HERRARA, 2004; NAULA et al., 2005; STRUMBERG and SEEBER, 2005).SEEBER, 2005).

Some researchers have suggested that one approach to fi nding new drugs and Some researchers have suggested that one approach to fi nding new drugs and rediscovering old ones is based on enzyme inhibitors that paralyze antioxidant systems, rediscovering old ones is based on enzyme inhibitors that paralyze antioxidant systems, which are essential to the parasites as they are attacked in the host by reactive oxygen which are essential to the parasites as they are attacked in the host by reactive oxygen species, such as peroxynitrite, hypochlorite, and Hspecies, such as peroxynitrite, hypochlorite, and H22OO22 (KRAUTH-SIEGEL et al (KRAUTH-SIEGEL et al.,., 2005). 2005). The antioxidant system of the trypanosome is thought to consist of some 20 thiol and The antioxidant system of the trypanosome is thought to consist of some 20 thiol and dithiol proteins centered around the unique dithiol trypanothione. Several workers have dithiol proteins centered around the unique dithiol trypanothione. Several workers have

256 Vet. arhiv 88 (2), 245-270, 2018


considered this antioxidant system as a potential drug target in trypanosomes (BUDDE and considered this antioxidant system as a potential drug target in trypanosomes (BUDDE and FLOHE, 2003; KRAUTH-SIEGEL et al., 2005; JAEGER and FLOHE, 2006). Evidence FLOHE, 2003; KRAUTH-SIEGEL et al., 2005; JAEGER and FLOHE, 2006). Evidence from gene disruption studies indicates that trypanothione and other low molecular mass from gene disruption studies indicates that trypanothione and other low molecular mass thiols are directly or indirectly maintained in a reduced state by trypanothione reductase, thiols are directly or indirectly maintained in a reduced state by trypanothione reductase, an apparently essential enzyme, which appears to be unique to this genus (KRIEGER an apparently essential enzyme, which appears to be unique to this genus (KRIEGER et al., 2000; BEIG et al., 2015). Blocking the synthesis of trypanothione could be a et al., 2000; BEIG et al., 2015). Blocking the synthesis of trypanothione could be a useful pathway for developing a drug which would kill the parasites without harming the useful pathway for developing a drug which would kill the parasites without harming the human host. KRIEGER et al. (2000), reported that trypanosomes lacking trypanothione human host. KRIEGER et al. (2000), reported that trypanosomes lacking trypanothione reductase are avirulent and show increased sensitivity to oxidative stress. Competitive reductase are avirulent and show increased sensitivity to oxidative stress. Competitive and irreversible inhibitors of the enzyme have been designed, and some have been tested and irreversible inhibitors of the enzyme have been designed, and some have been tested following attempts to exploit trypanothione reductase as a chemotherapeutic target following attempts to exploit trypanothione reductase as a chemotherapeutic target (STEENKAMP, 2002; STUMP et al., 2007; RICHARDSON et al., 2009; BELLUTI et (STEENKAMP, 2002; STUMP et al., 2007; RICHARDSON et al., 2009; BELLUTI et al., 2014).al., 2014).

Evidence from literature indicates that signifi cant advances are being made in the Evidence from literature indicates that signifi cant advances are being made in the search for new drugs, especially against Human Africa Trypanosomosis. Further studies search for new drugs, especially against Human Africa Trypanosomosis. Further studies will be required to ascertain the activities of these new drugs in treating Animal Africa will be required to ascertain the activities of these new drugs in treating Animal Africa Trypanosomosis.Trypanosomosis.

Improved drug delivery to target sites in the parasiteImproved drug delivery to target sites in the parasiteDrug resistance and the low therapeutic index of available trypanocides have been Drug resistance and the low therapeutic index of available trypanocides have been

