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Pharmacokinetic assessment of tylosin concomitantly administered with two anticoccidials diclazuril and halofuginone in broiler chickens.

Introduction

'Pharmacokinetic drug interactions are of great clinical significance in veterinary practice. Drugs have the same metabolic pathway usually show drug interactions in its concomitant administration [1,9]. These constitute a major problem facing the poultry production as many compounds (Over 13) have been usually add to poultry rations as feed additives [21] which may interact with any administered therapeutic agent. From this view point dosages of antimicrobials used in poultry farms must be adjusted to compensate for its interaction with these additives. Anticoccidials are one of these compounds, their programes have been substantially varied in its clinical application in poultry farms [26,15]. Diclazuril is a benzeneacetonitrile anticoccidial used in concentration of 1 ppm in poultry ration for treatment of coccidiosis [28,37]. Halofuginone is derived from an alkaloid isolated from Dichroa febrifuga plant [16]. It was established to be used, as coccidiostat at concerntration of 1.5 ppm and coccidiocidal at 3 ppm in poultry rations [10].

Tylosin is one of macrolide antibiotics, highly active than other antibiotics (e.g. vancomycin and gentamycin) mainly on aerobic garm--positive cocci and bacilli [32] and mycoplasma [2] Like all members of this group it has affenity to achieve higher tissue concentrations as much as 5 - 10 times serum concentrations [39,40]. Mycoplasma gallisepticum and Mycoplasma synoviae have shown sensitivity in vitro and in vivo to several antimicrobials including macrolides [22]. Interaction between anticoccidals and macrolides (e.g. erythromycin) has been studied [27,34,38]. The aim of this study is to emphasies the effect of diclazuril and halofuginone on the disposition kinetic of tylosin in broiler chickens.

Material and methods

I. Drugs:

* Tylosin (Tylan)[R]: It was obtained from Elanco-AF 1300--Speke Liverpool, England, as tylosin tartrate (98% tylosin base) in a pure water soluble powdered form, the administered doses calculated depending on the tylosin base.

* Diclazuril (Clinacox [R]): It is supplied by Pharmaceutic Animal Health Division Pfizer. It is formulated as a premix 0.5%.

* Halofuginone hydrobromide (Stenorol [R]): Supplied by Hoechst-Russel Vet. Co., as powdered form containing 0.5 g halofuginone per kg powder.

II. Birds:

One hundred and twinty five healthy broiler (Hubard breed) chickens of both sex with an average body weight of 1000-1500 g and of 45-50 day old age were used. They were housed in cages and supplied with water ad-libitum. Chickens were fed on a balanced ration free from any anticoccidial and antibiotic drugs for 15 days before starting experiments to ensure complete clearance of their bodies from any drug residues.

Experimental design:

1- Single dose studies (Pharmacokinetic studies):

Three main groups of 10 chickens each were used. Birds of the 1st group were fed on anticoccidial --free ration allover the study. Those in the 2nd and 3rd groups were fed on a ration containing diclazuril (1 ppm) and halofuginone (3 ppm) for 5 consecutive days, respectively. At the end of 5th day of feeding, Tylosin was dose injected i.v. in a single dose (25 mg.[kg.sup.-1] b.wt.) in the right brachial wing vein of each bird of these 3 main groups.

Blood samples were taken from the left brachial wing vein of each chicken just before and at 5, 10, 15, 30 min and 1, 2, 4, 6, 8 and 10 hours post antibiotic injection. Blood samples were allowed to clot at room temperature, centrifuged at 3000 g. for 15 min. and serum were collected and stored at--20[degrees]C until assayed for tylosin.

These chickens were kept for 15 days devoid of any antibiotic or anticoccidial drugs to ensure complete withdrawal of the administered drugs. Each of the 3 main groups was subdivided into 2 subgroups of 5 chickens each. Chickens in the 2nd and 3rd groups were fed on diclazuril and halofuginone containing ration, respectively for 5 consecutive days, while those of the 1st group were kept free of anticoccidial therapy. At the 5th day of feeding, Tylosin was administered in a single oral dose as 25 mg.kg-1 b.wt. and [micro]g.ml-1 to be consistent with the figures and tables in the results to all the chickens of the 1st subgroups, whereas those of the 2nd subgroups received tylosin intramuscularly in the in the thigh with the same dose.

Blood samples were collected from each bird in all groups at the same time intervals as mentioned before. Serum samples were collected and stored at -20[degrees]C until assayed for tylosin.

2- Multiple dose study:

Three groups of 30 birds each were used in this study. Chickens of the 1st group were fed an anticoccidial--free ration allover the time of experiment. Those in the 2nd and 3rd groups were fed on diclazuril (1 ppm) and halofuginone (3 ppm) containing rations, respectively allover the experiment. At the end of 5th day of feeding each of the 3 groups were subdivided into 2 equal subgroups of 15 chickens each. Tylosin was administered orally (25 mg/kg b.wt.) to birds of the three 1st subgroups, whereas it is injected intramuscularly in those of the three 2nd subgroups. This is continued once daily for 5 consecutive days

in all groups. Blood samples were collected every 24 h for 5 successive days from the wing viens of 5 markerd chickens in each subgroup. Serum was separated and stored at -20[degrees]C until assayed for tylosin. From each subgroup 3 chickens were slaughtered at the 1st. 3rd., 5th., 7th. and 9th. day after the last dose of antibiotic administration.

