bluuebunny/crossref_metadata_2025 huggingface dataset:
The effects of opioid and α2 adrenergic blockade on non‐steroidal anti‐inflammatory drug analgesia in sheep
Authors: CHAMBERS J.P. , WATERMAN A.E. , LIVINGSTON A.
Published: April 2008

The analgesic effects of the non‐steroidal anti‐Inflammatory drugs (NSAIDs) flunixin and dipyrone were assessed in healthy sheep with no pre‐existing inflammation, and in sheep with a chronic inflammatory lesion, using a mechanical noxious stimulus. Saline and dexamethasone were given as controls. Blood taken from healthy sheep after NSAID administration was assayed for thromboxane B2 (TxB2) to compare the ability of these drugs to inhibit cyclo‐oxygenase. Both flunixin and dipyrone produced a small but statistically significant rise in pain thresholds (18% and 21% of maximum possible effect respectively) in the healthy sheep which peaked at 30 min and had returned to pre‐drug values by 2–3 h. In the lame sheep a similar effect occurred but the response was smaller, much more variable and tended to be prolonged. Saline and dexamethasone had no effect on thresholds over 6 h in either group of sheep. The rise in thresholds was prevented by pre‐treatment with naloxone (an opioid antagonist) or attpamezole (an α2‐adrenergic antagonist) in the healthy sheep. Naloxone and atipamezole had no effect on thresholds when given alone to healthy sheep. Both NSAIDs Inhibited the production of TxB2 to a similar extent. These results indicate that central mechanisms may be involved in NSAID analgesia.
Comparative metabolism of R(‐)‐fenoprofen in rats and sheep
Authors: SORACI A. , BENOIT E. , DELATOUR P.
Published: April 2008

The chiral inversion of 2‐arylpropionic acids occurs in many species. It is a unique reaction specific to this group of drugs. In this study R‐(‐)‐fenoprofen (R‐(‐)‐FPF) was used as a model compound to investigate metabolic chiral inversion in sheep in vivo and in vitro and to compare the data with the results obtained in rats. Metabolic inversion in sheep was 80%. The apparent mean values of Km and Vmax of thioester formation were: 392 μm and 2.08 nmol/min/mg in sheep and 500 μm and 22 nmol/min/mg in rats. For hydroxylation, the apparent mean values were Vmax: 0.02 nmol/min/mg in rats and 0.01 nmol/min/mg in sheep. There was no correlation between in vitro thioesterification and in vivo chiral inversion in sheep as compared to rats. In sheep most of the thioester formed underwent inversion (80%) while in rats, where in vitro thioesterification was greater, in vivo inversion was less (42%). In consequence, in rats other metabolic pathways for R(‐)‐FPF‐CoA, such as incorporation into triacylglycerols and conjugation with amino acids, may be quantitatively more important
Coccidiosis: a radiological study of sulphaquinoxaline distribution in infected and uninfected chickens
Authors: WILLIAMS R.B. , FAREBROTHER D.A. , LATTER V.S.
Published: April 2008

Using scintillation counting and autoradiographical techniques, the whole‐body distribution in week‐old uninfected chickens of the anticoccidial agent sulphaquinoxaline (SQ) labelled with 35S was established at various time intervals after a single oral dose either alone or following continuous in‐feed medication with unlabelled SQ, and after a single intravenous dose. The distribution was also established in chickens infected with the coccidia Eimeria acervulina or E. tenella, after a single oral dose of radiolabelled SQ administered either alone or following continuous in‐feed medication with unlabelled SQ, as for uninfected chicks. In all uninfected chicks, SQ was rapidly absorbed from the gut and was distributed to all tissues. It appeared at high concentrations in the bile and kidneys 0.5 h after dosing. In chickens that had previously received unlabelled SQ in the diet, a radiolabelled dose maintained steadier tissue concentrations than the sharp rise and fall detected after a single oral dose. Intravenous dosing of uninfected chicks showed that SQ was secreted by the crop, gizzard and caecal epithelia into their lumina. Infection with E. acervulina or E. tenella coincided with an overall 3.5‐fold sustained increase of SQ concentration in chick tissues. An updated hypothesis including these new observations for the anticoccidial mode of action of SQ in chickens is expounded.
Pharmacokinetics of ketoprofen in healthy horses and horses with acute synovitis
Authors: OWENS J.G. , KAMERLING S.G. , BARKER S.A.
Published: April 2008