some of the limiting factors to the effective control of trypanosomosis by chemotherapy some of the limiting factors to the effective control of trypanosomosis by chemotherapy (DELESPAUX and De KONING, 2007). One mechanism by which trypanosomes (DELESPAUX and De KONING, 2007). One mechanism by which trypanosomes develop resistance is by alteration of the nucleoside transporter system associated develop resistance is by alteration of the nucleoside transporter system associated with the movement of drug molecules to target sites within the parasite (SHIFERAW with the movement of drug molecules to target sites within the parasite (SHIFERAW et al., 2015). Resistant populations of trypanosomes are known to take and accumulate et al., 2015). Resistant populations of trypanosomes are known to take and accumulate less trypanocides than sensitive ones (SUTHERLAND et al., 1992; MULUGETA less trypanocides than sensitive ones (SUTHERLAND et al., 1992; MULUGETA et al., 1997). While the search for new drugs is ongoing, efforts to develop new drug et al., 1997). While the search for new drugs is ongoing, efforts to develop new drug formulations, that would improve drug delivery to target sites within the parasite with formulations, that would improve drug delivery to target sites within the parasite with consequent increases in effi cacy and safety, are equally being pursued. Studies are consequent increases in effi cacy and safety, are equally being pursued. Studies are ongoing in several laboratories on the application of nanotechnology in the development ongoing in several laboratories on the application of nanotechnology in the development of drug delivery systems to treat parasitic diseases. Nanoparticle based drug delivery of drug delivery systems to treat parasitic diseases. Nanoparticle based drug delivery systems possess the advantage of improved effi ciency, arising from their ability to deliver systems possess the advantage of improved effi ciency, arising from their ability to deliver the drug to the required target. Effi cient drug delivery is also associated with reduced the drug to the required target. Effi cient drug delivery is also associated with reduced toxicity, prolonged drug effect, improved stability of therapeutic agents and reduction toxicity, prolonged drug effect, improved stability of therapeutic agents and reduction in drug dose (SINGH and LILLARD, 2009). The benefi t of nanoparticle-coupled drugs in drug dose (SINGH and LILLARD, 2009). The benefi t of nanoparticle-coupled drugs in drug targeting has been realized in cancer therapy, where such drugs act specifi cally in drug targeting has been realized in cancer therapy, where such drugs act specifi cally on the cancer cells (De JONG and BORM, 2008). Some reports are available on the on the cancer cells (De JONG and BORM, 2008). Some reports are available on the advantages of nanoparticle-coupled drugs in trypanosomosis. UNCITI-BROCETA advantages of nanoparticle-coupled drugs in trypanosomosis. UNCITI-BROCETA et al. (2015) using nanoparticles of chitosan loaded with pentamidine and coated by a et al. (2015) using nanoparticles of chitosan loaded with pentamidine and coated by a

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single domain nanobody that specifi cally targets the surface of African trypanosomes, single domain nanobody that specifi cally targets the surface of African trypanosomes, and have reported a 100 fold reduction in curative dose compared to pentamidine alone. and have reported a 100 fold reduction in curative dose compared to pentamidine alone. These authors also reported that pentamidine loaded onto chitosan was active against These authors also reported that pentamidine loaded onto chitosan was active against a trypanosome cell line known to be resistant to pentamidine, due to mutations in the a trypanosome cell line known to be resistant to pentamidine, due to mutations in the surface transporter. The higher effi cacy of the chitosan-pentamidine formulation was surface transporter. The higher effi cacy of the chitosan-pentamidine formulation was associated with improved entry of pentamidine into trypanosomes through endocytosis, associated with improved entry of pentamidine into trypanosomes through endocytosis, instead of via the classical cell surface transporters (UNCITI-BROCETA et al., 2015). instead of via the classical cell surface transporters (UNCITI-BROCETA et al., 2015). The nanoparticle delivery system has also been extended to natural products, such as The nanoparticle delivery system has also been extended to natural products, such as nerolidol, that possess antitrypanosomal actions. Nerolidol is an aliphatic sesquiterpene nerolidol, that possess antitrypanosomal actions. Nerolidol is an aliphatic sesquiterpene alcohol present in the essential oils of many plants with proven alcohol present in the essential oils of many plants with proven in vitroin vitro activity against activity against T. evansiT. evansi (MOHD-SHUKRI and ZAINAL-ABIDIN, 2011; BALDISSERA et al., 2016b). (MOHD-SHUKRI and ZAINAL-ABIDIN, 2011; BALDISSERA et al., 2016b). Orally administered nerolidol-loaded nanosphere in Orally administered nerolidol-loaded nanosphere in T. evansiT. evansi infected rats resulted in infected rats resulted in a survival rate of 66.66% compared to 0% when nerolidol was used alone, or 33.33% a survival rate of 66.66% compared to 0% when nerolidol was used alone, or 33.33% survival rate obtained with diminazene (BALDISSERRA et al., 2016b). Studies on survival rate obtained with diminazene (BALDISSERRA et al., 2016b). Studies on nanoparticle drug delivery systems have witnessed vigorous activity and expectations are nanoparticle drug delivery systems have witnessed vigorous activity and expectations are high. If the results obtained from pentamidine-loaded nanoparticles can be replicated in high. If the results obtained from pentamidine-loaded nanoparticles can be replicated in other aged trypanocides, the technology may well lead to the resurgence of the old drugs.other aged trypanocides, the technology may well lead to the resurgence of the old drugs.

