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Effects of experimentally induced Theileria annulatainfection on the pharmacokinetics of oxytetracycline in

cross-bred calvesRajiv Kumar, Jitender Kumar Malik

To cite this version:Rajiv Kumar, Jitender Kumar Malik. Effects of experimentally induced Theileria annulata infectionon the pharmacokinetics of oxytetracycline in cross-bred calves. Veterinary Research, BioMed Central,1999, 30 (1), pp.75-86. <hal-00902558>

Original article

Effects of experimentally induced Theileria annulatainfection on the pharmacokinetics of oxytetracycline

in cross-bred calves

Rajiv Kumara Jitender Kumar Malik

a Department of Pharmacology, College of Veterinary Science and Animal Husbandry.Gujarat Agricultural University, Anand Campus, Anand 388001, India

b Division of Veterinary Pharmacology and Toxicology, Indian Veterinary Research Institute,lzatnagar 243122, India

(Received 18 April 1996; accepted 16 October 1998)

Abstract - The effects of an experimental Tlzc ileria al1l1l1lata infection on the intravenous ( l0 mg kg-1)pharmacokinetics of oxytetracycline (OTC) were investigated in crossbred calves. The serum con-centration-time curve of oxytetracycline before and after the experimental infection was best describedby an open two-compartment model. The experimental infection was induced by a subcutaneousadministration of ground-up tick supernate (GUTS) equivalent to 30 Hyalornma anatolicum ana-tolicum ticks infected with Theilc ria annultit(i. It produced a definite temperature rise and symp-toms of clinical disease in the calves. The haemoglobin, packed cell volume (PCV), white bloodcell (WBC) counts and serum Cu, Fe and Zn concentrations decreased after onset of the infection. Thedistribution and elimination half-lives (t1/2<1 and tl/2!), volume of the central compartment (Vc)’AUCo!’ AUMC and mean residence time (MRT), were significantly reduced (P <_ 0.05) and the hybridrate constants K,2, K,,,, KI/K21 ratio and total body clearance (CI,3) of oxytetracycline were signif-icantly (P < 0.05) increased after infection. The infection, however, had no effect on the Cjj, K, appar-ent and steady-state volumes of distribution ( V!,_,,.!_,! and V!!!) of the drug. The above changes maynecessitate changes in the dosage regimen of oxytetracycline used to treat Theileria infections incattle under field conditions. &copy; Inra/Elsevier, Paris.

Tlzeileria annulata / pharmacokinetics / oxytetracycline / calf

* Correspondence and reprints: D-9, Staff Colony, Veterinary College, Bikanei 334003,Rajasthan, IndiaTel.: (91 ) 151 527 603

Résumé - Effets d’une infection expérimentale par Theileria annulata sur la pharmacocinétiquede l’oxytétracycline chez des veaux métis. Les effets d’une infection expérimentale par Thc ilc rinal/Ill/Iota sur la pharmacocinétique de l’oxytétracycline (OTC) injectée par voie intraveineuse( 10 mt kg-I) ont été étudiés chez des veaux métis. La courbe de concentration de l’oxytétracyclineen fonction du temps, avant et après infection expérimentale, était le mieux décrite par un modèle bi-

compartimental ouvert. L’infection expérimentale a été induite par une administration sous-cuta-née (équivalent à 30 tiques Hyalomma anatolicum anatolicum) d’un broyat de tiques infectées par Thei-leria annulata. L’infection a produit une augmentation nette de la température, ainsi que les symp-tômes de la maladie chez les veaux. Le taux d’hémoglobine, l’hématocrite, le taux de leucocytes, etles concentrations du sérum en Cu, Fe et Zn ont diminué après le début de l’infection. Les demi-viesde distribution et l’élimination (t!!2a et t!!2(3), le volume du compartiment central (VJ, l’aire sous lacourbe (AUC), l’aire sous la courbe au premier moment (AUMC) et le temps moyen de résidence(MRT), étaient significativement plus faibles (p 5 0,05) après infection. Les constantes hybridesKI 2, Kel’ K!2/K2! et la clairance corporelle totale (C’B) de l’oxytétracycline étaient significativementplus fortes après infection (p <_ 0,05). L’infection, cependant, n’a eu aucun effet sur la concentrationinitiale, K2,, les volumes de distribution apparent et à l’équilibre (Vd(area) et !dss) de l’oxytétracycline.Ces variations pourraient nécessiter un changement dans les doses d’oxytétracycline utilisées pour trai-ter les infections à Theileria chez les bovins, dans les conditions de terrain. &copy; Inra/Elsevier, Paris.