Tissue samples (1 gm for each sample) including liver, spleen, lung, kidney, heart, breast and thigh muscles were collected from each slaughtered chicken, stored at -20[degrees]C until tylosin assay. One gram of each sample was homoginised with 5 ml 0.1 M phosphate buffer (pH 7.9) and centrifuged at 3000 g for 15 minutes. Supernatante fluid then assayed for tylosin concentration.

Analytical procedure:

Tylosin concentration in serum and tissue samples was determined by the microbiological assay method using Micrococcus luteus as a test organism [4]. Standard curve for tylosin was constructed using antibiotic-free pooled serum samples collected by slaughtering of 5 non-medicated chickens. The in vitro protein binding percent of the tested antibiotic was determined by the method of Craig and Suh [8] with concentrations of 0.156, 0.125, 0.1, 0.08 and 0.064 ug.[ml.sup.-1]. The experimental samples and standards were analysed in triplicate. The measured widths of the zones of inhibition were converted to concentrations using standard curves developed for each plate. Standard curves were prepared as described by [13]. The calibration graphs obtained for tylosin in serum were linear within the range 0.08-0.156/[micro]g/ml; Y = 14.2 + 17.5x. the average recovery was 105%, the overall precision (between days, reported relative standard deviation) was 24%, and the limit of detection for the assay for serum samples was 0.05 [micro]g/mL.

Pharmacokinetic analysis:

A computerized curve stripping software program (Rstrip, Micromath Scientific software, Salt lake city, UT, USA) was used for determination of the best-fit compartmental model and for estimation of the model dependent pharmacokinetic parameters. Following i.v. injection, tylosin serum concentration time data for each chicken was fitted a two-compartment open model according to the following equation:

Cp = [Ae.sup.-at] + [Be.sup.-bt]

Where Cp = is the serum drug concentration at time t. A and B= the intercepts of the distribution and elimination lines with the concentration axis, respectively, they were expressed in ug.[ml.sup.-1].

[alpha] and b are the distribution and elimination rate constants, respectively, expressed in units of reciprocal time ([h.sup.-1]). e is the base of natural logarithm. The distribution and elimination half-lives ([t.sub.1/2a] and [t.sub.1/2b]), the rate constants for drug transferring from central compartment to peripheral one ([K.sub.12]) and from tissues to central compartment again ([K.sub.21]). The volume of distribution were calculated by the area ([Vd.sub.area]) and B ([Vd.sub.B]) methods. The total body clearance ([Cl.sub.B]) were calculated according to standard equations of Baggot [3] as follows:

[T.sub.1/2[alpha][beta]] = 0.693/[alpha] or [beta]l)

[Vd.sub.area] = dose/[AUC.sub.o -[alpha]] . [beta] L.[kg.sup.-1]

[Vd.sub.[beta] = dose/B L. [kg.sup.-1]

[CL.sub.B] = [K.sub.ei]. Vc (L.[h.sup.-1] . [kg.sup.-1]).

Following oral and I.M. administrations, data were analysed by compartmental and non-compartmental methods based on the statistical moment theory [36]. The peak plasma concentration ([C.sub.max]) and the time needed to reach this concentration ([T.sub.max]) were calculated mathematically by the following equations:

[T.sub.max] = 2.303/Ka - Kel log [K.sub.a]/K.sub.el]

[C.sub.max] = [Ae.sup.-kel] [t.sub.max] - [Be.sup.-kab] [t.sub.max]

Where [K.sub.a] is the absorption rate constant ([h.sup.-1]) and [K.sup.el] is the elimination rate constant ([h.sup.-1]). [AUC0.sub.-a] is the area under the serum concentration time curve from zero to the infinity by the trapezoidal rule.

The systemic bioavailability (F)= [AUC.sub.I.V]/AUC oral or IM] X 100.

The obtained results are represented as mean [+ or -] standard error (S.E.). The pharmacokinetic parameters in presence and absence of diclazuril and halofuginone were statistically analyzed using students t-test [35].

Results and discussion

The semilogarithmic serum concentrations-time curves of tylosin following I.V. injection in a single dose (25 mg.kg b.wt.) in chickens fed control ration, diclazuril and halofuginone containing ones are depicted in Figure 1. The obtained kinetic parameters are represented in Table 1. The drug concentrations were decreased gradually in a biphasic pattern that follow a 2--compartment open model. The corresponding kinetic parameters are described in Table 1.

The semilogarithmic serum concentration--time curves of tylosin after oral and I.M. administrations in a single dose (25 mg.kg b.wt.) in chickens fed anticoccidial free ration, diclazuril and halofuginone containing ones are plotted in Fig. 2 and 3 respectively. The obtained pharmacokinetic variables following oral dosing and I.M. injection are recorded in tables 2 and 3 respectively.

Consecutive daily single oral dosing of tylosin (25 mg/kg b.wt.) for 5 days showed that the drug was not detected in the serum at 24h after 1st dosing neither for tylosin alone nor in presence of the tested anticoccidials. After the 2nd dosing, the drug serum concentration could be still detected at 24h post dosing and these concentrations were progressively increased till the last dosing both in tylosin alone and in presence of diclazuril. However constant antibiotic level was determined in presence of halofuginone (Figure 4).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

[FIGURE 3 OMITTED]

Results of consecutive daily I.M. injection for 5 days in the same previous dose are plotted in Figure 5. The drug was not detected at 24 h after the 1st injection. These followed by constant daily tylosin serum concentrations at 24 h after each injection either for tylosin alone and in presence of halofuginone. Meanwhile, gradual increase in the drug concentration was recorded in presence of diclazuril.