Medicinal plants and natural products as potential sources of trypanocidal drugsMedicinal plants and natural products as potential sources of trypanocidal drugsIt is a truth universally acknowledged that plants are important sources of medicines. It is a truth universally acknowledged that plants are important sources of medicines.

Plants do not only contain active pharmacological principles, but their contents are also Plants do not only contain active pharmacological principles, but their contents are also used as template molecules for the production of new drugs. Hence, the knowledge used as template molecules for the production of new drugs. Hence, the knowledge gained from the use of medicinal herbs and their active ingredients has served as the gained from the use of medicinal herbs and their active ingredients has served as the foundation for much of modern pharmacology, and many modern drugs have their origin foundation for much of modern pharmacology, and many modern drugs have their origin in ethnopharmacology. Patronage of traditional based medical systems, in which higher in ethnopharmacology. Patronage of traditional based medical systems, in which higher plants constitute the main sources of drug therapy, has increased steadily over the past plants constitute the main sources of drug therapy, has increased steadily over the past decade. Novel treatment strategies for the management of several disease conditions, such decade. Novel treatment strategies for the management of several disease conditions, such as diabetes and many forms of cancer, have emanated from herbal medicines (GURIB-as diabetes and many forms of cancer, have emanated from herbal medicines (GURIB-FAKIM and MAHOMOODALLY, 2013).FAKIM and MAHOMOODALLY, 2013).

There is an abundance of reports in the literature from studies, both There is an abundance of reports in the literature from studies, both in vivoin vivo and and in vitroin vitro, , which have been conducted to investigate the effectiveness of traditionally used medicinal which have been conducted to investigate the effectiveness of traditionally used medicinal plants in alleviating the effect of trypanosomosis on the host (SALEM and WERBOVETZ, plants in alleviating the effect of trypanosomosis on the host (SALEM and WERBOVETZ, 2006; MANN and OGBADOYI, 2012). HOET et al. (2004), reviewed 120 plant derived 2006; MANN and OGBADOYI, 2012). HOET et al. (2004), reviewed 120 plant derived compounds, consisting of alkaloids, phenolic derivatives, quinones, terpenes and other compounds, consisting of alkaloids, phenolic derivatives, quinones, terpenes and other metabolites, which reportedly possess activity against African trypanosomes (mainly metabolites, which reportedly possess activity against African trypanosomes (mainly Trypanosoma brucei subspTrypanosoma brucei subsp., ., T. congolense and T. vivaxT. congolense and T. vivax) in a submicromolar range, out ) in a submicromolar range, out of which 12 were shown to be relatively selective. Chemical modifi cation of natural of which 12 were shown to be relatively selective. Chemical modifi cation of natural products, such as ascididemin, neocryptolepine, tryptanthrin and diospyrin, resulted in products, such as ascididemin, neocryptolepine, tryptanthrin and diospyrin, resulted in more trypanosomal activities and less toxicity, again illustrating how natural products can more trypanosomal activities and less toxicity, again illustrating how natural products can

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serve as a basis for developing derivatives with increased activity and/or lower toxicity serve as a basis for developing derivatives with increased activity and/or lower toxicity (HOET et al., 2004).(HOET et al., 2004).