Theileria annulata / pharmacocinétique / oxytétracycline / veau

1. INTRODUCTION

Dosage regimens for most drugs, includ-ing antibiotics, are formulated primarily onthe basis of experimental data obtained withhealthy subjects. Except for extensive workon the relationship of renal and hepatic dis-eases on drug elimination and therapy,experimental studies on the effects of diseaseon drug disposition are few [33, 45, 46].Febrile conditions have been shown to

markedly alter drug disposition in goats [1],calves [15] and rabbits [23, 30]. These alter-ations in pharmacokinetic parameters duringthe disease state may influence the efficacyof antimicrobial therapy.

To obtain the optimal efficacy of a drugit is necessary to modify its dosage regi-mens on the basis of pharmacokinetic dataobtained during the actual disease state.Tropical bovine theileriosis (Theileria annu-lata) is a major and usually fatal disease ofcross-bred (Boss indicus) and taurine (Bostaurus) cattle in the Indian sub-continent,the Middle East, Commonwealth of Inde-pendent States (CIS) and North Africa.Tetracyclines, particularly oxytetracycline,together with various supportive drugs havebeen used to treat all forms of theileriosisin cattle [4, 18, 21, 27, 35]. The tropicalbovine theileriosis model has recently beenused to evaluate various antitheilerial drugsin calves [5, 12, 31, 36J.

For several disease models, changes inplasma/serum copper, iron and zinc con-centrations have been described in differ-ent animal species [16, 25, 26, 42, 44].These changes are considered to be the partof the non-specific defence mechanism ofthe organism to infection [14, 42, 43, 44].

The purpose of the present study was toinvestigate the effect of disease: a) on bodytemperature, haemoglobin, packed cell vol-ume (PCV), white blood cell (WBC) countsand serum copper, iron and zinc concentra-

tions; and b) serum concentrations and thepharmacokinetics of oxytetracycline (OTC)in T. annulata-infected calves.

2. MATERIALS AND METHODS

2.1. Animals

Five healthy male cross-bred (Jersey xTharparkar) calves were used, ranging between4 and 6 months of age with an average weightof 70 kg. These animals were procured from auniversity farm with no history of theileriosis.The study was carried out in the months of Jan-uary and February when the average daily tem-peratures varied between 16 and 22 °C. The ani-mals were housed in tick-free animal sheds withconcrete floors and were maintained on greenfodder, hay and concentrate (0.50 kg antibiotic-free, pelleted feed fed twice daily). Water wasprovided ad libitum. Each animal was quaran-

tined for 2 weeks before the start of experimentand was determined to be healthy by regular clin-ical examination. During this period the animalswere given an acaricide [ButoxOO Vet

(deltamethrin); Hoechst India Ltd, Bombay]spray twice, at an interval of 7 days to rule outany possibility of tick infestation. The last spray-ing occurred 7 days before the commencement ofthe actual experiment.

2.2. Drugs

Oxytetracycline hydrochloride (OTC) wasinjected intravenously into the left jugular vein ofthe calves via a catheter as a 5 °Io solution (Ter-ramycin-50, Pfizer, Bombay, India) at a dose of10 mg kg Pure oxytetracycline, for preparing gthe standard curve, was obtained from CadilaPvt. Ltd, Ahemedabad (India).

2.3. Experimental disease model

Theileriosis was produced in the calves bysubcutaneously injecting 6 mL of ground-up ticksupernate (GUTS) [) 1 equivalent to 30 adultHyalomma anatolicum anatalicum ticks infectedwith ODE-Anand strain stock of Theileria annu-lata, cryopreserved earlier in liquid nitrogen andresuscitated just before use, as per the proceduredescribed by Singh et al. [36]. The GUTS wereobtained from the Animal Disease Research Lab-

oratory, National Dairy Development Board(NDDB), Anand, Gujarat (India). The rectal bodytemperatures of the calves were measured twice

daily on day 0 (before) and on days I-24, afterthe experimental infection. Two calves werenecropsied at the end of experiment to examinefor the presence of punched ulcers (pathognomiclesions) in the abomasum.