Tissue residues of the tested antibiotic following oral and I.M. administrations in a single dose (25 mgLkg b.wt.) for 5 consecutive days for tylosin alone, and in presence of diclazurile or halofuginone are represented in Table 4 and 5 respectively.

The in vitro serum protein binding percentage of tylosin in chicken's serum fed anticiccidial free ration was in average value of 20.32 %.

Discussion

After intravenous injection of tylosin (25 mg/kg b.wt.) in broiler chickens fed anticoccidial free, diclazuril or halofuginone containing rations the drug serum concentration -time curve was best to be described by a two compartment open model. This is in accordance with [24] in broiler chickens. Significant lowered tylosin serum concentrations were recorded in presence of diclazuril with a short distribution half-life ([t.sub.1/2[alpha]) 8.46 [+ or -] 0.28 min. Compared with 12.13 [+ or -] 0.59 min for tylosin alone indicates more rapid drug distribution in presence of diclazuril. This is confirmed by the higher value of [K.sub.12]/[K.sub.21] (3.12 [+ or -] 0.13) and volume of distribution represented as [Vd.sub.B] (15.02 [+ or -] 0.91 L/kg) and [Vd.sub.area] (12.96 [+ or -] 0.82 L/kg) in presence of diclazuril than drug alone (9.24 [+ or -] 0.86 and 8.34 [+ or -] 0.72 L/kg, respectively). High diclazuril protein binding affinity recorded by [11] in his study on horses could be explain this rapid tissue distribution of tylosin in diclazuril treated chickens. Differences in the extent of serum or plasma protein binding affinity of certain drug have been claimed to explain the recorded difference in pharmacokinetic variables [33,12]. Incontrast significant higher tylosin serum concentrations with a prolonged [t.sub.1/2[alpha] (18.52 [+ or -] 0.64 min) and lowered values of [K.sub.12]/[K.sub.21] ratio (1.26 [+ or -] 0.12), [Vd.sub.B] (5.84 [+ or -] 0.403 L/kg) and [Vd.sub.area] (5.79 [+ or -] 0.38 L.kg) in halofuginone treated chickens evidenced lower tylosin tissue distribution.

Competation between halofuginone and tylosin on the same tissue binding sites could be explain these findings holofuginone was previously determined in higher concentration in tissues than plasma in study of [23] in cattle. Lowering in tylosin tissue distribution was previously recorded in chicks fed flavomycin, Vitamine A. or new naphthoquinone antibiotic "A 149" containing ration [29].

Following oral administration in a single dose (25 mg/kg) a short absorption half life ([t.sub.1/2ab]) (8.29 [+ or -] 0.67 min) associated with high absorption constant rate ([K.sub.ab]) (5.23 [+ or -] 0.37 [h.sup.-1]) in presence of diclazuril than in drug alone (16.72 [+ or -] 1.13 min and 2.7 [+ or -] 0.393 [h.sup.-1], respectively). These revealed enhancement of tylosin absorption from the gut under the influence of diclazuril. In spite of, loweing in drug serum concentration which explained by high protein binding property for diclazuril [11].

A significant prolonged [t.sub.1/2ab] (40.95 [+ or -] 5.94 min) was obtained for tylosin in presence of halofuginone accompanied by lowered [K.sub.ab] (1.013 [+ or -] 0.064 [h.sup.-1]) indicating delayed drug absorption. Prolonged [t.sub.1/2ab], [T.sub.max] and [t.sub.1/2el] were previously recorded for tylosin orally administered in chickens fed avilamycin containing ration [30]. [C.sub.max] value obtained for tylosin alone (0.92 [+ or -] 0.12 ug/ml) attained at ([t.sub.max]) 1.58 [+ or -] 0.09 h was near to 1.2 ug/ml at 1.5h for a dose of 10 mg/kg b.wt. in normal chickens [24]. However it was higher than 0.403 [+ or -] 0.072 ug/ml reached at a prolonged time 3h for a dose of 20 mg/kg b.wt. [5]. Significant higher [C.sub.max] values were recorded for the drug both in presence of diclazuril (1.25 [+ or -] 0.074 ug/ml) attained at significant short time ([t.sub.max]) (0.84 [+ or -] 0.06 h) and in presence of halofuginone (1.59 [+ or -] 0.142 ug/ml) at a prolonged time (2.06 [+ or -] 0.14 h). The systemic bioavailability was non significantly higher in presence of diclazuril (78.92 [+ or -] 5.29%) than for drug alone (62.79 [+ or -] 5.48%) which is consequent result to lowered AUC both after oral and I.V. administrations owing to rapid drug tissue distribution as obtained following I.V. injection. Also non significant higher F% obtained in halofuginone treated birds (70.48 [+ or -] 6.85%) was resulted from elevated AUC values both after oral and I.V. administrations which explained by lowering in tylosin distribution in presence of halofuginone.