Few natural products have been evaluated in rodent models of African trypanosomiasis. Few natural products have been evaluated in rodent models of African trypanosomiasis. Some encouraging reports have been published (ASUZU and CHINEME, 1990; AKANJI Some encouraging reports have been published (ASUZU and CHINEME, 1990; AKANJI et al., 2009; OMOJA et al., 2011; MANN and OGBADOYI, 2012). Ascofuranone, a et al., 2009; OMOJA et al., 2011; MANN and OGBADOYI, 2012). Ascofuranone, a prenylated phenol antibiotic and a structural analog of coenzyme Q isolated from a prenylated phenol antibiotic and a structural analog of coenzyme Q isolated from a phytopathogenic fungus, phytopathogenic fungus, Ascochyta visiaeAscochyta visiae, resulted in 100% cure of mice infected with , resulted in 100% cure of mice infected with T. b. bruceiT. b. brucei when given by intraperitoneal route in combination with glycerol. The when given by intraperitoneal route in combination with glycerol. The compound was reported to be highly non-toxic compound was reported to be highly non-toxic in vivoin vivo and able to cross the blood-brain and able to cross the blood-brain barrier (MINAGAWA et al., 1997; YABU et al., 2003, 2006). Similarly, a fraction of the barrier (MINAGAWA et al., 1997; YABU et al., 2003, 2006). Similarly, a fraction of the oily extract from garlic bulbs cured mice infected with oily extract from garlic bulbs cured mice infected with T. b. bruceiT. b. brucei in four days, when in four days, when given intraperitoneally at a dose of 120 mg kggiven intraperitoneally at a dose of 120 mg kg-1-1 per day (NOK et al., 1996). per day (NOK et al., 1996).

Thorough understanding of the mode of action of the pharmacologically active Thorough understanding of the mode of action of the pharmacologically active principles in natural products is still lacking. However, possible mechanisms have been principles in natural products is still lacking. However, possible mechanisms have been suggested in some cases. For instance, NOK et al. (1996), attributed the action of the oily suggested in some cases. For instance, NOK et al. (1996), attributed the action of the oily extract from garlic bulbs to its interference with the parasites’ synthesis of membrane extract from garlic bulbs to its interference with the parasites’ synthesis of membrane lipids. Similarly, the mechanism of the action of ascofuranone, a structural analog of lipids. Similarly, the mechanism of the action of ascofuranone, a structural analog of coenzyme Q, is attributed to its binding at the coenzyme Q site of ubiquinol oxidase, thus coenzyme Q, is attributed to its binding at the coenzyme Q site of ubiquinol oxidase, thus blocking trypanosome alternative oxidase (TAO), one of the two enzymes associated blocking trypanosome alternative oxidase (TAO), one of the two enzymes associated with a unique mitochondrial electron transport system in with a unique mitochondrial electron transport system in T. b. bruceiT. b. brucei bloodstream forms. bloodstream forms. Glycerol suppresses the second enzyme, glycerol-3-phosphate dehydrogenase, by mass Glycerol suppresses the second enzyme, glycerol-3-phosphate dehydrogenase, by mass action. Hence, it has been observed that inhibitors of TAO become trypanocidal when action. Hence, it has been observed that inhibitors of TAO become trypanocidal when combined with glycerol, due to the total block of the energy production of bloodstream combined with glycerol, due to the total block of the energy production of bloodstream forms (NIHEI et al., 2002).forms (NIHEI et al., 2002).

The gap in the complete knowledge of these promising antitrypanosomal natural The gap in the complete knowledge of these promising antitrypanosomal natural products can be bridged by in-depth interdisciplinary investigations to elucidate their products can be bridged by in-depth interdisciplinary investigations to elucidate their actions and identify new leads. The ultimate benefi t for trypanosome endemic areas actions and identify new leads. The ultimate benefi t for trypanosome endemic areas would be to design inexpensive standardized medicines, following validation and would be to design inexpensive standardized medicines, following validation and identifi cation of the active principles in the plants used in traditional medicine to treat identifi cation of the active principles in the plants used in traditional medicine to treat African trypanosomosis.African trypanosomosis.

Vaccine productionVaccine productionSuccess has not been forthcoming in the production of vaccines against trypanosomosis. Success has not been forthcoming in the production of vaccines against trypanosomosis.

Studies have shown that bloodstream forms of trypanosomes circumvent the host immune Studies have shown that bloodstream forms of trypanosomes circumvent the host immune response by continuous changes to surface glycoprotein, hence continuous changes in response by continuous changes to surface glycoprotein, hence continuous changes in antigenicity. The variable surface glycoproteins (VSGs) are antigenically distinct due antigenicity. The variable surface glycoproteins (VSGs) are antigenically distinct due to extensive differences in the primary sequences (TAYLOR and RUDENKO, 2006; to extensive differences in the primary sequences (TAYLOR and RUDENKO, 2006; RUDENKO, 2011). Antigenic variation of the parasite has been seen as one of the RUDENKO, 2011). Antigenic variation of the parasite has been seen as one of the