2.4. Experimental design

First, OTC was administered intravenouslyat a dose of 10 mg kg Three weeks later thesame calves were infected with T. annulata. On

day 9 post-infection when the rectal body tem-perature of animals ranged from 40.4 to 41.3 °C,the same dose of OTC was administered to theanimals.

2.5. Sampling procedure

Blood samples were collected by jugularvenipuncture in sterile glass test tubes withoutanticoagulant prior to and at 5, 15, 30 and 45 minand I , 1.5, 2, 4, 6, 8, I 0, 12, 24, 30 and 36 h afterthe oxytetracycline administration. Blood sampleswere also taken for haemoglobin, PCV and WBCcounts and serum Cu, Fe and Zn concentrationson day 0 (before infection) and on days 1, 6, 9,12, 16, 20 and 24 after infection. Draining lymphnode biopsy fluid smears were prepared dailyfrom days 6-18 post-infection to monitor thepresence of schizonts. The percentage of piro-plasm-infected cells was counted from bloodsmears prepared daily from the ear vein fromdays 7 to 24 post-infection. The blood sampleswere allowed to clot for approximately 1-2 h atambient temperature and were then centrifugedat 1 200 g for l5 min. The serum was separatedand stored at-20 °C until analysed.

2.6. Bioassay

Serum oxytetracycline concentrations weremeasured using an agar-gel diffusion methodemploying Bacillu.s cereus var mvcoides ATCC1 1778 as the test organism [13]. This methodestimated the level of drug having antibacterialactivity, without differentiating between the par-ent drug and its metabolites. The minimum detec-tion limit of the assay was 0.125 pg mL-1. Thestandard curve of oxytetracycline in calf serumwas linear between 0.125 and 4 pg mL-!. Thevalue of the correlation coefficient (r) was morethan 0.99. The repeatability of this method wasexcellant and the within day estimation error wasless than 5 %.

2.7. Haematologicaland chemical blood analysis

Haemoglobin, PCV and WBC counts weredetennined using methods described by Jain [ 17!.The presence of piroplasms in the blood smearsand schizonts in the draining lymph node biopsyfluid were determined by the Uilenberg method[41 The serum Cu, Fe and Zn concentrationswere measured with an atomic absorption/flaiiiespectrophotometer (Model, AA-646-V2, Shi-madzu corporation Kyoto, Japan) using the tech-nique described by Oser [29J. ] .

2.8. Pharmacokinetic analysis

Pharmacokinetic analysis of OTC concentra-tions was performed with the aid of MULTI, acomputer program for nonlinear regression anal-ysis [47]; data points were weighted according tothe equation:

where W! is the weight, and y. is the fitted valueof the ith observation. The general polyexpo-nential equation:

was then fitted to the OTC concentrations fromindividual calves. In this equation, C(tJ rcpre-sents the serum OTC concentration at time t, Y, isthe coefficient of the ith exponential term and Xis the exponent of the ith exponential term. Initialpharmacokinetic variable estimates were obtainedusing a linear regression method. The numberof exponents (2 or 3) needed for each data setwas determined by applying Akalkc’s informa-tion criterion (AIC) !48J. Serum OTC concen-trations versus time following intravenous admin-istration were best fitted by an opentwo-compartment model described by the biex-ponential equation:

where Cirr is the serum concentration at time t, Aand B are zero-time intercepts, a is the distribu-tion rate constant and (3 is the elimination rateconstant.

The two-compartment pharmacokinctic pro-gram used provided simultaneous estimates ofthe extrapolated zero-time concentrations (A andB), initial concentrations (Co = A + B), hybridrate constants (a and (3), and the distribution andelimination half-lives 11/20. and tl/W The firstorder rate constants for the elimination of thedrug from the central compartment (Kel)’ and forthe transfer of the drug from the central com-partment to the peripheral compartment and back(K12 and K21)’ were calculated using classicalequations. The area under the zero momcnt curve(AUCo-=) and the area under the first momentcurve (AUMC) were calculated using the lineartrapeooidal rule and extrapolated to infinity [3]. ] .