The pharmacokinetlc properties of a single intravenous dose of ketoprofen (2.2 mg/kg) in plasma and synovial fluid were compared in four healthy animals and four horses with experimentally induced acute synovitis. Synovitis was induced by the injection of a 1% solution of sterile carrageenan into the left intercarpal joint Ketoprofen was administered at the same time as carrageenan infection. The plasma disposition followed a biexponential equation or a two‐compartment model in most horses. The plasma harmonic mean half‐life in healthy horses (0.88 h) was longer than in horses with synovitis (0.5 5 h). Synovial fluid concentrations of ketoprofen in healthy horses approximated those in plasma by 3 h post‐dose. In horses with synovitis, synovial fluid concentrations approximated plasma concentrations by 1 h. Synovial fluid concentrations of ketoprofen in horses with synovitis were 6.5 times higher than those in healthy horses at 1 h. The area under the synovial fluid concentration curve for horses with synovitis was greater than in healthy horses. These data suggest that the inflamed joint serves as a site of sequestration for ketoprofen. Furthermore, these results indicate that plasma pharmacokinetics may be altered by inflammation in a peripheral compartment such as the joint
The effect of xylazine on the isolated sheep trachea
Authors: PAPAZOGLOU L. , RAPTOPOULOS D. , KOUNENIS G.
Published: April 2008

The effect of xylazine on the isolated sheep trachea and its possible interactions with the α2‐adrenergic antagonist, atipamezole, and the anticholinergic agent, atropine, was studied. The mechanical responses of the tracheal preparations were recorded after exposing each one to cumulatively increasing concentrations of xylazine alone or in the presence of atipamezole or atropine.

Xylazine exerted a concentration‐dependent contractile effect, with a threshold concentration of 10‐‐7M while the maximum activity was produced at a concentration of 10‐‐5M (EC50= 2.3 × 10‐‐7). This xylazine‐induced contractile effect was inhibited by atipamezole, but not significantly modified by atropine. Thus, it is concluded that α2‐adrenoceptors exist in the sheep trachea and it is suggested that α2‐adrenoceptor agonists may act on airways in sheep directly through stimulation of peripheral α2‐adrenergic receptors and indirectly via central α2‐adrenergic receptor activation of parasympathetic tone.
Comparative plasma and tissue pharmacokinetics and drug residue profiles of different chemotherapeutants in fowls and rabbits
Authors: LI T. , QIAO G.L. , HU G.Z. , MENG F.D. , QIU Y.S. , ZHANG X.Y. , GUO W.X. , YIE H.L. , LI S.F. , LI S.Y.
Published: April 2008

Blood and tissue pharmacokinetics and drug residue profiles of six chemotherapeutants were studied. Ceftriaxone (CEF), intravenously at 50 mg/kg, sulfamonomethoxine (SMM) and sulfaquinoxaline (SQ), orally at 200 mg/kg, and olaquindox (OLA), orally at 50 mg/kg, were administered to young broilers. Penicillin (PEN), intramuscularly at 200 000 U/kg, and albendazole (ALB), orally at 20 mg/kg, were given to rabbits. For each drug, 13–18 groups (n= 5–10 individuals/group) of the dosed animals were killed at different post‐dosing times. Drug and/or metabolite concentrations in plasma, liver, kidney, heart, lung, and muscle tissues were analysed by HPLC procedures. Multi‐exponential kinetic models were fitted to the observed tissue concentration‐time data by applying a non‐linear least‐squares regression computer program. Tissue half‐life, peak tissue concentration, and time of peak tissue concentration were determined. Half‐life of CEF, SMM, SQ, OLA, PEN, ALB, and two metabolites of ALB (sulfoxide and sulfone) in various tissues ranged 0.6–1.4, 4.7–9.0, 4.5–18.9, 1.8–3.1, 0.9–3.0, 3.4–9.6, 5.0–16.1 and 7.4–12.2 h. The times required for CEF, SMM, SQ, OLA, PEN, and ALB residue concentrations to decline to 0.1 μg/g in various tissues ranged from 5.0–11.6. 70.0–110.5. 114.0–179.8, 21.3–30.3,4.1–24.8 and 47.8–84.4 h. Drug kinetic characteristics in tissues differed significantly from those in plasma, and also varied from tissue to tissue. It is necessary, therefore, to evaluate tissue kinetics when designing dosage regimens in tissue infection chemotherapy with these drugs. Knowledge of tissue kinetics is also important in predicting and controlling drug residues in edible tissues of food‐producing animals.
Plasma/muscle ratios of sulfadimethoxine residues in channel catfish (Ictalurus punctatus)
Authors: WALKER C.C. , THUNE R.L. , BARKER S.A.
Published: April 2008