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most spectacular adaptive mechanisms exhibited by the African trypanosomes, and the most spectacular adaptive mechanisms exhibited by the African trypanosomes, and the main reason why the development of vaccine has been elusive (MURRAY et al, 1979). main reason why the development of vaccine has been elusive (MURRAY et al, 1979). The trypanosome has therefore been credited as the ultimate immune destroyer and The trypanosome has therefore been credited as the ultimate immune destroyer and escape artist (La GRECA and MAGEZ, 2011). A review of the various attempts made escape artist (La GRECA and MAGEZ, 2011). A review of the various attempts made to vaccinate both domestic livestock and laboratory animals showed from the reported to vaccinate both domestic livestock and laboratory animals showed from the reported studies that complete protection was readily achieved only if the same variable antigen studies that complete protection was readily achieved only if the same variable antigen type (VAT) was used for immunization and challenge (GRAY, 1976; MURRAY et al., type (VAT) was used for immunization and challenge (GRAY, 1976; MURRAY et al., 1979; TABEL et al., 2008). When a distant VAT was used for challenge, no protection 1979; TABEL et al., 2008). When a distant VAT was used for challenge, no protection occurred. Following these observations, many researchers in the area of trypanosomosis occurred. Following these observations, many researchers in the area of trypanosomosis control have assumed that an effective vaccine would have to contain all VATS, possibly control have assumed that an effective vaccine would have to contain all VATS, possibly an insurmountable task as the number of VATS is likely to be large. Hence many consider an insurmountable task as the number of VATS is likely to be large. Hence many consider the possibility of vaccination to be remote.the possibility of vaccination to be remote.

Although this view has been widely held and propagated, some workers have shown that Although this view has been widely held and propagated, some workers have shown that failure to achieve effective vaccination to control trypanosomosis is due to factors other than failure to achieve effective vaccination to control trypanosomosis is due to factors other than antigenic variation (WEI and TABEL, 2008; WEI et alantigenic variation (WEI and TABEL, 2008; WEI et al.., 2011; TABEL et al, 2011; TABEL et al.., 2013). Studies , 2013). Studies have shown that antibodies to the VSG are required for the control of African trypanosomes have shown that antibodies to the VSG are required for the control of African trypanosomes infecting the blood, whereas infections of the skin by low numbers of trypanosomes are infecting the blood, whereas infections of the skin by low numbers of trypanosomes are controlled by innate resistance and do not require antibodies for their control. Low numbers controlled by innate resistance and do not require antibodies for their control. Low numbers of trypanosomes infecting the skin, although killed by innate resistance, do not induce of trypanosomes infecting the skin, although killed by innate resistance, do not induce protection, but enhance susceptibility to re-infections due to suppression of the innate protection, but enhance susceptibility to re-infections due to suppression of the innate resistance by adaptive immune responses (MANSFIELD and PAULNOCK, 2005; WEI and resistance by adaptive immune responses (MANSFIELD and PAULNOCK, 2005; WEI and TABEL, 2008; WEI et al., 2011; TABEL et alTABEL, 2008; WEI et al., 2011; TABEL et al.., 2013). These workers concluded that immune , 2013). These workers concluded that immune suppression, which is one of the cardinal effects of Trypanosomosis, is responsible for vaccine suppression, which is one of the cardinal effects of Trypanosomosis, is responsible for vaccine failure. DARJI et al. (1992) proposed that immune suppression is attributed to the coexistence failure. DARJI et al. (1992) proposed that immune suppression is attributed to the coexistence of at least two unlinked suppressive mechanisms that block different T-cell regulatory steps of at least two unlinked suppressive mechanisms that block different T-cell regulatory steps and operate through different effector mechanisms, and the authors linked these mechanisms and operate through different effector mechanisms, and the authors linked these mechanisms to the generation of prostaglandin-producing macrophages which are entirely responsible for to the generation of prostaglandin-producing macrophages which are entirely responsible for the suppression of IL-2 production, whereas the induction of a prostaglandin-independent the suppression of IL-2 production, whereas the induction of a prostaglandin-independent suppressive mechanism accounts for the suppression of the expression of IL-2 receptors (IL-suppressive mechanism accounts for the suppression of the expression of IL-2 receptors (IL-2R). This point of view had been expressed by other workers (SILEGHEM et al2R). This point of view had been expressed by other workers (SILEGHEM et al.., 1989; , 1989; SCHLEIFER and MANSFIELD, 1993). Following the results of their studies, TABEL et alSCHLEIFER and MANSFIELD, 1993). Following the results of their studies, TABEL et al.. (2013) concluded that any attempt to produce an effective vaccine should fi rst address the (2013) concluded that any attempt to produce an effective vaccine should fi rst address the problem of induction of immunosuppression by the trypanosomes. problem of induction of immunosuppression by the trypanosomes.

