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Abstract
The aim of the present study was to determine the efficacy of 5-chloro-2-methylthio-6-(1-naphthyloxy)-ih-
benzimidazole called compound alfa, which was compared with two commercial fascioliscides through the
percentage of F. hepatica egg-reduction in naturally infected cattle. Forty Holstein-Friesian adult cows, previously
determined as positive to fluke eggs by the sedimentation test, were used. They were divided in 4 groups (G) of
10 animals each, and were treated with the corresponding dose on day cero. G1 was treated with compound alfa
at 12 mg/kg/per os; G2 with triclabendazole at 12 mg/kg/per os; G3 with closantel at 3.5 mg/kg subcutaneously, and
G4 remained as the non-treated control. All animals were sampled for feces to carry out coprological examinations
on days 15, 8, 0, 7, 14, 21, 28, 60 and 90. Efficacy was assessed on the reduction of egg output on days 14 and 21
after the treatment with respect to the control group. Results showed an efficacy of 90.1% and 85.3% for compound
alfa, 91.5% and 96.5% for triclabendazole and 82.1% and 92.1% for closantel. Additional parameters such as
percentage of prevalence, mean number of F. hepatica eggs, standard deviation, extension and intensity effect were
also measured. No statistical differences were found between treatments. It is concluded that all compounds tested
considerably reduced the percentage of egg excretion, showing an acceptable fasciolicide efficacy.
Resumen
Introduction Introduccin
asciolosis is one of the most important diseases a fasciolosis es una de las ms importantes
in cattle and sheep worldwide.1 This disease is enfermedades parasitarias del ganado vacuno
caused by the action and presence of Fasciola y ovino en el mundo.1 Esta enfermedad es
hepatica, a trematode which is located in the bile ducts ocasionada por la accin y presencia de Fasciola hepati-
of the hosts.2 Its importance lies in the tremendous ca, parsito que se aloja en los conductos biliares de sus
losses it produces via several means.3-6 Therefore, the hospederos.2 Su relevancia radica en cuantiosas prdi-
pharmaceuthic in Mexico industry has introduced a das que se generan por diversos conceptos.3-6 Por tal
considerable number of fasciolicides which are razn, la industria farmacutica ha introducido en
imported and are of high cost. Mxico un considerable nmero de compuestos fascio-
Compound alfa or 5-cloro-2-metiltio-6-(1- licidas, que son de importacin y de alto costo.
naftiloxi)-ih-bencimidazole is a bencimidazole de- El compuesto Alfa o 5-cloro-2-metiltio-6-(1-naftiloxi)-
rivative of Mexican synthesis (patent still pending), ih-bencimidazol es un derivado bencimidazlico de sn-
which has proven to be highly effective against dif- tesis mexicana (patente en trmite), el cual a travs de
ferent F. hepatica infections in sheep.7-11 It is a white varias evaluaciones quimioteraputicas ha demostrado
powder with a characteristic smell and has a molecu- ser altamente eficaz para eliminar infecciones por F.
lar weight of 340.86 g/mol; its melting point is 171- hepatica en ovinos.7-11 Es un polvo blanco con ligero olor
179oC and it is insoluble in water but slightly soluble caracterstico, con un peso molecular de 340.86 g/mol y
in organic solvents. It is rapidly metabolized to a un punto de fusin de 171-179oC, insoluble en agua y
sulphoxide and its elimination half-life ranges be- ligeramente soluble en disolventes orgnicos. Se meta-
tween 13.5 and 24.9 hours. In cattle the maximum boliza rpidamente a sulfxido, y su vida media de
level is reached at 18 h.12 eliminacin oscila entre las 13.5 y 24.9 horas. En bovinos
On the other hand, Wood et al.13 have mentioned that los niveles mximos se alcanzan a las 18 h.12
to evaluate the efficacy of compounds in clinical trials Por otro lado, Wood et al.13 sealan que para evaluar
under natural infection situations, the most recom- eficacia de compuestos en pruebas clnicas con infeccin
mended course of action is to evaluate egg and parasite natural, se recomienda evaluar la reduccin de huevos
reduction between days 14 and 21 post-treatment. o parsitos entre los das 14 y 21 postratamiento.
