Efficacy of Some Trypanocidal Drug Against Trypanosoma equiperdum OVI in Experimentally Infected Mice in Debre Zeit, Ethiopia
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European Journal of Biological Sciences 7 (1): 07-13, 2015
ISSN 2079-2085
© IDOSI Publications, 2015
DOI: 10.5829/idosi.ejbs.2015.7.01.91173
Efficacy of Some Trypanocidal Drug Against Trypanosoma equiperdum
OVI in Experimentally Infected Mice in Debre Zeit, Ethiopia
1
Beletu Habte, 1Abrha Bsrat, 2Hagos Ashenafi and 2Fikru Regassa
College of Veterinary Medicine, Mekelle University, P.O. Box 231, Mekelle, Ethiopia
1
2
Addis Ababa University College of Veterinary Medicine, P.O. Box 1176, Addis Ababa, Ethiopia
Abstract: Trypanocidal drugs remain the principal method of animal Trypanosomiasis control in most African
counties. However, there is growing concern that future effectiveness may be severely curtailed by wide spread
drug resistance. This study was therefore, conducted to assess the efficacy of diminazene diaceturate and
cymelarsan against Trypanosoma equiperdum OVI South Africa strain in experimentally infected mice.
Sensitivity study was conducted using range doses of diminazene diaceturate (3.5mg/kg, 7.0mg/kg, 14mg/kg
and 28mg/kg) and cymelarsan (0.25 mg/kg, 0.5 mg/kg 1.0 mg/kg and 2.0mg/kg) using 50 mice each being grouped
into 10 having 5 mice each. Diminazene diaceturate at doses of 3.5mg/kg, 7.0mg/kg, 14mg/kg failed completely
to cure but only 1(20%) mice out of 5 was survive up to 60 days treated with diminazene diaceturate at dose of
28mg/kg body weight. Cymelarsan at dose of 0.25mg/kg body weight failed completely to cure mice but a dose
of 0.50mg/kg body weight, only 2(40%) mice were cure. All mice treated at higher dose of the cymelarsan
1.0mg/kg and 2.0mg/kg body weight cured and the parasitaemia was not detected for more than 60 days.
All mice in the control groups showed higher level of parasitaemia and died completely up to 4 days after
infection. From this study it is indicated that the minimum curative dose of cymelarsan required to cure
Trypanosoma species causing dourine (South Africa strain) in experimentally infected mice was greater than
1mg/kg. However, further studies should be conducted to know the effect of the drugs on the local strain of
Trypanosoma equiperdum like Dodala strain from dourine endemic area in equine from Ethiopia so as to work
out the best possible therapeutic strategies and/or alternative control measures.
Key words: Cymelarsan Diminazene Diaceturate Ethiopia, Mice T. Equiperdum
INTRODUCTION Despite the significance of horses in the sector of
transportation and agriculture to the economy of the
World equine population is about 111.2 million nation, the treatment accorded to these species of animal
consisting of 44.5 million Donkeys, 57.6 million Horses has been far below than the attention given to other
and 5.02 Mules [1]. Among this, Ethiopia possesses economic animal species. This can partly be due to the
2.75 million horses, 5.02 million Donkeys and 0.63 million age old erroneous concept that these species are hardy,
mules [2]. Horses have a prominent position in the tolerant and probably because their meat and milk is not
agricultural and transport systems as draft, pack and edible in Ethiopia [4]. African horse sickness, Anthrax,
riding animals. In a country where there is less developed Epizootic Lymphangitis, Dourine, Equine piroplasmosis,
modern transport and communication service, the natural Horse mange, Rabies, Glander and Ulcerative
choice rests on the let human and pack animals mode of Lymphangitis are among the major diseases affecting
transport, as it has been the case in some parts of the horses in Ethiopia [3].
world. Thus, in a developing country like Ethiopia, the Trypanosomosis is a serious parasitic disease, which
contribution of equines in the energy scenario is of occurs in large areas of Africa, Latin America, the Middle
considerable significance. The provisions of transport East and Asia. It affects most species of domestic
through pack animals, drawing carts, as riding animals or livestock, many types of wild animals and human. The
taxi operations, almost certainly contributes more to the most important trypanosomes in terms of economic loss
national economy [3]. in domestic livestock are the tsetse transmitted species
Correspondence Author: Abrha Bsrat, College of Veterinary Medicine, Mekelle University, P.O. Box 231, Mekelle, Ethiopia.