Following I.M. injection tylosin was rapidly absorbed either in presence of diclazuril or halofuginone than drug alone. That observed from significant short [t.sub.1/2ab] (4.29 [+ or -] 0.47 and 3.57 [+ or -] 0.146 h) and elevated [K.sub.ab] (7.29 [+ or -] 0.53 and 11.49 [+ or -] 1.79 [h.sup.-1]) respectively. Significant higher [C.sub.max] values were recorded both in diclazuril (1.83 [+ or -] 0.064 ug/ml) and halofuginone treated chickens (4.67 [+ or -] 0.28 ug/ml) than drug alone (0.408 [+ or -] 0.52 ug/ml). These attained at ([T.sub.max]) 0.49 [+ or -] 0.083 and 0.32 [+ or -] 0.024 and 0.79 [+ or -] 0.052 h, respectively.

Higher [C.sub.max] values were recorded in quil, pigeons and cranes (4.31, 5.63 and 3.62) [25] than our recorded one for drug alone. The lowered systemic bioavailability (F%) for drug alone (21.54 [+ or -] 1.86%) indicating lesser tylosin absorption from I.M. injection site. However this value was significantly increased to be 80.49 [+ or -] 6.81 and 94.28 [+ or -] 7.78% in diclazuril and halofuginone administered birds.

Regarding the multiple dose study either for oral and I.M. administrations (25 mg/kg b.wt.) once daily for 5 consecutive days) it is revealed that tylosin was not detected at 24 h following the 1st dosing either for drug alone, or in presence of the tested anticoccidials. This is an expected result for the short [t.sub.1/2el] recorded either for the orally and I.M. administered drug.

Cummulative tendency was noticed for the drug serum concentrations (both for oral and I.M. route) beginning from the 1st - 5th, 24 h post dosing during daily administration either for tylosin alone and in presence of diclazuril. These with significant higher conc. in diclazuril treated chickens. Otherwise stable drug concentration was determined at the 2nd till the 5th 24h post dosing for bothe oral and I.M. administration in presence of halofuginone.

These obtained concentrations either for drug alone or concomitantly administered with the tested anticoccidials were higher than the MIC of tylosin < 1 ug.[ml.sup.-1] and MIC for Mycoplasma species 0.5 -0.62 ug.[ml.sup.-1] [20,7]. Accordingly tylosin oral or I.M. administration in the tested dose once daily for 5 days could maintaine a sufficient therapeutic serum level in broiler chickens.

Tissue residue studies following either oral and 1. M. administration evidenced that tylosin was still detected in all the tested samples for 5 days after stopping of drug administration. The highest concentration was recorded in lung for the orally administered drug. [9] determined tylosin in lung tissue of broiler chickens in 5.15 times more higher than in serum. Following I.M. injection the highest concentration was recorded in thigh muscle reflecting to lesser tylosin absorption from site of injection. In this respect [31] recorded persistence of tylosin for 25 day in the injection site following I.M. injection (62.5 mg) in broiler chickens, while it was detected only for 3, 6 and 5 days in the uninjected site, liver and kidney respectively. Non significant differences were obtained in drug tissue conc. following either oral and I.M. administrations in presence of the tested anticoccidials.

For oral dosing all tissues were considered tylosin free at the 9th day post dosage cessation. However following I.M. injection the drug still detected in thigh muscle of diclazuril treated birds, thigh muscle, lung and heart in halafuginone treated ones at the 9th day after stopping of injection.

References

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Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, B.O. Box 12211 Giza, Egypt.

Corresponding Author

Aziza M.M. Amer, Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, B.O. Box 12211 Giza, Egypt.

E-mail: aziza_amer@hotmail.com Fax: 002025725240
Table 1: Mean kinetic parameters of tylosin (25 mg.[kg.sup.-1] b.wt.)
following a single intravenous injection in chickens fed anticoccidial
free, diclazuril (1 ppm) and halofuginone (3 ppm) containing rations
(n = 10).

                                                 Mean [+ or -] S.E.

Parameter              Unite                          Tylosin

Cp[degrees]            [micro]g.[ml.sup.-1]     10.37 [+ or -] 0.64
A                      mg.[ml.sup.-1]            7.45 [+ or -] 0.64
a                      [h.sup.-1]                3.49 [+ or -] 0.14
[t.sub.1/2[alpha]]     min.                     12.13 [+ or -] 0.59
[K.sub.21]             [h.sup.-1]                1.13 [+ or -] 0.05
[K.sub.12]             [h.sup.-1]                2.11 [+ or -] 0.12
[K.sub.12]/[K.sub.21]                            2.01 [+ or -] 0.16
Vc                     L.[kg.sup.-1]             2.53 [+ or -] 0.18
[Vd.sub.(B)]           L.[kg.sup.-1]             9.24 [+ or -] 0.86
[Vd.sub.(ss)]          L.[kg.sup.-1]              3.9 [+ or -] 0.29
[Vd.sub.(area)]        L.[kg.sup.-1]             8.34 [+ or -] 0.72
B                      [micro]g.[ml.sup.-1]      2.92 [+ or -] 0.26
[beta]                 [h.sup.-1]                0.13 [+ or -] 0.002
[t.sub.1/2[beta]]      h                         5.35 [+ or -] 0.09
[AUC.sub.o-[alpha]]    [micro]g.[ml.sup.-1].     24.7 [+ or -] 2.11
                       [h.sup.-1]
[CL.sub.tot]           L.kg.[h.sup.-1]           1.07 [+ or -] 0.09
[K.sub.el]             [h.sup.-1]                0.43 [+ or -] 0.023

                                                 Mean [+ or -] S.E.