To date, there is no study concerning the fasciolicide Hasta la fecha no se cuenta con ningn estudio
activity of this compound in cattle. Thus, the aim of the sobre la actividad fasciolicida de este compuesto en
present study was to determine the efficacy of com- bovinos, por lo que el objetivo del presente estudio fue
pound alpha, through the percentage of egg reduction determinar la eficacia del compuesto alfa a travs del
in cattle naturally infected with Fasciola hepatica, by porcentaje de reduccin de huevos de F. hepatica en
comparing it with two commercial fasciolicides. ganado infectado en forma natural, para compararla
con la de dos fasciolicidas comerciales.
Material and methods
Material y mtodos
Location of the study
Localizacin del estudio
The study was carried out on the El Colorado ranch,
located in the municipality of Tulancingo in the State of El estudio se realiz en el rancho El Colorado, ubica-
Hidalgo, Mexico. do en el municipio de Tulancingo, Hidalgo, Mxico.
238
Animals Animales
Forty adult Holstein-Friesian cows naturally infected Se utilizaron 40 bovinos adultos de raza Holstein
with F. hepatica were used. Friesian infectados con F. hepatica en forma natural.
The animals were previously determined to be Los bovinos fueron previamente seleccionados como
positive to fluke eggs by the sedimentation test.14 positivos a huevos del parsito utilizando la tcnica
The average number of F. hepatica eggs obtained on coprolgica de sedimentacin.14 Con base en los prome-
day considerably 15 were used to evenly distribute dios de huevos de F. hepatica obtenidos en el da 15, los
the animals into four groups (G), each with ten animales fueron asignados proporcionalmente en cada
cows. On day zero, G1 was treated with compound grupo, tratando de obtener una distribucin uniforme.
alpha at 12 mg/kg per os ; G2, with triclabendazole Seguidamente se conformaron cuatro grupos (G) de
at 12 mg/kg per os ; G3, with closantel at 3.5 mg/kg diez animales cada uno. El da cero, el G1 fue tratado
subcutaneously, G4 made up the non-treated con- con el compuesto alfa a dosis oral de 12 mg/kg. El G2
trol. recibi triclabendazol a dosis oral de 12 mg/kg. El G3
recibi closantel por va subcutnea a dosis de 3.5 mg/
Coprological analysis kg. El G4 fungi como testigo sin tratamiento.
All animals were sampled for feces in order to per- Anlisis coproparasitoscpico
form coprological examinations on days15, 8, 0, 7,
14, 21, 28, 60 and 90. Individual egg counting was Se colectaron muestras fecales de los bovinos los das
carried out on 5 g of feces. The study concluded on 15, 8, 0, 7, 14, 21, 28, 60 y 90, para realizar de manera
day 90. individual los conteos de huevos de F. hepatica en 5 g de
heces. El estudio concluy el da 90.
Efficacy evaluation
Evaluacin de la eficacia
The criteria used to evaluate the efficacy of com-
pound alpha in the treated groups, with respect to El criterio para valorar la eficacia del compuesto alfa en
the non-treated control, were based on the percent- los grupos tratados con respecto al testigo sin trata-
age of positive samples obtained on days 14 and 21, miento, se realiz con base en el porcentaje de mues-
using the formula described by Besvir et al., 15 i n tras positivas obtenido en los das 14 y 21, utilizando la
which: frmula descrita por Besvir et al.,15 en donde:
Likewise, the intensity effect or mean number of Asimismo, se determin la intensidad o promedio
eggs per gram (epg), the standard error as well as the de huevos (x de hpg), la desviacin estndar, la mxi-
maximum and minimum quantity of eggs of the trema- ma y mnima cantidad de huevos del trematodo.