7Europ. J. Biol. Sci., 7 (1): 07-13, 2014
such as Trypanosoma congolense, Trypanosoma vivax With the wide spread of drug resistant parasites in to
and Trypanosoma brucei [5]. Mechanically transmitted all trypanosomosis endemic areas, development of new
trypanosomes such as Trypanosoma evansi and anti-trypanosmal compounds and drugs to circumvent
Trypanosoma vivax cause major production losses in the resistance is urgently needed. However, it appears
respective hosts. unlikely that new compounds will be introduced into the
Dourine is the only form of trypanosomosis caused near future because of lack of interest by the
by Trypanosoma equiperdum, which is transmitted pharmaceutical industry in investing in research and
directly from one animal host to another of the same development of antitrypansomal drugs [15]. Hence, there
species without the intervention of an insect vector but it is an urgent need for assessment of efficacy of the drug
transmitted almost exclusively during coitus. The in which representative number of trypanosomes isolated
causative agent of Dourine, T. equiperdum, differs from and examined for distribution and degree of efficacy so as
other mammalian trypanosomes also in the fact that is to work out the best possible therapeutic strategies
primarily tissue parasite. The clinical course of the disease and/or alternative control measures. As prerequisite
depends on the pathogenecity of the trypanosome, the for such undertaking it is necessary to first obtain
resistance of the breed and the physical condition of the information on in vivo trypanocidal drug sensitivity
animals. The incubation period ranges from two weeks till patterns of the parasites in a mice model. Hence, the
three months, clinical signs might be suppressed during present study was initiated and designed to undertake
cold months [6]. Generally the disease is divided in to studies related to the assessment of trypanocidal drug
three phases such as primary stage (Genital Oedema), sensitivity of T. equiperdum OVI, South African strain
secondary stage (plaques and skin eruptions) and tertiary with the available trypanocidal drugs. Therefore, the
stage (Neurological signs) [7]. Anemia, cachexia and objective of the present study was to assess the
genital oedema are often seen at post mortem [8]. Dourine trypanocidal drug sensitivity of Diminazene diaceturate
is strictly limited to the equine. Thus the host range is and Cymelarsan against T. equiperdum OVI, South
limited to horses, donkeys and mules under natural African strain in experimentally infected mice.
condition [6].
Diagnosis of T.equiperdum, in horse, by standard MATERIALS AND METHODS
parasitological techniques is difficult, owing to the low
number of parasites present in the blood or tissue fluids Study Area: The present study was undertaken in
and frequent absence of the clinical sign of the molecular parasitology laboratory of Ethio-Belgium VLIR-
disease. Consequently the demonstration of UOS funded dourine project which is found inside the
trypanosomal antibodies in the serum has become the compound of Addis Ababa University Faculty of
most important parameter in the determining the disease Veterinary Medicine, Debre Zeit, Ethiopia from November
status of the animals [9].The principal reason for using 2009 to April 2010. Debre Zeit is found 47Kms south east
serological testes of diagnosis Trypanosomiasis is to over of Addis Ababa at (8° 44 N and 38° 58° E) at an altitude of
came the low level of sensitivity testes in detecting 1850 meters above sea level. The mean annual rain fall is
chronic infection. Alternative strategies, utilizing nuclic 885.4mm with a bimodal distribution. There are alternating
acid technologies such as the PCR also often high dry and rainy season in the area. The long rainy extends
sensitivity and might be of use in the diagnosis of from June to September and contributes about 84% of the
T.equiperpum [10]. total annual rainfall. While the dry season last from
For the treatment of T.equiperdum infection the October to February. The short rainy season lasts from
same drug which is used for T.evansi are available. March to May. The mean annual minimum and maximum
Evidence from in vitro drug sensitivity determination of temperatures are 14°C and 26.3°C respectively with an
T.equiperdum indicates that Suramin, Diminazen, overall average of 18.7°C. The mean relative humidity is
Quinapyramine and Cymelarsan are effective against this 61.3 % [16].
trypanosome species [11, 12]. In Ethiopia, Dourine is an
endemic problem of horses in the Arsi –Bale highland Experimental Animals: Swiss white mice about 6 weeks
where treatment and control of the disease becomes of age weighing 20-25 gm were obtained from the
difficult. The difficulty is mainly in terms of trypanocidal breeding colony of the National Veterinary Institute (NVI).
drug shortage which plays an influencing role in The mice were maintained under standard commercial
controlling and prevention of the disease in an endemic pelleted ration and water adlibitum in the laboratory of
area [13, 14]. the VLIR-UOS.