Parameter              Unite                    Tylosin + diclazuril

Cp[degrees]            [micro]g.[ml.sup.-1]   8.134 [+ or -] 0.54 *
A                      mg.[ml.sup.-1]          6.47 [+ or -] 0.27
a                      [h.sup.-1]              5.18 [+ or -] 0.14 ***
[t.sub.1/2[alpha]]     min.                    8.46 [+ or -] 0.28 ***
[K.sub.21]             [h.sup.-1]             1.184 [+ or -] 0.05
[K.sub.12]             [h.sup.-1]              3.38 [+ or -] 0.15 ***
[K.sub.12]/[K.sub.21]                          3.12 [+ or -] 0.13 ***
Vc                     L.[kg.sup.-1]           3.02 [+ or -] 0.12 *
[Vd.sub.(B)]           L.[kg.sup.-1]          15.02 [+ or -] 0.91 ***
[Vd.sub.(ss)]          L.[kg.sup.-1]           4.21 [+ or -] 0.19
[Vd.sub.(area)]        L.[kg.sup.-1]          12.96 [+ or -] 0.82 ***
B                      [micro]g.[ml.sup.-1]    1.58 [+ or -] 0.07 ***
[beta]                 [h.sup.-1]             0.124 [+ or -] 0.006
[t.sub.1/2[beta]]      h                       5.47 [+ or -] 0.18
[AUC.sub.o-[alpha]]    [micro]g.[ml.sup.-1].  14.65 [+ or -] 0.964 ***
                       [h.sup.-1]
[CL.sub.tot]           L.kg.[h.sup.-1]         1.72 [+ or -] 0.101 **
[K.sub.el]             [h.sup.-1]              0.56 [+ or -] 0.016 ***

                                                 Mean [+ or -] S.E.

Parameter              Unite                   Tylosin + halofuginone

Cp[degrees]            [micro]g.[ml.sup.-1]   10.63 [+ or -] 0.58
A                      mg.[ml.sup.-1]          5.18 [+ or -] 0.44
a                      [h.sup.-1]              2.21 [+ or -] 0.21 ***
[t.sub.1/2[alpha]]     min.                   18.52 [+ or -] 0.64 ***
[K.sub.21]             [h.sup.-1]             1.304 [+ or -] 0.08
[K.sub.12]             [h.sup.-1]              1.75 [+ or -] 0.08 *
[K.sub.12]/[K.sub.21]                          1.26 [+ or -] 0.12 **
Vc                     L.[kg.sup.-1]           2.41 [+ or -] 0.13
[Vd.sub.(B)]           L.[kg.sup.-1]           5.84 [+ or -] 0.403 **
[Vd.sub.(ss)]          L.[kg.sup.-1]           4.05 [+ or -] 0.36
[Vd.sub.(area)]        L.[kg.sup.-1]           5.79 [+ or -] 0.38 **
B                      [micro]g.[ml.sup.-1]    4.47 [+ or -] 0.29 ***
[beta]                 [h.sup.-1]             0.129 [+ or -] 0.002
[t.sub.1/2[beta]]      h                       5.37 [+ or -] 0. 13
[AUC.sub.o-[alpha]]    [micro]g.[ml.sup.-1].  31.47 [+ or -] 1.59 *
                       [h.sup.-1]
[CL.sub.tot]           L.kg.[h.sup.-1]         0.83 [+ or -] 0.07
[K.sub.el]             [h.sup.-1]              0.35 [+ or -] 0.02 *

* Significant at P [less than or equal to] 0.05.

** Significant at P [less than or equal to] 0.01.

*** Significant at P [less than or equal to] 0.001.

Table 2: Mean kinetic parameters of tylosin (25 mg.[kg.sup.-1] b.wt.)
following a single oral administration in chickens fed anticoccidial
free, diclazuril (1 ppm) and halofuginone (3 ppm) containing rations
(n = 10).

                                                 Mean [+ or -] S.E.

Parameter              Unite                          Tylosin

A                      [micro]g.[ml.sup.-1]      1.35 [+ or -] 0.144
[K.sub.ab]             [h.sup.-1]                 2.7 [+ or -] 0.398
[T.sub.1/2ab]          min.                     16.72 [+ or -] 1.13
B                      [micro]g.[ml.sup.-1]      2.08 [+ or -] 0.178
[K.sub.el]             [h.sup.-1]               0.126 [+ or -] 0.009
[t.sub.1/2el]          h                         5.67 [+ or -] 0.28
[C.sub.max]            [micro]g.[ml.sup.-1]      0.92 [+ or -] 0.12
[T.sub.max]            h                         1.58 [+ or -] 0.09
AUC                    [micro]g.[ml.sup.-1].   15.508 [+ or -] 2.39
                       [h.sup.-1]
F                      %                        62.79 [+ or -] 5.48

                                                 Mean [+ or -] S.E.

Parameter              Unite                    Tylosin + diclazuril

A                      [micro]g.[ml.sup.-1]    1.34 [+ or -] 0.081
[K.sub.ab]             [h.sup.-1]              5.23 [+ or -] 0.37 **
[T.sub.1/2ab]          min.                    8.29 [+ or -] 0.67 ***
B                      [micro]g.[ml.sup.-1]    1.63 [+ or -] 0.096
[K.sub.el]             [h.sup.-1]             0.138 [+ or -] 0.019
[t.sub.1/2el]          h                       4.57 [+ or -] 0.26 *
[C.sub.max]            [micro]g.[ml.sup.-1]    1.25 [+ or -] 0.074 *
[T.sub.max]            h                       0.84 [+ or -] 0.06 ***
AUC                    [micro]g.[ml.sup.-1].  11.56 [+ or -] 1.62
                       [h.sup.-1]
F                      %                      78.92 [+ or -] 5.29

                                                 Mean [+ or -] S.E.