Channel catfish (n= 84) maintained at a water temperature of 27°C were used in a feeding study to determine the plasma to muscle concentration ratios of sulfadimethoxine (SDM) and 4‐N‐acetylsulfadimethoxine residues. Sulfadimethoxine medicated feed was provided free choice at 42 mg SDM/kg body weight once daily for 5 days and the plasma and muscle concentrations of SDM were determined at selected withdrawal times (6, 12, 24, 48, 72, and 96 hours) following the last dose. Considerable variation in total SDM tissue concentration among fish within a sampling period was observed. For fish (n= 12) at six hours post‐dose, total SDM concentrations ranged from 1.4–24.8 μg/mL and 0.6–12.6 μg/g, with mean total SDM concentrations of 9.1 μg/mL and 5.3 μg/g for plasma and muscle, respectively. However, a mean plasma:muscle concentration ratio of 1.8:1 ± 0.3:1 was obtained over all concentrations and sampling periods. The plasma:muscle 95%tdistribution interval for individual fish was 1.2:1 to 2.4:1. A correlation coefficient of 0.967 was obtained for the relationship between plasma and muscle total SDM concentration among individual fish (n= 25). Results of this study indicate that plasma total SDM concentration may be used to identify samples containing violative SDM muscle residue. No fish contained total SDM muscle residues greater than the FDA tolerance (0.1 μg/g) by 48 hours following the final dose.
Atipamezole increases medetomidine clearance in the dog: an agonist—antagonist interaction
Authors: SALONEN S. , VUORILEHTO L. , VAINIO O. , ANTTILA M.
Published: April 2008

Medetomidine, an α2‐adrenoceptor agonist, is a potent sedative and analgesic agent in the dog. When necessary, its action can be effectively antagonized by atipamezole. The present work was designed to study the effects of these drugs on each others' pharmacokinetics when a single intramuscular dose of medetomidine (50 μg kg‐1) was followed by a dose of atipamezole (250 μg kg‐1). Three different treatments were used: medetomidine alone, atipamezole alone, and atipamezole after medetomidine. Drug concentrations in plasma were measured by GC‐MS. Statistical analysis of the results (anova) revealed significant differences between treatments in the kinetic parameters of medetomidine. Atipamezole decreased the AUC of medetomidine from 41.3 to 28.6 ng h ml“1(P = 0.005), t1/4 from 1.44 to 0.87 h (P= 0.015), and increased Cl from 21 to 31 ml min‐1kg‐1(P = 0.017). Differences in V2 did not reach statistical significance. The only statistically significant effects of medetomidine on the pharmacokinetics of atipamezole in this study were the slight decrease of Cl and Cmax as well as the increase of AUC. It is suggested that the large dose of medetomidine used caused haemodynamic changes, resulting in decreased hepatic circulation and slower drug metabolism. Antagonism by atipamezole restored the hepatic blood flow and, consequently, increased the elimination of medetomidine by biotransformation.
Florfenicol pharmacokinetics in lactating cows after intravenous, intramuscular and intramammary administration
Authors: SOBACK S. , PAAPE M.J. , FILEP R. , VARMA K.J.
Published: April 2008

Pharmacokinetics of florfenicol 30% injectable solution was determined in lactating cows after intravenous, intramammary and intramuscular administration. Serum concentration‐time data generated in the present study were analysed by non‐compartmental methods based on statistical moment theory. Florfenicol half‐life was 176 min, mean residence time 129 min, volume of distribution at steady‐state 0.35 L/kg, and total body clearance 2.7 mL/min·kg after intravenous administration at 20 mg/kg. The absorption after intramuscular administration appeared slow and the kinetic parameters and the serum concentration vs. time curve were characteristic of absorption rate‐dependent elimination. The absorption after intramammary administration of florfenicol at 20 mg/kg was good (53.9%) and resulted in serum concentrations with apparent clinical significance. The intramammary administration resulted in serum florfenicol concentrations that were significantly higher than the respective serum concentrations following Intravenous administration 4 h after administration and thereafter. Florfenicol absorption was faster from the mammary gland than from the muscle. The maximum serum concentrations (Cmax) were 6.9 μg/mL at 360 min after intramammary administration and 2.3 μg/mL at 180 min after intramuscular administration. The bioavailability of florfenicol was 54% and 38% after intramammary and intramuscular administration, respectively. The Cmax in milk was 5.4 μg/mL at 180 min after intravenous and 1.6 μg/mL at 600 min after intramuscular administration.
Relationship between plasma creatinine concentration and glomerular filtration rate in dogs
Authors: FINCO D.R. , BROWN S.A. , VADEN S.L. , FERGUSON D.C.
Published: April 2008

Glomerula filtration rate (GFR), plasma creatinine concentration (CR), and plasma urea nitrogen concentration (BUN) were measured in 129 adult dogs with reduced renal mass. A preliminary examination of the relationship between CR and GFR was conducted, and the inverse model (GFR vs. 1/CR) was chosen for further evaluation. The slope of the regression of GFR on 1/CR which was computed from actual data was not statistically different from a theoretical regression line generated from the clearance equation.