Continued efforts to develop effective vaccines have resulted in studies of other non-Continued efforts to develop effective vaccines have resulted in studies of other non-variable molecules in the trypanosome. African trypanosomes express numerous non-variable molecules in the trypanosome. African trypanosomes express numerous non-variable antigens (LUBEGA et al., 2002; RASOOLY and BALABAN, 2004; LI et al., variable antigens (LUBEGA et al., 2002; RASOOLY and BALABAN, 2004; LI et al., 2009). The fl agellar pocket has been of particular interest, as an organelle specialized in 2009). The fl agellar pocket has been of particular interest, as an organelle specialized in endocytosis and exocytosis, containing relatively well-conserved receptors (MKUNZA et endocytosis and exocytosis, containing relatively well-conserved receptors (MKUNZA et

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al., 1995; FIELD and CARRINGTON, 2009), cytoskeleton proteins (HUTCHINSON et al., 1995; FIELD and CARRINGTON, 2009), cytoskeleton proteins (HUTCHINSON et al., 2004) and trypanosomal microtubulin (LUBEGA et alal., 2004) and trypanosomal microtubulin (LUBEGA et al.., 2002; LI et al., 2007). RASOOLY , 2002; LI et al., 2007). RASOOLY and BALABAN (2004) reported 100% protection from an otherwise lethal challenge of a and BALABAN (2004) reported 100% protection from an otherwise lethal challenge of a heterologous strain of heterologous strain of T. bruceiT. brucei when they used native or recombinant microtubule-associate when they used native or recombinant microtubule-associate protein (MAP p15) as a vaccine in mice. Similarly, LUBEGA et alprotein (MAP p15) as a vaccine in mice. Similarly, LUBEGA et al.. (2002), reported 60-80% (2002), reported 60-80% protection by renatured protection by renatured T. bruceiT. brucei tubulin against tubulin against T. bruceiT. brucei, , TT. . congolensecongolense or or T. rhodesienseT. rhodesiense challenge in mice, and that four out of fi ve mice, given passive immunity by the transfer of challenge in mice, and that four out of fi ve mice, given passive immunity by the transfer of anti-nTbTub serum, were completely protected, while one of the fi ve was partially protected. anti-nTbTub serum, were completely protected, while one of the fi ve was partially protected. LI et alLI et al.,., (2007) also reported 83.3%, 70% and 76% protection by renatured recombinant T. (2007) also reported 83.3%, 70% and 76% protection by renatured recombinant T. evansievansi beta-tubulin against strains of beta-tubulin against strains of T. evansi, T. equiperdumT. evansi, T. equiperdum and and T. b. bruceiT. b. brucei, respectively. , respectively. Serum collected from rabbits immunized with recombinant beta-tubulin inhibited the growth Serum collected from rabbits immunized with recombinant beta-tubulin inhibited the growth of of T. evansi, T. equiperdum T. evansi, T. equiperdum andand T. b. brucei in vitro T. b. brucei in vitro (LI et al., 2007). (LI et al., 2007).

ConclusionConclusionIf trypanosomosis must be controlled relatively cheaply, vaccination still remains If trypanosomosis must be controlled relatively cheaply, vaccination still remains

the best theoretical option. This is particularly expedient considering the fact that the best theoretical option. This is particularly expedient considering the fact that trypanosomosis affects poor economies and the cost of developing new effective drugs trypanosomosis affects poor economies and the cost of developing new effective drugs is exorbitant. There is little doubt that the introduction of an effective vaccine, if used is exorbitant. There is little doubt that the introduction of an effective vaccine, if used strategically, along with improved treatment methods and tsetse control measures, would strategically, along with improved treatment methods and tsetse control measures, would make an enormous contribution to the control of African trypanosomosis. This would make an enormous contribution to the control of African trypanosomosis. This would be followed by increased human productivity and livestock production in endemic be followed by increased human productivity and livestock production in endemic trypanosome areas of the African continent.trypanosome areas of the African continent.