Parameter              Unite                   Tylosin + halofuginone

A                      [micro]g.[ml.sup.-1]    2.38 [+ or -] 0.22 **
[K.sub.ab]             [h.sup.-1]             1.013 [+ or -] 0.064 **
[T.sub.1/2ab]          min.                   40.95 [+ or -] 5.94 ***
B                      [micro]g.[ml.sup.-1]    3.14 [+ or -] 0.253 **
[K.sub.el]             [h.sup.-1]             0.128 [+ or -] 0.016
[t.sub.1/2el]          h                       5.08 [+ or -] 0.148
[C.sub.max]            [micro]g.[ml.sup.-1]    1.59 [+ or -] 0.142 **
[T.sub.max]            h                       2.06 [+ or -] 0.14 *
AUC                    [micro]g.[ml.sup.-1].  22.18 [+ or -] 3.13
                       [h.sup.-1]
F                      %                      70.48 [+ or -] 6.85

* Significant at P [less than or equal to] 0.05.

** Significant at P [less than or equal to] 0.01.

*** Significant at P [less than or equal to] 0.001.

Table 3: Mean kinetic parameters of tylosin (25 mg.[kg.sup.-1] b.wt.)
following a single intramuscular injection in chickens fed
anticoccidial free, diclazuril (1 ppm) and halofuginone (3 ppm)
containing rations (n = 5).

                                                 Mean [+ or -] S.E.

Parameter              Unite                          Tylosin

A                      [micro]g.[ml.sup.-1]      0.54 [+ or -] 0.078
[K.sub.ab]             [h.sup.-1]                4.29 [+ or -] 0.38
[T.sub.1/2ab]          min.                     10.25 [+ or -] 1.08
B                      [micro]g.[ml.sup.-1]      1.19 [+ or -] 0.095
[K.sub.el]             [h.sup.-1]                0.22 [+ or -] 0.015
[t.sub.1/2el]          h                        3.202 [+ or -] 0.24
[C.sub.max]            [micro]g.[ml.sup.-1]     0.408 [+ or -] 0.52
[T.sub.max]            h                         0.79 [+ or -] 0.052
AUC                    [micro]g.[ml.sup.-1].     5.32 [+ or -] 0.29
                       [h.sup.-1]
F                      %                        21.54 [+ or -] 1.86

                                                 Mean [+ or -] S.E.

Parameter              Unite                    Tylosin + diclazuril

A                      [micro]g.[ml.sup.-1]    2.15 [+ or -] 0.13 ***
[K.sub.ab]             [h.sup.-1]              7.29 [+ or -] 0.53 **
[T.sub.1/2ab]          min.                    4.29 [+ or -] 0.47 ***
B                      [micro]g.[ml.sup.-1]    2.08 [+ or -] 0.11 ***
[K.sub.el]             [h.sup.-1]             0.172 [+ or -] 0.014 *
[t.sub.1/2el]          h                        4.1 [+ or -] 0.27 *
[C.sub.max]            [micro]g.[ml.sup.-1]    1.83 [+ or -] 0.064 ***
[T.sub.max]            h                       0.49 [+ or -] 0.083 *
AUC                    [micro]g.[ml.sup.-1].  11.79 [+ or -] 0.85 ***
                       [h.sup.-1]
F                      %                      80.49 [+ or -] 6.81 ***

                                                 Mean [+ or -] S.E.

Parameter              Unite                   Tylosin + halofuginone

A                      [micro]g.[ml.sup.-1]    5.36 [+ or -] 0.458 ***
[K.sub.ab]             [h.sup.-1]             11.49 [+ or -] 1.79 ***
[T.sub.1/2ab]          min.                    3.57 [+ or -] 0.146 ***
B                      [micro]g.[ml.sup.-1]    6.75 [+ or -] 0.38 ***
[K.sub.el]             [h.sup.-1]             0.224 [+ or -] 0.012
[t.sub.1/2el]          h                       3.14 [+ or -] 0.17
[C.sub.max]            [micro]g.[ml.sup.-1]    4.67 [+ or -] 0.28 ***
[T.sub.max]            h                       0.32 [+ or -] 0.024 ***
AUC                    [micro]g.[ml.sup.-1].  29.67 [+ or -] 2.49 ***
                       [h.sup.-1]
F                      %                      94.28 [+ or -] 7.78 ***

* Significant at P [less than or equal to] 0.05.

** Significant at P [less than or equal to] 0.01.

*** Significant at P [less than or equal to] 0.001.

Table 4: Mean [+ or -] S.E. of tylosin tissue concentration (ppm)
following oral administration (25 mg.[kg.sup.-1] b.wt.) once daily
for 5 consecutive days in chickens fed anticoccidial free, diclazuril
(1 ppm) and halofuginone (3 ppm) containing ration (n = 3).

                                  Mean [+ or -] S.E.