The elimination rate constant of the drug fromcentral compartment (K!1) was obtained usingthe equation:

The rate constant of transfer of drug from tis-sue to the central compartment (KZi) wasobtained using the equation:

’

The rate constant of transfer of drug fromcentral to the tissue compartment (A!-,) wasobtained using the equation:

The distribution volume based on area

( V,j!_,,_!_,) was obtained using the equation:

The central compartment volume (V!) wasobtained using the equation:

The steady-state of distribution volume (Vdss)was obtained using the equation:

The mean residence time was obtained usingthe equation:

The distribution clearance (Cldistributioll) ofdrug was obtained using the equation:

The total body clearance (Clt3) was obtainedusing the equation:

2.9. Statistical procedures

The significance of the differences was testedwith Student’s paired t-test or independent l-test,where appropriate. The null-hypothcsis wasrejected at the 5 % level. All values are presentedas means ± standard error of the mean.

3. RESULTS

3.1. T. annulata disease model

The response to sub-cutaneous adminis-tration of GUTS was marked by depressionand laboured breathing coupled with anincrease in rectal body temperature. Super-ficial lymph nodes, particularly the

prescapular lymph nodes were markedlyenlarged. Blood smears and draining lymphnode biopsy fluid smears showed the pres-

ence of piroplasms in the erythrocytes andschizonts in the lymphocytes, respectively.There were significant (P < 0.05) reduc-tions in haemoglobin, PCV, WBC countsand serum Cu, Fe and Zn concentrations.The febrile response was rapid in onset andpersisted above 40 °C for at least 4 days.The increase in rectal temperature and

changes in serum Cu, Fe and Zn concentra-tions, haemoglobin and white blood cellcounts of calves after experimental infec-tion with T. annulata, are shown in,figuresI-4, giving an indication of the severity ofthe experimental infection. Throughout theexperiment the calves ate 1-1.5 kg hay and0.50 kg of pelleted concentrate per day.However, after the experimental infectionwith T. annulatn, the animals went off theirfeed, and two calves almost stopped feedingcompletely in the advanced stage of their

illness. The water intake was reduced onlyfor the first 12 h after infection.

3.2. Oxytetracycline administrationand pharmacokinetic data

The intravenous administration of OTCdid not cause any observable pain or dis-comfort to the calves. The serum concen-tration-time curves of OTC prior to andafter experimental T. annulata infection areshown in figure 5. The experimental infec-tion caused a significant reduction

(P 5 0.05) in the serum OTC concentra-tions as measured at 0.50, 0.75, I , 4, 8, 10,12 and 24 h compared with healthy calves.Mean serum drug concentrations >1.0 pg mL-1 were maintained for nearly30 h in calves before infection as compared

to 12 h after infection. The drug was unde-tectable in the serum of infected calves after24 h.

The pharmacokinetic parameters ofoxytetracycline after intravenous adminis-tration, before and after experimental infec-tion, are presented in table I. The experi-mental infection caused a significantreduction in the mean distribution and elim-ination half-lives (t’/2a and t1/2(3)’ Vc’AUCO--, AUMC and MRT and increasedA, K12, K,,, K¡lK21 and CIB of OTC incalves. The infection had no effect on themean values of C!!, K21’ Vd(area) and Vdss’

4. DISCUSSION

Theileriosis was produced by T. crnnu-lata infection in all challenged calves, as

evidenced by clinical symptoms, increasedrectal body temperature and the presence ofpiroplasms in the blood and schizonts in thedraining lymph node biopsy smears pre-pared from each calf. In addition, the infec-tion resulted in a significant (P < 0.05)decrease in haemoglobin, PCV, WBCcounts and serum concentrations in Cu, Feand Zn. The observed symptoms of the pro-tozoal disease were comparable with find-ings reported previously [24, 36, 38, 39J. ].

Several disease models, including theendotoxin model, Salmonella sp. infectionmodel and E. coli mastitis model have beenused to study the influence of disease on:a) body temperature, white blood cell count,pyrogenic cytokines and plasma levels of