Evaluation of subsets of the population revealed no significant difference between male (n= 69) and female (n = 60) dogs on the slope of the regression equations. Diets differing in protein concentration (16% protein, n = 35: 21% protein, n = 75: 32% protein,n= 19) did not cause a significant difference in the slope of the regression equations.

The regression equation and the confidence intervals generated in this study may be used to predict a probable range of GFR values from CR in individual dogs. Such values may be useful in adjusting drug dosages in dogs with renal disease. However, since the derived equation did not differ significantly from the theoretical inverse relationship between GFR and CR, it remains to be established whether the equation is advantageous.
Metocurine pharmacokinetics and pharmacodynamics in goats
Authors: ANTOGNINI J.F. , WOOD R. , GRONERT G.A.
Published: April 2008

Non‐depolarizing muscle relaxants can facilitate surgery and anaesthesia in numerous species, and volatile inhalational anaesthetics such as isoflurane potentiate their action. We studied the effect of isoflurane on the pharmacodynamics and pharmacokinetics of metocurine in six goats. Each was studied twice: once during barbiturate‐opiate anaesthesia and once during isoflurane anaesthesia. The evoked response to sciatic nerve stimulation was measured using a force transducer attached to the hoof. Metocurine was infused until approximately 80–90% blockade. Plasma metocurine concentration was determined by high‐performance liquid chromatography. Isoflurane increased the potency of metocurine significantly; IC50 (the concentration in the effect compartment at 50% paralysis) was 70 ± 15 ng/mL during isoflurane anaesthesia and 129 ± 42 ng/mL during barbiturate‐opiate anaesthesia (P < 0.03). Volume of distribution (63 ± 18 mL/kg), clearance (1.6 ± 0.4 mL/min±kg) and elimination half‐life (99 ± 9 min) during barbiturate‐opiate anaesthesia were not significantly different during isoflurane anaesthesia: 64 ± 25 mL/kg, 1.5 ± 0.7 mL/kgmin, 116 ± 16 min respectively. We conclude that, relative to barbiturate‐opiate anaesthesia, isoflurane potentiates metocurine in goats.
Influence of closure of the reticular groove on the bioavailability and disposition kinetics of meclofenamate in sheep
Authors: ENCINAS T. , VINAGRE E. , BOGGIO J. C. , ANDRÉS M.D. SAN , RODRÍGUEZ C. , ANDRÉS M.I. SAN
Published: April 2008

Sodium meclofenamate is a non‐steroidal anti‐inflammatory drug with anaphylactic protective activity in cattle. The objectives of this study were to describe the pharmacokinetic behaviour of sodium meclofenamate after intravenous and oral administration to sheep and to determine the influence of closure of the reticular groove on the bioavailability of the drug. Sodium meclofenamate was administered by the intravenous (2.2 mg/kg) and oral (20 mg/kg) routes to sheep (n = 6). During the oral study the reticular groove was closed by intravenous administration of lysine vasopressin (0.3 IU/kg) or left open (saline solution). The closure of the reticular groove was assessed by determination of the blood glucose curves after oral administration of a glucose solution. After intravenous administration of meclofenamate, the distribution and elimination half‐lives of the drug were 7.2 min and 542 min respectively, Vss was 1.68 L/kg and ClB was 2.47 mL/min kg. Two different patterns of the plasma concentration curves were observed after oral administration of sodium meclofenamate. When the reticular groove was closed, two peaks were observed (tmax‐2 12‐15 min, Cmax‐1 3.30‐24.01 μg/mL; and tmax‐2′, 52.50‐75 min, Cmax‐2′ 6.45‐11.08 μg/mL).
Pharmacokinetics of cefoperazone in horses
Authors: SORACI A. L. , MESTORINO O. N. , ERRECALDE J. O.
Published: April 2008