                                       Tylosin

Tissue                   1st day                     3rd day

Liver             2.078 [+ or -] 0.14          1.306 [+ or -] 0.107
Lung              2.078 [+ or -] 0.16          1.648 [+ or -] 0.124
Spleen            1.648 [+ or -] 0.113         1.306 [+ or -] 0.097
Kidney            1.648 [+ or -] 0.12          1.306 [+ or -] 0.104
Heart              1.58 [+ or -] 0.126         1.306 [+ or -] 0.11
Thigh Muscle      1.035 [+ or -] 0.088        0.8206 [+ or -] 0.042
Breast Muscle      1.18 [+ or -] 0.087         0.922 [+ or -] 0.047

                                  Mean [+ or -] S.E.

                                       Tylosin

Tissue                   5th day                     7th day

Liver             1.035 [+ or -] 0.099        0.8206 [+ or -] 0.046
Lung              1.306 [+ or -] 0.108         1.035 [+ or -] 0.089
Spleen            1.035 [+ or -] 0.046                  --
Kidney            1.035 [+ or -] 0.068                  --
Heart               1.2 [+ or -] 0.09          1.035 [+ or -] 0.086
Thigh Muscle       0.73 [+ or -] 0.026                  --
Breast Muscle      0.73 [+ or -] 0.035                  --

                   Mean [+ or -] S.E.

                         Tylosin

Tissue                   9th day

Liver                      --
Lung              0.7306 [+ or -] 0.063
Spleen                     --
Kidney                     --
Heart                      --
Thigh Muscle               --
Breast Muscle              --

                                  Mean [+ or -] S.E.

                                 Tylosin + diclazuril

Tissue                   1st day                     3rd day

Liver            1.306 [+ or -] 0.103 *        1.14 [+ or -] 0.094
Lung             2.078 [+ or -] 0.14           1.28 [+ or -] 0.108
Spleen           1.306 [+ or -] 0.102          1.14 [+ or -] 0.098
Kidney           1.306 [+ or -] 0.097         1.035 [+ or -] 0.068
Heart            1.306 [+ or -] 0.12           1.14 [+ or -] 0.103
Thigh Muscle     1.306 [+ or -] 0.122          1.16 [+ or -] 0.103 *
Breast Muscle     1.28 [+ or -] 0.104          1.14 [+ or -] 0.068

                                  Mean [+ or -] S.E.

                                 Tylosin + diclazuril

Tissue                   5th day                     7th day

Liver            1.035 [+ or -] 0.077         0.8206 [+ or -] 0.0535
Lung              1.16 [+ or -] 0.098          1.035 [+ or -] 0.054
Spleen           1.035 [+ or -] 0.047         0.8206 + 0.036
Kidney          0.8206 [+ or -] 0.028 *                 --
Heart            1.035 [+ or -] 0.087         1.8206 [+ or -] 0.06
Thigh Muscle     1.035 [+ or -] 0.095 **       0.922 [+ or -] 0.038
Breast Muscle    0.922 [+ or -] 0.034 *                 --

                   Mean [+ or -] S.E.

                  Tylosin + diclazuril

Tissue                   9th day

Liver                      --
Lung                       --
Spleen                     --
Kidney                     --
Heart                      --
Thigh Muscle               --
Breast Muscle              --

                                  Mean [+ or -] S.E.

                                Tylosin + halofuginone

Tissue                   1st day                     3rd day

Liver            1.648 [+ or -] 0.11          1.306 [+ or -] 0.086
Lung              2.08 [+ or -] 0.18          1.649 [+ or -] -.13
Spleen           1.648 [+ or -] 0.106 *       1.306 [+ or -] 0.088
Kidney           1.306 [+ or -] 0.09           1.28 [+ or -] 0.092
Heart             2.08 [+ or -] 0.19          1.648 [+ or -] 0.102
Thigh Muscle     1.306 [+ or -] 0.103          1.18 [+ or -] 0.097 *
Breast Muscle    1.648 [+ or -] 0.065 *       0.922 [+ or -] 0.052

                                  Mean [+ or -] S.E.

                                Tylosin + halofuginone

Tissue                   5th day                     7th day

Liver            1.1467 [+ or -] 0.086         0.922 [+ or -] 0.056
Lung              1.306 [+ or -] 0.085         1.035 [+ or -] 0.068
Spleen             1.15 [+ or -] 0.097        0.8206 [+ or -] 0.05
Kidney            1.035 [+ or -] 0.077         0.922 [+ or -] 0.048
Heart             1.306 [+ or -] 0.089         1.035 [+ or -] 0.07
Thigh Muscle      1.035 [+ or -] 0.088 *      0.8206 [+ or -] 0.046
Breast Muscle    0.8206 [+ or -] 0.038                  --

                   Mean [+ or -] S.E.

                 Tylosin + halofuginone

Tissue                   9th day

Liver                      --
Lung              0.8206 [+ or -] 0.033
Spleen                     --
Kidney                     --
Heart             0.8206 [+ or -] 0.047
Thigh Muscle               --
Breast Muscle              --

-- Non detected

* Significant at P [less than or equal to] 0.05

** Significant at P [less than or equal to] 0.01.

Table 5: Mean [+ or -] S.E. of tylosin tissue concentration (ppm)
following intramuscular injection (25 mg.[kg.sup.-1] b.wt.) once daily
for 5 consecutive days in chickens fed anticoccidial free, diclazuril
(1 ppm) and halofuginone (3 ppm) containing ration (n = 3).

                                  Mean [+ or -] S.E.