tode were determined. La informacin obtenida se someti a un anlisis no
The information obtained was submitted to paramtrico de Friedman, comparando el porcentaje
Friedmans non-parametric analysis for days 14 de eficacia entre los das 14 y 21 de cada grupo. Asimis-
and 21, comparing efficacy percentage between mo, el porcentaje de reduccin de huevos generado
groups. Kruskal-Wallis16 was used to compare the entre frmacos para los das sealados fue sometido a
same samples between different groups. un anlisis no paramtrico de Kruskal Wallis.16
When a statistical difference was observed, the Por otro lado, con los datos del conteo de huevos
Nemengi test17 was applied, using the difference obtenidos en cada uno de los muestreos, se compara-
between samples. ron los tratamientos utilizando la prueba de Kruskal
In addition, with the data obtained from all Wallis y en aquellos muestreos en donde se encontra-
samples obtained after treatment, the fasciolicide ron diferencias se procedi a realizar una comparacin
effect was determined and the extension effect (per- mltiple, utilizando la prueba de Nemengi.17
Results Resultados
The percentage of efficacy exerted by the El porcentaje de eficacia ejercida por los compuestos y
compounds and evaluated based on F. hepatica egg valorada con base en la reduccin de huevos de F. hepatica
reduction on days 14 and 21 post treatment, was en los das 14 y 21 postratamiento, fue de 90% y 85% para
90% and 85% for compound alpha; 91% and 96%, el compuesto alfa; 91% y 96% para triclabendazol y 82%
for triclabendazole and 82% and 92% for closantel, y 92% para closantel, respectivamente.
respectively. El anlisis estadstico no indic diferencias significati-
The statistical analysis showed no differences be- vas entre la eficacia conferida por los tratamientos. Sin
tween the efficacies exerted by the treatments; how- embargo, las comparaciones entre tratamientos contra el
ever, comparisons between treatments versus the nmero de huevos observados el da 15, fueron estadsti-
number of eggs observed on day 15, were statisti- camente diferentes (P < 0.05) el da 14 y (P < 0.01) el da 21.
cally different (P < 0.05) on day 14 and (P < 0.01) on La Figura 1 muestra el porcentaje de eficacia con
day 21. base en el seguimiento coprolgico secuencial con res-
Figure 1 shows the percentage of efficacy on the pecto al porcentaje de muestras positivas de fasciolosis
basis of sequential coprologic examinations with re- postratamiento para cada uno de los compuestos, a lo
spect to the percentage of positive samples post treat- largo del estudio, as como del grupo testigo. Se obser-
ment for each of the compounds, throughout the study, va una reduccin clara en el nmero de huevos en
as well as for the control group. A clear reduction on the heces a partir del da siete, llegando a valores ms bajos
number of eggs in feces from day seven was observed, el da 21 que empiezan a ascender para ser nuevamen-
lower values having been reached by day 21, then te positivos todos los grupos en el muestreo del da 60.
rising, with all groups being positive on samples from El anlisis estadstico indic que no haba diferencia
day 60. significativa entre grupos (P > 0.05).
Figura 1. Prevalencia fasciolosis postratamiento con los compuestos alfa, triclabendazol y closantel, as como del grupo no tratado en bovinos
infectados en forma natural.
Prevalence of fasciolosis post treatment with the compounds alpha, triclabendazole and closantel as well as the control group in naturally
infected cattle.
240
Cuadro1
PORCENTAJE DE REDUCCIN DE HUEVOS DE Fasciolahepatica
EN BOVINOS HOLSTEIN FREISIAN INFECTADOS EN FORMA NATURAL
PERCENTAGE OF EGG REDUCTION OF Fasciola hepatica
IN NATURALLYINFECTEDHOLSTEINFREISIANCATTLE
a
Comparisons in the same row or column with the same superscript, are not significant different (P>0.05).
* Comparisons of treatments versus the number of eggs on day 15 were statistically different (P<0.05)
for day 14 and (P<0.01) for day 21.
The statistical analysis showed no differences be- El Cuadro 2 muestra los conteos de huevos de F.
tween groups (P > 0.05). hepatica postratamiento. De manera general, se observa
Table 2 shows the F. hepatica egg counts post treatment. que el promedio de huevos por grupo correspondiente
It is generally observed that the egg average per group a cada fecha de muestreo, decrece en los das siete a 28.
corresponding to each sampling decreases from days Para el da 60, la eliminacin de huevos aumenta nue-
seven to 28. Elimination of eggs increases again by day 60, vamente y aparecen todos los bovinos positivos a hue-
when cattle are all positive to the trematode eggs. The vos del trematodo. El anlisis estadstico no mostr
statistical analyses showed no differences between the diferencias significativas entre los promedios de hue-
average numbers of eggs in the treated groups (P < 0.05). vos en los grupos tratados (P < 0.05).