Cu, Fe and Zn; and b) the pharmacokineticbehaviour of drugs in cattle. It was sug-

gested that the rise in the body temperatureand alterations in plasma/serum levels ofCu, Fe and Zn observed in those modelswere due to the effects on the system of

pyrogenic cytokines, tumour necrosis fac-tor (TNF ex) and interleukin-1 (IL-I releasedfrom the activated macrophages. in responseto the invading microorganisms or their tox-ins 19, 42, 43 The acute drop in

serum/plasma Fe and Zn concentrations indiseased animals is considered to be partlydue to the redistribution in the reticulo-endothelial system [43, 44] and partly torapid uptake by the liver [8, 191. The actualmechanism by which Theileria organisms

produce fever is not known. It is proposedthat it might be due to excessive release ofmetabolic and toxic products by a largenumber of multiplying Theileria parasitesin the blood of the infected calves [39].Moreover, it has been established that com-mon endogenous pyrogens are released fromactivated cells (monocytes, neutrophils, leu-cocytes and kupfer cells), regardless ofwhether the activator or inducer of the feveris a virus, bacterium or bacterial toxin. Oncereleased into the circulation, they act on thethermoregulatory centre of the hypothala-mus through PGE2 which raises the

hypothalamic thennostat to febrile levels1431. No relationship, however, could beestablished in the current study, betweenchanges in body temperature and those in

serum levels of Cu, Fe and Zn. These find-

ings indicate that the febrile reaction andserum trace metal alterations may be medi-ated by different polypeptides. The mainobjective of this study was to observe theeffect of experimentally induced theileriosison serum Cu, Fe and Zn levels together withits effect on rectal temperature, and also toascertain if this protozoal infection inducedsimilar changes on the serum trace metalsand body temperature as are produced incalves in response to a number of bacterialinfections and their toxins. Severe anaemiain calves as evidenced by a marked reduc-tion in Hb and PCV might be due to autoim-mune reactions and erythrophagocytosisinduced by the T. nruu!latu infection 124]. ].Immunological reactions leading to pro-

duction of anaemia have also been demon-strated in other intra-erythrocytic infectionmodels, including avian malaria [37], avianspirochaetosis [22] and Babesia rodhainiinfection in rats [34]. Marked leukopeniaduring infection, on the other hand, might bedue to a radical reduction in the number of

lymphocytes and neutrophils in the bloodof calves as reported earlier [32].

The pharmacokinetic parameters foroxytetracycline, recorded in healthy calvesbefore the infection are consistent with those

reported previously in cattle [28, 40]. Asshown in figure 5 and table I, the experi-mental T. annulata infection produced amarked effect on the serum OTC concen-trations and disposition kinetics in calves.The increased body clearance is perhaps thesingle most important factor responsible forsignificantly shorter half-life of OTC ininfected calves. Plasma clearance is a prod-uct of cardiac output and an overall extrac-tion ratio (E). Consequently, the fact thatinfection doubles the clearance may either bedue to an increase in cardiac output or to anincrease in E, i.e. the efficiency of the bodyto clear the drug. Oxytetracycline is a watersoluble drug which seems to be eliminatedalmost entirely as a parent compound byglomerular filtration [3, 6, 20]. Thus, renalfiltration rate may be having a more promi-nent effect on the elimination of OTC [10]. 1.During fever, the renal blood flow and con-sequently the renal clearance of drugs areincreased and the urine pH is decreased [43]which might affect the drug excretion. Thepossibility of OTC undergoing extensivebiotransformation in T. annulata infectedcalves is less likely as it does not undergoappreciable biotransformation but is excretedin bile, albeit as a minor route comparedwith urine [20, 28]. A similar reduction inthe elimination half-life of OTC has alsobeen reported previously in calves suffer-ing from pneumonic pasteurellosis [10]. Incontrast, a significant increase in the elimi-nation half-life of OTC has been reportedin goats with tick-borne fever [1 ].

Experimental infection also producedsignificant alterations in the values of K-1Kl2 and Ke!. Since the infection had no sig-nificant effect on distribution clearance ofthe drug, the significant increase in the valueof K12 could be directly attributed to the fallin K, while that of Kel to the opposite effectsof T. annulata infection on the values of

CIB and Vc as shown in table I. A relativelyhigh value of Kl2 with no change in K21 ofOTC in the infected animals indicated that

experimental T. annulata infection enhancedthe movement of the drug from the centralperipheral compartment without affectingits back-flow. A high value of K,2lK2, inthe infected animals further suggested theaccumulation of OTC in a peripheral com-partment, possibly tissues as a result of ion-trapping or increased tissue binding in dis-eased animals [7]. Since OTC concentrationsin the tissues were not measured during thepresent study, the suggestion that T. annu-lata infection caused accumulation of OTCin tissues, could not be confirmed.