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Received: 15 November 2016Received: 15 November 2016Accepted: 2 May 2017Accepted: 2 May 2017

__________________________________________________________________________________________________________________________________________________________________________EGHIANRUWA, K. I., O. A. ORIDUPA: EGHIANRUWA, K. I., O. A. ORIDUPA: Kontrola tripanosomoze kemoterapeuticima Kontrola tripanosomoze kemoterapeuticima - pregled prošlih mjera, sadašnje stanje i budući trendovi. Vet. arhiv 88, 245-270, - pregled prošlih mjera, sadašnje stanje i budući trendovi. Vet. arhiv 88, 245-270, 2018.2018.

SAŽETAKSAŽETAKAfrička tripanosomoza glavna je nametnička bolest ljudi i životinja na afričkom kontinentu južno od Afrička tripanosomoza glavna je nametnička bolest ljudi i životinja na afričkom kontinentu južno od

Sahare. Njezini su uzročnici različite vrste tripanosoma koje se prenose na domaćina ubodom zaraženog Sahare. Njezini su uzročnici različite vrste tripanosoma koje se prenose na domaćina ubodom zaraženog prijenosnika muhe ce-ce. Napori koji se ulažu u kontroli bolesti uključuju i pokušaje za smanjenje populacije prijenosnika muhe ce-ce. Napori koji se ulažu u kontroli bolesti uključuju i pokušaje za smanjenje populacije prijenosnika uporabom klopki, primjenom insekticida, postupkom sterilnih mužjaka kao i liječenjem te prijenosnika uporabom klopki, primjenom insekticida, postupkom sterilnih mužjaka kao i liječenjem te profi laksom kemoterapeuticima poput izometamidija, homidija, kvinapiramina i diminazena. Ti su lijekovi u profi laksom kemoterapeuticima poput izometamidija, homidija, kvinapiramina i diminazena. Ti su lijekovi u uporabi više od pedeset godina i povezani su s teškom toksičnošću organizma i otpornošću parazita. Prijetnja uporabi više od pedeset godina i povezani su s teškom toksičnošću organizma i otpornošću parazita. Prijetnja od ove bolesti nije uklonjena unatoč višegodišnjim naporima nekih laboratorija za pronalaženje novih oblika od ove bolesti nije uklonjena unatoč višegodišnjim naporima nekih laboratorija za pronalaženje novih oblika liječenja proučavanjem farmakokinetike tripanocida, zatim kombiniranom terapijom, uporabom medicinskog liječenja proučavanjem farmakokinetike tripanocida, zatim kombiniranom terapijom, uporabom medicinskog bilja te primjenom antioksidansa. Ni razvoj učinkovitog cjepiva nije bio uspješan, zbog antigenskih promjena bilja te primjenom antioksidansa. Ni razvoj učinkovitog cjepiva nije bio uspješan, zbog antigenskih promjena na površinskoj ovojnici tripanosoma. To je smanjilo nade za napredak u razvoju cjepiva, ako ga nije i potpuno na površinskoj ovojnici tripanosoma. To je smanjilo nade za napredak u razvoju cjepiva, ako ga nije i potpuno zaustavilo. Ipak, najnovija istraživanja pokazuju da bi tripanosomski mikrotubulin mogao biti održiv antigen zaustavilo. Ipak, najnovija istraživanja pokazuju da bi tripanosomski mikrotubulin mogao biti održiv antigen za razvoj cjepiva. Ovaj je pregledni članak usredotočen na mjere poduzimane za kontrolu tripanosomoze u za razvoj cjepiva. Ovaj je pregledni članak usredotočen na mjere poduzimane za kontrolu tripanosomoze u afričkih životinja kemoterapijom. U njemu se također razmatraju buduće mjere i perspektive s obzirom na to da afričkih životinja kemoterapijom. U njemu se također razmatraju buduće mjere i perspektive s obzirom na to da dosadašnje mjere nisu bile uspješne u kontroli bolesti. dosadašnje mjere nisu bile uspješne u kontroli bolesti.

Ključne riječi: Ključne riječi: kemoterapija; tripanosomoza; mjere kontrole; dvostruko liječenje; kombinirana terapija; kemoterapija; tripanosomoza; mjere kontrole; dvostruko liječenje; kombinirana terapija; ljekovito bilje; antigenska varijacija; antigen tubulinljekovito bilje; antigenska varijacija; antigen tubulin________________________________________________________________________________________________________________________________________________________________________________

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