8Europ. J. Biol. Sci., 7 (1): 07-13, 2014
Sample Collection: Appropriate blood sample was control group. Mice in the treatment group were
collected regularly to evaluate the level of parasitemia by weighed on a digital balance prior to administration of
cutting the tip of the tail of the mice. Whenever large the trypanocidal drugs.
volume of blood (up to 2ml) is required for preparation of The mice in the different treatment and control
cryostabilates a cardiac puncture was performed after group were then being infected with T. equiperdum
humanely euthanizing the mice with ether. OVI, South African strain adapted to mice with 1-10
trypanosomes per preparation which is estimated to be
Experimental Design: Totally 60 mice were used in which 103 - 104 trypanosomes per ml blood [17] by intraperitoneal
10 (grouped in to two having 5 mice each) for adaptation inoculation with 0.2 ml blood from donor mice taken at
of the parasite and 50 for treatments and control. Initially, peak parasitaemia.
ten (10) donor mice (5 mice for each drug) were infected
with T. equiperdum OVI South African strain stabilates Treatment and Monitoring: Diminazene diaceturate
originated from Institute of Tropical Medicine, Antwerp, (Diminasan, Batch DG/20337 DUIPER WEG 9, 3449 JA
Belgium. Before infected the cryostabilates were woerden, Holland) and Bis (aminoethylthio) 4-
preserved in liquid nitrogen, following defrosting at room melaminophenylarsine dihydrochloride (cymelarsan, lot B
temperature or preferably at 37°C in water bath. The 09118A, MERIAL-17, rue Bourgelat 6900Z Lyon-France)
defrosted stabilates was then being mixed with were used for treatment of infected mice in the each
Phosphate Substrate Glucose (PSG). The route of treatment group. Diminazene diaceturate was administered
infection of the mice was intra peritoneal route with via intraperitoneal route at doses of 3.5 mg /kg, 7.0 mg/kg,
maximum dose of 0.2 ml. 14.0 mg/kg and 28.0 mg/kg body weight. Similarly
The ten donor mice were checked for parasitemia Cymelarsan was administered via intraperitoneal route at
daily by taking a drop of blood from the tip of the tail of doses of 0.25 mg/kg, 0.5 mg/kg, 1.0 mg/kg and 2.0 mg/kg
the animals. Once parasitemia gets highly multiplied body weight (Table 1). The control groups received the
within three to five days, it was successfully possible to same amount of sterile distilled water by intraperitoneal
serially passage Trypanosoma equiperdum OVI South route in replacement of the treatment. Each drug was
Africa strain to the next mice then mice were humanely prepared by dissolving the required quantity of each
euthanized to collect blood via intracardial puncture. Each compound in sterile distilled water before use according
time the cryostabilates were prepared and kept in liquid to respective manufacturer instruction and required dose
nitrogen. Two drugs, diminazene diaceturate and of the drug was administered in 0.2 ml of solution for all
Cymelarsan, were studied for their sensitivity on T. treatment groups [18]. Mice were monitored every
equiperdum OVI, South African strain. In each of the alternate day up to 60 days for the presence of
study 25 mice were divided randomly in to five trypanosomes by microscopic examination of wet smears
experimental groups (group I-V) of five mice each. of tail blood. Presence of trypanosomes in the blood
The first four groups (I-IV) comprise the treatment groups smear was considered as indication of ineffectiveness of
(those to be infected and treated with different doses of the trypanocidal drug used or possibly drug resistance.
diminazene diaceturate). The fifth group (group V) served
as infected untreated control group. While,the groups Data Analysis: Data were collected, stored properly in
from VI toXV infected and treated with different doses of Micro soft Excel sheet and then analyzed using GMP-5
Cymelarsan, while group X keept as infected untreated Statistical soft ware [19].
Table 1: Treatment groups for T. equiperdum OVI South Africa strain in mice using diminazene diaceturate and cymelarsan.
Trypanocidal drugs used
----------------------------------------------------------------------------------------------------
Treatment groups No of mice per group Diminazene Diaceturate (mg/kg bw) Cymelarsan (mg/kg bw)
I 5 3.5 -
II 5 7.0 -
III 5 14.0 -
IV 5 28.0 -
V 5 0a 0a
VI 5 - 0.25
VII 5 - 0.5
VIII 5 - 1.0
IX 5 - 2.0
X 5 0a 0a
a
=Distilled water instead of Trypanocidal drug
9Europ. J. Biol. Sci., 7 (1): 07-13, 2014
Table 2: Results of diminazene diaceturate and cymelarsan to Trypanosoma equiperdum OVI South Africa strain in mice at different dose range.