It is concluded that experimental T. annu-lata infection markedly influences the dis-position kinetics of oxytetracycline in calves,and to obtain optimal therapeutic effect, theclinician may have to alter the dosage regi-men of the drug to treat Theileria infectionsunder field conditions. However, the pre-sent study gives no information on appro-priate OTC concentrations at the site ofinfection. This aspect needs further clarifi-cation.

ACKNOWLEDGEMENTS

The first author is indebted to the Council ofScientific and Industrial Research (CSIR), NewDelhi for the financial assistance to carry out this

investigation. The deputation granted byRajasthan Agricultural University to the firstauthor for his doctoral programme is also grate-fully acknowledged.

REFERENCES

[11 Anika S.M., Nouws J.F.M., van Gogh H.,Nieuwenhuijs J., Vree T.B., van Miert

A.S.J.P.A.M., Chemotherapy and pharmacoki-netics of some antimicrobial agents in healthydwarf goats and those infected with Ehrlichiaphagocytophilia (tick-bome fever), Res. Vet. Sci.41 (1986) 386-390.

[2] Baggot J.D., Principles of drug disposition indomestic animals, in: The Basis of VeterinaryClinical Pharmacology, WB Saunders, Philadel-phia PA, USA, 1977, pp. 144-189.

[31 Baggot J.D., Powers T.E., Powers J.D., KowalskiJ.J., Kerr K.M., Pharmacokinetics and dosage ofoxytetracycline in dogs, Res. Vet. Sci. 24 (1977)77-81. 1 .

[4] Bagherwal R.K., Oxytetracycline (Telon LA) aschemotherapeutic agent against bovine tropicaltheileriosis in crossbred cattle, Indian Vet. J 66(1989)652-655.

[5] Bansal G.C., Sharma S.P., Efficacy of parvaquoneand long-acting oxytetracycline in Thieleria annu-lata infection, Vet. Parasitol. 21 (1986) 145-149.

[6] Barza M., Brown R.B., Shanks C., Gambie C.,Weinstein L., Relation between lipophilicity andpharmacologic behaviour of minocycline, doxy-cycline, tetracycline and oxytetracycline in dogs,Antimicrob. Agents Chemother. 8 (1975)713-720.

[7] Baxter P., MeKellar Q.A., Distribution of oxyte-tracycline in normal and diseased ovine lung tis-sue, J. Vet. Pharmacol. Ther. 13 (1990) 428-431. 1.

[8] Beisel W.R., Sobocinski P.Z., Endogenous medi-ators of fever-related metabolic and hormonal

responses, in: Lipton J.M. (Ed.), Fever, RavenPress, New York, 1980, pp. 39-48.

[9] Bielefeldt-Ohmann H., Campos M., Snider M.,Rapin N., Beskorwayne T., Popowych Y., Law-man M.J.P., Rossi A., Babink L.A., Effect ofchronic administration of recombinant bovinetumour necrosis factor to cattle, J. Vet. Pathol.26(1989)462-472.

[10] Burrows G.E., Barto P.B., Weeks B.R., Chlo-ramphenicol, lincomycin and oxytetracycline dis-position in calves with experimental pneumonicpasteurcllosis, J. Vet. Pharmacol. Ther. 9 (1986)213-222.

111 J Cunningham M.P., Brown C.G.D., Burridge M.J.,Irvin A.D., Purnell R.E., Radley D.E., Theileriaparva: Comparative infectivity of a ground tickstabilate and a classical 10-tick challenge, Res.Vet. Sci. 15 (1973) 263-265.

! 12! Dhar S., Malhotra D.V., Bhushan C., GautamO.P., Chemoimmunoprophylaxis against bovinetropical theileriosis in young calves: a comparisonbetween buparvaquone and long-acting oxyte-tracycline, Res. Vet. Sci. 49 (1990) 110-1 12.

[13J Dornbush A.C., Abbey A., Microbiological assayof tetracyclines, in: Kavanagh F. (Ed.), Analyti-

cal Microbiology, Vol. 11, Academic Press, NewYork, 1972, pp. 365-383.

[14] Groothuis D.G., Pharmacokinetics of someantimicrobial drugs in veal calves and their activ-ity in relation to Salmonella dublin infections,Ph.D. thesis, University of Utrecht, the Nether-lands, 1983.