By day seven the calculations carried out for com- Para el da siete los clculos efectuados para los compues-
pound alpha, triclabendazole and closantel were tos alfa, triclabendazol y closantel fueron de 60%, 80% y
60%, 80% and 20%, respectively. On day 21, com- 20%, respectivamente. Ya en el da 21, el alfa toma ventaja
pound alpha reached 70% on the extensity effect con 70% de efecto de extensin y 40% y 60% para
with 40% and 60% for triclabendazole and closantel, triclabendazol y closantel, respectivamente. Este efecto
respectively. This effect continued until day 28 in a contina para el da 28 en una relacin de 40%, 10% y 60%,
relation of 40%, 10% and 60%, respectively, and by respectivamente, y para los das 60 y 90, este parmetro ya
days 60 and 90, this parameter was impossible to no fue posible calcularlo, en virtud de que todos los anima-
calculate since all animals were positive to the tre- les estaban positivos a huevos del trematodo (Cuadro 3).
matode eggs (Table 3). El anlisis estadstico indic que no hubo diferen-
The statistical analysis indicated that no differences cias en el efecto de extensin al comparar tratamientos
were observed on the extension effect when treat- entre grupos (P < 0.05). Los datos obtenidos mostraron
ments were compared between groups (P < 0.05). The gran similitud para cada uno de los das de muestreo
data obtained showed great similarity for each of the analizados, por lo que el anlisis estadstico no registr
days analyzed, and therefore the statistical analysis diferencias en el efecto de intensidad de los frmacos.
did not register differences on the intensity effect of the
fasciolicides. Discusin
Discussion La fasciolosis bovina en Mxico rebasa considerable-
mente en importancia a la ovina,20 razn por la cual se
Bovine fasciolosis in Mexico is considerably more decidi comparar inicialmente la eficacia del compues-
important than ovine fasciolosis;20 this is the reason to alfa con dos de los fasciolicidas comerciales ms
Min - Max x E.D..** Min - Max x E.D..** Min - Max x D.E.** Min - Max x D.E.**
* Average of eggs with same script in the same row are not statistically different (P < 0.05).
** Standard deviation
*** Treatment
Cuadro3
EFECTO DE EXTENSIN E INTENSIDAD GENERADO POR LOS FASCIOLICIDAS EN BOVINOS
HOLSTEINFREISIANINFECTADOSENFORMANATURAL
EXTENSION AND INTENSITY EFFECT EXERTED BY THE FASCIOLICIDES IN NATURALLY INFECTED
HOLSTEIN FREISIAN CATTLE
A l p h a+ Triclabendazole + Closantel +
Days E.E.* I.E.** E.E. I.E. E.E. I.E.
% % % % % %
0 (Tx)
7 60 80 80 86 20 91
14 30 93 70 93 30 84
21 70 94 40 98 60 96
28 40 95 10 98 60 93
60 0 84 0 86 0 73
90 0 77 0 73 0 77
* Extensity effect.
** Intensity effect
242
why it was decided to initially compare the efficacy of utilizados en vacunos en el mundo, originalmente
compound alpha with two of the most used commercial usados para ganado ovino, analizando el porcentaje de
fasciolicides used in cattle worldwide which were reduccin de huevos del parsito.
originally used on sheep, by analyzing the percentage Powers et al.21 sealan que estas pruebas clnicas de
of egg reduction of the parasite. campo sobre porcentajes de reduccin de huevos del
Powers et al.21 have shown that these clinical field parsito aportan informacin muy valiosa, an cuando
tests on percentages of egg reduction afford very valu- se desconoce si todas las fasciolas fueron eliminadas.
able information even when it is not known whether De hecho, estos autores tambin mencionan que el
all fasciolas are eliminated or not. As a matter of fact, tiempo ms adecuado para evaluar la eficacia de un
compuesto es a los 14 o 21 das postratamiento, razn
these authors also mention that the most suitable time
por la cual se dio mayor relevancia a la informacin
to evaluate the efficacy of a compound is at 14 or 21
sobre eficacia obtenida en estos das.
days after treatment which is why greater relevance
Los datos colectados mostraron que ninguno de los
was given to these data.