The pharmacokinetics and bioavailabilty of cefoperazone (CPZ) were studied following intravenous (IV) and intramuscular (IM) administration of single doses (30 mg/kg) to horses. Concentrations in serum, urine and synovial fluid samples were measured following IV administration. CPZ concentrations in serum, synovial fluid and spongy bone samples were measured following IM administration. After IV administration a rapid distribution phase (t1/2(α):4.22 ± 2.73 min) was followed by a slower elimination phase (t1/2(β) 0.77 ± 0.19 h). The apparent volume of distribution was 0.68 ± 0.10 L/kg. Mean synovial fluid peak concentration was 5.76 ± 0.74 μg/mL. After IM administration a bioavailability of 42.00±5.33% was obtained. Half‐life of absorption was 2.51 ± 0.72 min and t1/2(β) was 1.52±0.15 h. The mean synovial fluid and spongy bone peak concentrations at 2 h after IM administration were 2.91±0.85 μg/mL and 5.56±0.70 μg/mL, respectively.
Characterization of a sterile soft‐tissue inflammation model in Thoroughbred horses
Authors: GUTHRIE A. J. , SHORT C. R. , SWAN G. E. , MÜLDERS M.S.G. , KILLEEN V. M. , NURTON J. P.
Published: April 2008

This paper describes the use of subcutaneously‐placed tissue chambers as a sterile soft‐tissue inflammation model in Thoroughbred horses. Acute, nonimmune inflammation was initiated by injecting a sterile lambda carrageenan solution into a tissue chamber. This model was used to study the temporal changes in oxygen and carbon dioxide tensions, pH, bicarbonate, protein, albumin, prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) concentrations, cell counts and differential counts in tissue fluid from inflamed tissue chambers and control chambers. Skin temperatures over control and inflamed chambers were also compared. Carrageenan‐induced inflammation resulted in significant increases in tissue‐fluid carbon dioxide tension, leucocyte count, albumin, and PGE2 and LTB4 concentrations. It also resulted in a significant decrease in tissue fluid pH and HCO3‐ concentration. Inflammation did not result in significant changes in tissue‐fluid protein concentration, differential cell counts or skin temperature over the chambers. The use of this type of tissue chamber is wellsuited for studying the pathophysiology of a self‐contained, non‐immune inflammatory process. The model described in this paper could prove to be very useful in studies of the distribution of anti‐inflammatory drugs and the effects of such drugs on various aspects of the inflammatory process.
Bioavailability and pharmacokinetics of ibuprofen in the broiler chicken
Authors: RODER J. D. , CHEN C. L. , CHEN H. , SANGIAH S.
Published: April 2008

The intravenous, intramuscular and oral pharmacokinetics of ibuprofen in broiler chickens were investigated. In a preliminary study, plasma ibuprofen concentration‐time profiles, following i.v. (25 mg/kg) dosing were best described by a 2‐compartment model. After intravenous administration, the volume of distribution at steady‐state (Vd(ss)), the total systemic clearance (ClB), the elimination half‐life (t1/2p) and theMRTwere 0.303 L/kg, 482.3 ml/h‐kg, 2.71 h and 1.02 h, respectively. After intramuscular administration of ibuprofen, thetmaxandCmaxwere 0.37 h, and 42.2μg/mL, respectively, with an estimated bioavailability of 46.7%. After oral administration of ibuprofen, thetmaxandCmaxwere 0.31 h and 23.91 μg/mL, respectively, with an estimated bioavailability of 24.2%. This is a preliminary study, examining the use of ibuprofen in broiler chickens, and should be followed by tissue residue and efficacy studies in different disease states.
The behaviour of healthy awake cats following intravenous and intramuscular administration of midazolam
Authors: ILKIW J. E. , SUTER C. M. , FARVER T. B. , McNEAL D. , STEFFEY E. P.
Published: April 2008