[15] Groothuis D.G., van Gogh H., van MiertA.S.J.P.A.M., The effect of E. coli endotoxininduced fever on the blood levels of antimicrobial

drugs after intravenous and intramuscular admin-istration in veal calves, in: van Micrt

A.S.J.P.A.M., Frens J., van der Kreek F.W. (Eds.),Trends in Veterinary Pharmacology and Toxi-cology, Elsevier Scientific Publ. Co., Amster-dam, 1980,pp.77-86

[ 16] Groothuis D.G., van Miert A.S.J.P.A.M., Schot-man A.J.H., Zinc concentration in plasma dur-ing experimental Salmonella dublin infection andendotoxin induced fever in calves, Vet. Rec. 109( 1981 ) l76-177.

[17] Jain N.C., Schalm’s Veterinary Haematology,Lea and Febiger, Philadelphia, PA, USA, 1986.

I 181 JoYner L.P., Brocklesby D.W., Chemotherapy ofanaplasmosis, babesia and theileriasis, Adv. Phar-macol. Chemother. I 1 (1973) 321-355.

[ 19] Kampschmidt R.F., Metabolic alterations elicitedby endogenous pyrogens, in: Lipton J.F. (Ed.),Fever, Raven Press, New York, 1980, pp. 49-56.

[20] Kelly R.G., Buyske D.A., Metabolism of tetra-cycline in the rat and the dog, J. Pharmacol. Exp.Ther. 130 (1960) 144-149.

[21 ] Kumar S.P., Setty D.R.L., Yathiraj S., KamalapurP.N., Use of levamisole along with oxytetracy-cline and supportive therapy for the treatment oftheileriosis in cattle, Indian Vet. J. 65 (1988)634-637.

1221 Lad P.L., Soni J.L., Role of cold agglutinin (CA)in anaemia production in acute avian spirochaeto-sis, Indian J. Anim. Sci. 53 (1983) 937-943.

[23] Ladefoged 0., Pharmacokinetics of antipyrincand trimethoprim in pigs with endotoxin inducedfever, J. Vet. Pharmacol. Ther. 2 (1979) 209-214.

[24] Lal H., Soni J.L., Auto-immune reactions asso-ciated with experimental Theilerica annul!zta infec-tion, Indian J. Anim. Sci. 53 ( 1983) 654-658.

!25! Lohuis J.A.C.M., Sutter H.M., Graser T., Lud-wig B., van Miert A.S.J.P.A.M., Rehm W.F.,Rohde E., Schneider B., Wanner M., Van WervenT., Effects of endotoxin-induced mastitis on thepharmacokinetic properties of aditoprim in dairycows, Am. J. Vet. Res. 53 (1992) 2311-2314.

[261 Mevius D.J., Breukink H.J., van MiertA.S.J.P.A.M., Kessels B.G.F., Jobse A.S., SmitJ.A.H., Effects of experimentally induced Pa.s-teurelln haemolytica infection in dairy calves onthe pharmacokinetics of flumequinc, J. Vet. Phar-macol. Ther. 14 ( 1991 ) 174-184.

[27] Mishra K.C., Achar K.C., Lama N.D., Efficacy ofsome chemotherapeutic agents against clinical

Theilerin alltll[14Ltil infection in exotic cattle,Indian Vet. J. 60 ( I Y83) 313-318.

[281 Nouws J.F.M., Breukink H.J., Binkhorst G.J.,Lohuis J., van Lith P., Mevius D.J., Vree T.B.,Comparativc pharmacokinetics and bioavailabil-ity of eight parenteral oxytetracycline - 10 °lr· for-mulations in dairy cows, Vet. Q. 7 ( 1985)306-3 I 4.

[291 Oser B.L., Hawk’s Physiological Chemistry,McGraw Hill Book’s Co., Bombay, India, 1979.

[301 Pijpers A., Schoevers E.J., van Gogh H., vanLeengoed L.A.M.G., Visser I.J.R., van MiertA.S.J.P.A.M., Verheijden J.H.M., The phanna-cokinetics of oxytetracycline following intra-venous administration in healthy and diseasedpigs, J. Vet. Pharmacol. Ther. 13 (1991 ) 320-326.

1311 Pipano E., Samish M., Kriegel Y., Ycruham I.,Immunization of Friesian cattle against 7’/!c<7<?-rio tiiiiiiilata by the infection-treatment method.Br. Vet. i37()98))4)6!t20.