fasciolicidas utilizados fueron capaces de eliminar a los
The collected data show that none of the fasciolicides trematodos presentes en los animales, segn se de-
used were capable of eliminating all present trema- mostr por la presencia de huevos los das 14 y 21,
todes in the animals, as was demonstrated by the respectivamente.
presence of fasciola eggs on days 14 and 21, respec- Ibarra et al. 22 e Ibarra y Vera 23 sealan que en bovinos
tively. fasciolosos con infeccin natural localizados en clima
Ibarra et al.22 and Ibarra and Vera 23 have pointed out templado (Tulancingo, Hidalgo, Mxico) y otros en
that in naturally infected bovines located in a temper- clima clido-hmedo (Nautla, Veracruz, Mxico), tra-
ate climate (Tulancingo, Hidalgo, Mexico) and others tados con triclabendazol a dosis oral de 12 mg/kg, no se
located in a warm humid climate (Nautla, Veracruz, eliminaron todas las fasciolas en virtud de que 30% del
Mexico), treated with triclabendazole at oral doses of ganado presentaban huevos del parsito a las tres
12 mg/kg, did not eliminate all fasciolas present since semanas postratamiento. Estas observaciones tambin
30% of cattle harbored parasite eggs three weeks after concuerdan con Quiroz,24 quien indica que despus de
the treatment. These observations are in accord with aplicar una dosis de 12 mg/kg de triclabendazol, se
Quiroz,24 who indicates that after a 12 mg/kg of encontr 25% de animales positivos.
triclabendazole dose, 25% of animals were found to be Echevarra et al.25 mencionan que hay reduccin en la
positive. excrecin de huevos aun sin tratamiento, como se puede
Echevarra et al.25 have mentioned that there is re- observar en el grupo testigo en los muestreos de los das
duction of egg excretion even without treatment, as 21 y 28. Esto tambin es explicable porque en bovinos la
can be observed in the control group in samples from produccin de huevos de Fasciola declina despus de
days 21 and 28. This can also be explained since, in que los parsitos han alcanzado los seis meses de edad.23
cattle, the egg production of F. hepatica decreases once Por otro lado, Shing-Sung et al.26 trataron 41 vacas
the parasites reach six months of age.23 fasciolosas con closantel a una dosis oral de 5 mg/kg. Sus
On the other hand, Shing-Sung et al.26 treated 41 resultados indicaron que desde la tercera semana postra-
tamiento, aparecieron huevos del trematodo, lo que refle-
cows with closantel at an oral dose of 5 mg/kg. Their
ja que algunas fasciolas inmaduras sobrevivieron hasta
results indicate that after the third week post treat-
alcanzar madurez y comenzaron a eliminar huevos.
ment, there were trematode eggs, indicating that some
En otro estudio, Romaniuk et al.27 sealan las bonda-
immature fasciolas survived and reached maturity,
des de closantel al administrarlo a dosis de 5 mg/kg/sc en
and then began to eliminate eggs. 2 335 bovinos jvenes con fasciolosis provenientes de
In another study, Romaniuk et al.27 administered ocho ranchos. Los autores sealan que al analizar mues-
closantel at a dose of 5 mg/kg/sc on 2 335 young cattle tras fecales de 560 reses tomadas al azar, para determinar
from eight ranches. The authors randomized 560 la presencia de huevos del trematodo, se obtuvo una
fecal samples, which were analyzed to determine eficacia de 97.5%. Al comparar esta informacin con los
the presence of eggs of the trematode; 97.5% efficacy datos de Shing-Sung et al.26 y con la del presente estudio,
was obtained. This information was analyzed with se observan nuevamente diferencias de eficacia que
the data of Shing-Sung et al.26 and some differences pueden indicar una falta de constancia para mantener
of the efficacy were observed which might indicate actividad fasciolicida con este frmaco a la dosis reco-
a lack of consistence in maintaining the fasciolicide mendada. En el presente estudio, el comportamiento de
activity with this compound at the recommended closantel fue mejor al citado por estos autores.
dose. In the present study, the performance of Con relacin a los efectos de extensin e intensidad,
closantel was better than the one mentioned by se observ que sus valores fueron disminuyendo en los
Shing-Sung et al.26 muestreos ms cercanos al da del tratamiento y poste-
244
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