                                       Tylosin

Tissue                   1st day                     3rd day

Liver             q.306 [+ or -] 0.106          1.14 [+ or -] 0.102
Lung              1.648 [+ or -] 0.12           1.45 [+ or -] 0.108
Spleen            1.306 [+ or -] 0.102         1.138 [+ or -] 0.079
Kidney            1,648 [+ or -] 0.11          1.035 [+ or -] 0.088
Heart             1.035 [+ or -] 0.078         0.922 [+ or -] 0.042
Thigh Muscle      2.622 [+ or -] 0.14          1.035 [+ or -] 0.086
Breast Muscle     1.648 [+ or -] 0.106         1.306 [+ or -] 0.088

                                  Mean [+ or -] S.E.

                                       Tylosin

Tissue                   5th day                     7th day

Liver              1.035 [+ or -] 0.086         0.82 [+ or -] 0.052
Lung               1.306 [+ or -] 0.094        1.035 [+ or -] 0.086
Spleen             1.035 [+ or -] 0.066                 --
Kidney              0.92 [+ or -] 0.064                 --
Heart             0.8206 [+ or -] 0.037                 --
Thigh Muscle        0.82 [+ or -] 0.063                 --
Breast Muscle      0.922 [+ or -] 0.036                 --

                   Mean [+ or -] S.E.

                         Tylosin

Tissue                   9th day

Liver                      --
Lung                       --
Spleen                     --
Kidney                     --
Heart                      --
Thigh Muscle               --
Breast Muscle              --

                                  Mean [+ or -] S.E.

                                 Tylosin + diclazuril

Tissue                   1st day                     3rd day

Liver            1.306 [+ or -] 0.103 *       1.106 [+ or -] 0.09
Lung             1.648 [+ or -] 0.104         1.306 [+ or -] 0.101
Spleen           1.306 [+ or -] 0.087         1.106 [+ or -] 0.072
Kidney           1.035 [+ or -] 0.076 *      0.8206 [+ or -] 0.052
Heart            1.035 [+ or -] 0.082        0.8206 [+ or -] 0.046
Thigh Muscle     2.622 [+ or -] 0.17          2.078 [+ or -] 0.13 **
Breast Muscle    1.306 [+ or -] 0.089         1.035 [+ or -] 0.069 *

                                  Mean [+ or -] S.E.

                                 Tylosin + diclazuril

Tissue                   5th day                     7th day

Liver            1.035 [+ or -] 0.085                   --
Lung             1.035 [+ or -] 0.074                   --
Spleen           1.035 [+ or -] 0.058                   --
Kidney                     --                           --
Heart                      --                           --
Thigh Muscle     1.648 [+ or -] 0.11 ***     1.306 [+ or -] 0.089 ***
Breast Muscle   0.8206 [+ or -] 0.048                   --

                   Mean [+ or -] S.E.

                  Tylosin + diclazuril

Tissue                   9th day

Liver                      --
Lung                       --
Spleen                     --
Kidney                     --
Heart                      --
Thigh Muscle    0.8206 [+ or -] 0.057 ***
Breast Muscle              --

                                  Mean [+ or -] S.E.

                                Tylosin + halofuginone

Tissue                   1st day                     3rd day

Liver            1.648 [+ or -] 0.13          1.426 [+ or -] 0.107
Lung             2.078 [+ or -] 0.193         1.648 [+ or -] 0.14
Spleen           2.078 [+ or -] 0.16 *        1.648 [+ or -] 0.102 *
Kidney           1.306 [+ or -] 0.0827         1.14 [+ or -] 0.074
Heart            2.078 [+ or -] 0.16 **       1.648 [+ or -] 0.13 **
Thigh Muscle     2.622 [+ or -] 0.17          1.648 [+ or -] 0.126 *
Breast Muscle    1.648 [+ or -] 0.104         1.306 [+ or -] 0.102

                                  Mean [+ or -] S.E.

                                Tylosin + halofuginone

Tissue                   5th day                     7th day

Liver            1.306 [+ or -] 0.098        0.922 [+ or -] 0.064
Lung             1.306 [+ or -] 0.096        1.035 [+ or -] 0.067
Spleen           1.306 [+ or -] 0.089       0.8206 [+ or -] 0.053 ***
Kidney           1.035 [+ or -] 0.074        0.822 [+ or -] 0.046 ***
Heart            1.306 [+ or -] 0.102 *      1.035 [+ or -] 0.098 ***
Thigh Muscle     1.306 [+ or -] 0.093 *      1.035 [+ or -] 0.0826 ***
Breast Muscle    1.035 [+ or -] 0.074        0.822 [+ or -] 0.038 ***

                   Mean [+ or -] S.E.

                 Tylosin + halofuginone

Tissue                   9th day

Liver                      --
Lung            0.822 [+ or -] 0.036 ***
Spleen                     --
Kidney                     --
Heart           0.822 [+ or -] 0.046 ***
Thigh Muscle    0.822 [+ or -] 0.047 ***
Breast Muscle              --

-- Non detected

* Significant at P [less than or equal to] 0.05

** Significant at P [less than or equal to] 0.01.
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Title Annotation:Original Article
Author:Atef, M.; El-Gendi, A.Y.I.; Amer, Aziza M.M.; Kamel, Gehan M.
Publication:Advances in Environmental Biology
Article Type:Report
Geographic Code:7EGYP
Date:Sep 1, 2009
Words:7133
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