Drugs Doses (mg/kg) No. mice treated/relapsed Mean relapse interval in days ± SD
Diminazene diaceturate 3.5 mg/kg 5/5 1 ± 0.0
7.0 mg/kg 5/5 1.2± 0.45
14.0 mg/kg 5/5 1.4 ± 0.55
28.0 mg/kg 5/4 2.5 ± 1.0
---------------------------------------------------------------------------------------------------------------------------------------------------
P value 0.002
Cymelarsan 0.25 mg/kg 5/5 6.6 ±1.67
0.50 mg/kg 5/3 11.0 ± 1.0
1.0 mg/kg 5/0 Cured
2.0 mg/kg 5/0 Cured
---------------------------------------------------------------------------------------------------------------------------------------------------
P value 0.0001
Control Distilled water !0/10a Died after 3 days of post infection but
after one day of parasitemia detection.
a
= Treated /Died
RESULTS occurred after a heavy parasitemia development which
may last only 3 to 5 days after infection [20].
Diminazene diaceturate at doses 3.5mg/kg, 7mg/kg The results from the drug sensitivity showed that
and 14mg/kg body weight failed completely to cure but Diminazene diaceturate at dose range of 3.5mg/kg,
only 1(20%) mice was survived up to 60 days Which 7.0mg/kg, 14mg/kg body weight failed completely to cure
treated at dose of 28mg/kg body weight (Table 2). Trypanosoma equiperdum OVI South Africa strain due to
However, after 60 days of dexamethasone inoculation, sever parasitemia. However, only 1(20%) mouse was
parasitemia of dourine causing Trypanosoma spp (South survived up to 60 days after treatment with diminazene
Africa strain) was demonstrated in the blood of the diaceturate at dose of 28mg/kg body weight. The mean
mouse. In case of cymelarsan, mice infected with relapse interval for the dose range of 3.5mg/kg, 7.0mg/kg,
T.equipardum OVI South Africa strain and treated at dose 14.0mg/kg and 28mg/kg body weight used was 1± 0.0, 1.2±
of 0.25mg/kg body weight were failed completely to cure 0.45, 1.4 ±0.55 and 2.5 ± 1.0 days respectiviliy.
but 2(40%) of mice treated at a dose of 0.50mg/kg body From other similar studies it was indicated that
weight survived and the remaining 3(60%) mice were diminazene diaceturate is less effective against
relapsed within 11.0 ± 1.0 days. However, mice treated Trypanosomes of subgenus Trypanozoon than
with cymelarsan at higher doses of 1.0mg/kg and 2.0mg/kg T. congolense and T. vivax. This could be attributed
body weight were completely cured from the infection to the relatively rapid excretion of the drug [5].
with no relapse at least for more than 60 days. All mice in Moreover, diminazene diaceturate can not cross the
the control groups showed higher level of parasitaemia blood brain barrier and somatic tissue. Due to this
and died completely up to 4 days after infection. Hence, fact, it cannot be the curative drug for trypanosomes
as per this study the minimum curative dose (MDC) of with tissue affinity such as T. equiperdum [11, 12]. The
cymelarsan required to cure Trypanosoma equiperdum relapse of T. equiperdum after 60 days post diminazene
OVI from experimentally infected mice was recorded to be diaceturate therapy could be associated with the release
more than 1mg/kg. of the trypanosomes from tissues inaccessible by the
drug.
DISCUSSION Although diminazene diaceturate probably exerts its
action at the level of the kinetoplast DNA, this has not
Blood from infected horses produce disease very been proven in vivo and other mechanisms of action
rarely when inoculated directly in to healthy mice. cannot be excluded [21]. Similarly the molecular basis of
Therefore, in the current study the infection was first resistance to diminazene in trypanosomes is not clear. The
established in mouse using already prepared accumulation of diminazene was markedly reduced in
cryostabilates of the parasite from horse and then it was arsenical-resistant T. brucei brucei owing to alterations in
inoculated in to study mice groups. Parasite appeared in the nucleoside transporter system. However, there might
the blood of study mice with in 2 or 3 days and death be other resistance mechanisms [11].