The onset of action and behavioural effects following intravenous (i.v.) and intramuscular (i.m.) administration of 0.05, 0.5, 1.0, 2.0 and 5.0 mg/kg of midazolam were studied for 2 h in 20 awake, healthy cats. All cats, except one that received 0.05 mg/kg i.m., showed effects of the drug, whereas no effects were observed in cats administered only the vehicle in which midazolam was dissolved. The onset of action was rapid following both i.v. and i.m. administration, some cats became ataxic, while others assumed positions of sternal or lateral recumbency. Even after administration of the highest dose (5.0 mg/kg), anaesthesia was not induced, with swallowing reflexes and conscious perception of a clamp placed on the tail still present in all cats. An abnormal arousal state was observed in many cats after administration of midazolam. During the first hour, restlessness was more commonly observed, while from 1 to 2 h, sedation was more prominent in cats that received the highest dose. Ataxia occurred in all but one cat, was short‐lived in cats that received the lower doses, but still present at 2 h in all cats that received 2.0 and 5.0 mg/kg. Midazolam caused some of the cats to behave differently when approached and restrained compared with behavioural patterns identified prior to administration of the drug. The cats were more likely to behave abnormally following i.v. administration rather than i.m. administration and, for the most part, abnormal behaviour was equally distributed between the two extremes; cats being easier to approach and restrain and cats being more difficult to approach and restrain. Food consumption increased significantly, during the 2 h period, following all i.m. doses and all but the highest (5.0 mg/kg) i.v. dose, with most of the food being consumed in the first hour after administration.
Cardiovascular effects of the macrolide antibiotic tilmicosin, administered alone and in combination with propranolol or dobutamine, in conscious unrestrained dogs
Authors: MAIN B. W. , MEANS J. R. , RINKEMA L. E. , SMITH W. C. , SARAZAN R. D.
Published: April 2008

Tilmicosin(TM), a macrolide antibiotic and active ingredient in formulated Micotil 300TM (Eli Lilly and Co., Indianapolis, IN, USA), is the active ingredient in a formulated animal product used for the treatment of respiratory tract infections in cattle. Owing to the concern of governmental regulatory agencies over the possibility of an accidental injection of the antibiotic to a livestock handler, the cardiovascular effects of sub lethal doses of TM were evaluated in conscious mixed‐breed dogs. Left ventricular function, systemic arterial blood pressure, and heart rate (HR) responses to TM alone and in combination with propranolol(P) or dobutamine HCl(DOB) were evaluated. Dogs were instrumented with indwelling micromanometers implanted in the left ventricular chamber and in the thoracic aorta. Cardiovascular variables were recorded, and the peak value of the first derivative of left ventricular pressure (dp/dt(max)) was used as an index of left ventricular inotropic state. Six treatments were randomly assigned to each of the six dogs using a Latin square design. The six treatments were vehicle, TM alone (2.5 mg/kg of body weight), TM immediately followed by P. and TM immediately followed by 1 of 3 dosages of DOB infused for ≅45 min. Additionally, doses of TM alone (0.25, 1.0, 2.5, and 5.0 mg/kg) were administered to complete a dose‐response curve. TM caused dose dependent decreases in (dp/dt(max)) and aortic pulse pressure. HR increased dose‐dependently. Left ventricular end‐diastolic pressure increased at the 2.5 and 5.0 mg/kg dosages. Left ventricular systolic pressure was reduced dose‐dependently at the 2.5 and 5.0 mg/kg dosages. Treatment with P exacerbated the negative inotropic effect and the decrease in left ventricular systolic pressure, but did not attenuate the tachycardia associated with TM treatment. DOB attenuated the changes in ventricular inotropic state in a dose‐dependent manner. DOB infusion also restored left ventricular systolic pressure at dosages of 3 or 10 μg/min/kg. Our data indicate that toxic doses of TM may have a negative inotropic effect in conscious dogs. HR increased in a dose‐dependent manner and was not the result of β1‐receptor stimulation. DOB reversed some, but not all, of the effects caused by TM administration.
Pharmacokinetics and bioavailability of doxycycline in turkeys
Authors: SANTOS M.D.F. , VERMEERSCH H. , REMON J. P. , SCHELKENS M. , BACKER P. DE , van BREE H.J.J. , DUCATELLE R. , HAESEBROUCK F.
Published: April 2008