[321 Preston P.M., Brown C.G.D., Bell-Sakyi L.,Richardson W., Sanderson A., Tropical thcrile-riosis in Bos tauru.s and Bo.s taums cross Bosilldicus calves: response to infection with gradeddoses of sporozoites of 77!c ileria nnnulutu, Res.Vet. Sci. 53 ( 1992) 230-243.

[ 3 3 Rowland M., Blaschke T.F., Meffin P.J., WilliamsR.L., Pharmacokinetics in disease states modi-

tying hepatic and metabolic function, in: BenetL.Z. (Ed.), The Etlect of Disease State on DrugPhannacokinctics, American PharmaceuticalAssociation, Washington, DC, 1976, pp. 53-75.

!34! Schroeder W.F., Auto-immune processcs asso-ciatcd with anaemia of infection with Babe.siaroclhaini, Pletsipioilittiii bc rghei and Allaplas/l/anrurginale, Ph.D. thesis, University of Illinois,Albana, USA, 1966.

[351 Singh B., Samad A., Ananlwar L.G., BhonsleV.G., Chemotherapeutic activity ofoxytetracy-cline against clinical cases of 1ï,eileria annulatainfection in exotic and cross-bred cattle, IndianVet. J. 57 ( 1980) 849-852.

! 3(!! Singh D.K.. Thakur M.. Raghav P.R.S., VarshneyB.C., Chemotherapeutic trials with four drugs incrossbred calvcs experimentally infcctcd withTheileria fifimihii<I, IZes. Vet. Sci. 54 (1993)68-71. 1 .

[371 Soni J.L., Cox H.W.. 1’athogenesis of acute avianmalaria. 2. Anaemia mediated by cold auto-hacmagglutinin from the blood of chickens with

acute Plasmndium gullinacenm infection, Am. J.Trop. Med. Hyg. 24 ( 1975) 424-430.

[38J Sudhan N.A., Sinha B.P., Effect of Berenil-Reverin combinations on some haematobio-chemical parameters in clinical cases of bovinetropical theileriosis, J. Vet. Parasitol. 5 (1991)55-57

[39! Sudhan N.A., Sinha B.P., Verma S.P., Haema-tological and biochemical changes in crossbredcalves infected experimentally with 7’/)f;/fna<;nou/a!a. J. Vet. Parasitol. 2 (1988) 2S-30.

[4()j T’outain P.L., Raynaud J.P., Pharmacokinetics ofoxytetracycline in young cattle: Comparison ofconventional vs long-acting formulations, Am.J. Vet. Res. 44 ( 1983) 1203-1209.

141 Uilenbcrg G., ’Theileria’ infections other thanEast coast fever, in: Ristic M., Melntyre 1. (Eds.),Diseases of Cattle in the Tropics, MartinusNijhoff, The Haguc, 1981, pp. 411-427.

[42! van Miert A.S.J.P.A.M., Fever and associatedclinical, haeinatoloic and blood biochemicalchanges in the goat and other animal species, Vet.Q. 7 ( 1985) 200-216.

1431 van Miert A.S.J.P.A.M., Influence of febrile dis-ease on the pharmacokinetics of veterinary drugs,Ann. Rech. Vet. 21 (1990) 1 I-28.

[441 Verheijden J.H.M., van Miert A.S.J.P.A.M.,Scotman A.J.H., van Duin C.T.M., Plasma zincand iron concentration as measurements for eval-

uating the influence of endotoxin nevrtralizingagents in Escherichia coli endotoxin induced mas-titis, Am. J. Vct. Res. 43 ( 1982) 724-728.

!45j Wellington P.G., Craig W.A.. Pharmacokineticsin disease states modifying renal function, in:Benet L.Z. (Ed.), The Effect of Disease States onDrug Pharrnacokinetics, American Pharmaceu-(ical Association. Washington DC, 1976, pp.I .55-187.

1461 Wilkinson G.R., Schenker S., Drug dispositionand liver disease, Drug Metabol. Rev. 4 (1976)139-175.

[47 j Yamaoka K., Nakagawa T., Uno T.. Applicationof Akaikes information criterion (AIC) in theevaluation of linear pharmacokinctic equations. J.Pharmacokinet. Biopharm. 6 ( 1978) 165-175.

[481 Yamaoka K.. Tanigawara Y.. Nakagawa T., UnoT., A pharmacokinetic analysis program (MULTIjfor microcomputer, J. Pharmacobiol. Dyn. 41 I 981 ) 879-889.