10Europ. J. Biol. Sci., 7 (1): 07-13, 2014
The result from the drug sensitivity study showed treatment. Yet, currently stamping out strategy is applied
that only a single shoot of cymelarsan at dose of 1.0mg/kg by the OIE with slaughtering of CFT positive horses
and 2.0 mg/kg body weight becomes effective treatment where treatment is prohibited [30]. However, it is not
for Trypanosoma equiperdum OVI South Africa strain in economically feasible to apply strict test and slaughter
experimentally infected mice with no relapse for at least policy of the OIE to control dourine at least in developing
two months. However, cymelarsan at doses rate of country like Ethiopia. From the present study mice
0.25mg/kg body weight failed to cure the infection but in infected with T.equiperdum OVI South Africa strain were
case of 0.5mg/kg only 2(40%) mice survived. In lower cure after being treated with cymelarsan than those
doses of cymelarsan at 0.25mg/kg and 0.5mg/kg body treated with diminazene diaceturate. Therefore,
weight mean relapse intervals were between 6.6 ± 1.67 and cymelarsan can be recommended as choose of treatment
11.0 ±1.0 days. in controlling strategy of the studied Trypanosomes
Cymelarsan however, was found to be ineffective species.
against Trypanosoma equiperdum in mice at doses of
0.25mg/kg and 0.5mg/kg body weight. The inability of this CONCLUTION
drug to clear parasitemia in mice as well as domestic
animal at the standard dose of 0.25mg/kg for T.evansi Trypanocidal drugs remain the principal method of
has supported by previously reports. For instance animal Trypanosomiasis control in most African
cymelarsan was ineffective in buffaloes treated at doses counties. However, there is growing concern that future
ranging from 0.5mg/kg to 3mg/kg [22], in goats treated at effectiveness may be severely curtailed by wide spread
a dose of 0.3mg/kg [23], in mice treated at dose of 0.25 and drug resistance. The present study was done in
0.5mg/kg [24] and in cattle treated at a dose of 0.5mg/kg accordance with the aim of assessing the Trypanocidal
[25]. drug efficacy of diminazene diaceturate and cyamelarsan
Cymelarsan was found to be very effective against against T.equiperdum OVI South Africa strain in
T. equiperdum, T. evansi and T. brucei brucei, in horses, experimental infected mice. As study result indicate that
camels, buffalo, goats and pigs [11, 22, 23, 26]. The cymelarsan at dose rate of 1mg/kg and above was found
arsenical compound contains the trivalent arsenic element highly effective than diminazene diaceturate considering
with a markedly reactive arsenoxide group. The presence the toxicity of the drug if over dosed. Regarding animal
of arsenoxide confers the physicochemical ability of lipid welfare this would be a big step forward, because it can
solubility that allows passage across the blood brain release an alarming sign to the developed countries that
barrier (BBB) [27]. The arsenical compound melarsoprol apply the OIE’s test and slaughter policy. To combat the
revealed the remarkable ability to cross the BBB and kill problems associated with trypanosomes, further research
Trypanosoma brucei gambiense and Trypanosoma into existing drugs is a prerequisite for their optimal usage
brucei rhodesiense parasites residing in the CSF. in the overall effort of improving animal health and
It was clearly evident that cymelarsan was quite productivity through control of trypanosomiasis.
effective against T.evansi infection in camels at standard Therefore, in vitro assays should be performed to
recommended dose rate of 0.25mg/kg body weight [28]. detect drug resistance against the available isolates of
This ineffectiveness of the drug for the present study Trypanosoma equiperdum from equine rearing area of
probably confirms the suggestion made previously [23] Ethiopia where dourine is endemic and major problem.The
that the recommended dose might have been applied current strategies of OIE against dourine eradication
strictly for the treatment of camels only but the higher programmes should be reconsidered, since there could be
doses are needed to treat T. evansi in other animals and some effective drugs against Trypanosoma equiperdum.
mice. By the same scenario in the present study the mice Besides, The toxicity of the cymelarsan should further be
were treated under dosage where the metabolic weight of studied in Ethiopia before being imported and distributed
camels versus mice should be considered. it in endemic area to control dourine.
The proposed mechanism of action of the drug can
be explained in terms of the very strong binding ACKNOWLEDGEMENTS
characteristics of cymelarsan with targets on the parasite
known as thiol containing enzymes like glycerol-3- This investigation received financial support from
phosphate dehydrogenase (G3PDH) [29]. Ethio-Belgium VLIR-UOS funded dourine project and free
Hence, it can be recommended to the OIE to replace access of laboratory facilities, technical and kind support
the current strategy of eradication by an appropriate drug from Addis Ababa University College of Veterinary
11Europ. J. Biol. Sci., 7 (1): 07-13, 2014
Medicine. The authors also extend special 14. Hagos, A., 2005. Serological and parasitological
acknowledgement to Dr. Fufa Dawo, Dr. Yacob Hailu and survey of dourine (Trypanosoma equiperdum) in
Mr. Alemu senior laboratory technician for their selected site of Ethiopia. MSc Thesis, Addis Ababa
professional support. University, Faculty of Veterinary Medicine, Debre
Zeit, Ethiopia.
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