The pharmacokinetic parameters of doxycycline (DOX) were determined in 3 day, 3‐, 6‐ and 12‐week‐old fasted turkeys, after a single intravenous (i.v.) dose of 25 mg doxycycline. HCl/kg body weight. Doxycycline disposition fitted an open two‐compartment model. The mean (± SD) elimination half‐life was 10.6 ± 0.7, 10.8 ± 1.5, 7.9 ± 1.4 and 10.0 ± 0.9 h in 3 day, 3‐, 6‐ and 12‐week‐old turkeys, respectively. Mean (± SD) total body clearance was 0.19 (± 0.01), 0.27 (± 0.03), 0.11 (± 0.03) and 0.06 (± 0.01) L/h.kg in 3 day, 3‐, 6‐ and 12‐week‐old turkeys, respectively. The steady‐state volume of distribution was 1.77 (± 0.2), 2.1 (± 0.2), 0.7 (± 0.4) and 0.5 (± 0.2) L/kg in turkeys of the above mentioned ages, respectively. TheAUCvalue significantly increased with the age of the turkeys. An oral doxycycline solution at a single dose of 25 mg/kg of body weight was administered to 3 day, 3‐, 6‐ and 12‐week‐old turkeys. The maximal plasma concentrations in fasted turkeys were 3.8, 5.6, 7.4 and 5.7 μg/mL, withtmaxvalues of 4.7, 1.5, 2.8 and 5.4 h, for the different ages, respectively. In fed turkeys theCmaxvalues were 2.5, 6.1, 4.8 and 3.0 μg/mL, withtmaxvalues of 4.2, 5.3, 4.5 and 7.5 h, respectively. The absolute bioavailability in fasted turkeys varied between 25.0 ± 9.0% (for 12‐week‐old birds) and 63.5 ± 7.1% (for 3‐week‐old birds). The relative bioavailability varied between 40.0 ± 13.0% (for 12‐week‐old birds) and 83.7 ± 14.3% (for 3‐week‐old birds).
In vitro and in vivo binding of trimethoprim and sulphachlorpyridazine to equine food and digesta and their stability in caecal contents
Authors: DUIJKEREN E. VAN , KESSELS B.G.F. , van OLDRUITEN‐BORGH‐OOSTERBAAN M. M. SLOET , BREUKINK H. J. , VULTO A. G. , van MIERT A.S.J.P.A.M.
Published: April 2008

Binding of antibiotics to food has received little attention in equine medicine, although such binding could potentially reduce the bioavailability and clinical efficacy. In the present study, binding of trimethoprim (TMP) and sulphachlorpyridazine (SCP) to hay, grass silage and concentrate was investigated in vitro in buffer at pH 6.8 at different concentrations. The binding of TMP and SCP to caecal contents was also studied. In addition, the degradation of TMP and SCP by the caecal microflora was investigated by incubating sterilized and non‐sterilized caecal contents for 3 h at 37° under anaerobic conditions and comparing the TMP and SCP contents. Further, a TMP/SCP powder formulation was adminstered orally with concentrate at a dose rate of 5 mg/kg TMP and 25 mg/kg SCP to three ponies with a caecum fistula; the animals were deprived of food for 8 h before administration. Blood samples, caecal contents samples and faecal samples were collected and analysed for TMP and SCP concentrations by means of high performance liquid chromatography (HPLC). Three non‐fistulated ponies, acting as control animals, were fed the same dose of TMP/SCP with concentrate after 8 h of food deprivation and blood samples were taken. The percentage of in vitro binding of TMP as well as SCP to hay, grass silage and concentrate at concentrations of 4 μg/mL to 10 μg/mL was high (60‐90%). TMP and SCP were also extensively bound to caecal contents (50‐70%). At spiking concentrations above 10 μg/mL the percentage of binding decreased. There was no evidence of biodegradation of TMP or SCP in caecal contents. In vivo, both drugs could be detected in the caecal contents and in the faeces of three fistulated ponies. However, the fistulated ponies differed from the control ponies in that their TMP and SCP plasma concentrations were higher, and two fistulated ponies did not show double peaks in their plasma concentration‐time curves. Therefore, the fistulated ponies did not provide an optimal model for in vivo binding studies. Despite this limitation, it can be concluded that binding of TMP and SCP to food is a major cause of the limited bioavailability of these drugs in the horse. It is hypothesized that the binding is reversible, and that a second absorption phase occurs in the large intestine, but part of the administered dose remains bound as both drugs were found in the faeces.
Bioequivalence study in calves of three commercial penicillin/ dihydrostreptomycin fixed combination products for intramuscular injection
Authors: GROEN K. , MEVIUS D.J. , FAUW D.P.K.H. PEREBOOM‐DE , de NEELING A. J. , VULTO A. G.
Published: April 2008

A bioequivalence study with three penicillin/dihydrostreptomycin fixed combination products for intramuscular administration was performed in dairy calves. In addition to plasma concentrations of penicillin and dihydrostreptomycin, creatine phosphokinase concentrations were determined during a period of 72 h after administration of the drug products. Considerable differences were observed in the pharmacokinetics of penicillin from the three products. Although the extent of absorption was similar for all products, one product showed a significantly slower release from the site of injection. Except for the AUC, the 90% confidence intervals for these parameters exceeded the acceptable range of 0.80‐1.20. Therefore, these products are not bioequivalent with respect to the rate of absorption of penicillin. Concerning the pharmacokinetics of dihydrostreptomycin in calves, it could not be concluded that the products were bioequivalent, since the 90% confidence intervals of the ratios for Cmax, tmax and MRT exceeded the range of 0.80‐1.20. From this study in calves, it was also found that the product with the slowest release of penicillin from the injection site caused the most severe tissue damage, based on plasma creatine phosphokinase concentrations. Comparing the results from this study in calves with those from a previous study in rabbits, it can be concluded that the rabbit is a good animal model that could substitute for large animals, at least calves, in bioequivalence studies for penicillin/dihydrostreptomycin fixed combination products.
Distribution of penicillins into subcutaneous tissue chambers in ponies
Authors: ENSINK J. M. , KLEIN W. R. , BARNEVELD A. , VULTO A. G. , van MIERT A.S.J.P.A.M. , TUKKER J. J.
Published: April 2008

The distribution of penicillins into a tissue chamber implanted subcutaneously in ponies was studied. Ampicillin sodium (equivalent to 15 mg/kg ampicillin) was administered intravenously. Pivampicillin, a prodrug of ampicillin, was administered by nasogastric tube to fed ponies at a dose of 19.9 mg/kg (equivalent to 15 mg/kg ampicillin). Procaine penicillin G was administered intramuscularly at a dose of 12 mg/kg (equivalent to 12 000 IU/kg). Six ponies were used for each medication. Antibiotic concentrations in plasma and tissue chamber fluid (TCF) were measured for 24 h after administration. Mean peak concentrations of ampicillin in TCF were 7.3 μg/mL, reached at 1.7 h, and 1.3 μg/mL, reached at 2.7 h, after administration of ampicillin sodium and pivampicillin respectively. The mean peak concentration of penicillin G of 0.3 μg/mL was reached 12.3 h after administration of procaine penicillin G. Concentrations in TCF remained above the minimum inhibitory concentration of Streptococcus zooepidemicus for the proposed dosing intervals of 8, 12 and 24 h for ampicillin sodium, pivampicillin and procaine penicillin G respectively.
The effect of inflammation on the disposition of phenylbutazone in Thoroughbred horses
Authors: MILLS P. C. , NG J. C. , AUER D. E.
Published: April 2008

The effect of inflammation on the disposition of phenylbutazone (PBZ) was investigated in Thoroughbred horses. An initial study (n= 5) in which PBZ (8.8 mg/kg) was injected intravenously twice, 5 weeks apart, suggested that the administration of PBZ would not affect the plasma kinetics of a subsequent dose. Two other groups of horses were given PBZ at either 8.8 mg/kg (n= 5) or 4.4 mg/kg (n= 4). Soft tissue inflammation was then induced by the injection of Freud's adjuvant and the administration of PBZ was repeated at a dose level equivalent to, but five weeks later than, the initial dose. Inflammation did not appear to affect the plasma kinetics or the urinary excretion of PBZ and its metabolites, oxyphenbutazone (OPBZ) or hydroxyphenylbutazone (OHPBZ) when PBZ was administered at 8.8 mg/kg. However, small but significant increases (P<0.05) in total body clearance (CLB; 29.2 ± 3.9 vs. 43.8 ± 8.1 mL/ h‐kg) and the volume of distribution, calculated by area (Vd(area); 0.18 ± 0.05 vs. 0.25 ± 0.03 L/kg) or at steady‐state (Vd(SS); 0.17±0.04 vs. 0.25 ± 0.03 L/ kg), were obtained in horses after adjuvant injection, compared to controls, when PBZ was administered at 4.4 mg/kg which corresponded to relatively higher tissues concentrations and lower plasma concentrations (calculated) at the time of maximum peripheral PBZ concentration. Soft tissue inflammation also induced a significantly (P<0.05) higher amount of OPBZ in the urine 18 h after PBZ administration but the total urinary excretion of analytes over 48 h was unchanged. These results have possible implications regarding the administration of PBZ to the horse close to race‐day.
Pharmacokinetics of valacyclovir in the adult horse
Authors: MAXWELL L. K. , BENTZ B. G. , BOURNE D. W. A. , ERKERT R. S.
Published: April 2008

Recent outbreaks of equine herpes virus type‐1 infections have stimulated renewed interest in the use of effective antiherpetic drugs in horses. The purpose of this study was to investigate the pharmacokinetics of valacyclovir (VCV), the prodrug of acyclovir (ACV), in horses. Six adult horses were used in a randomized cross‐over design. Treatments consisted of 10 mg/kg ACV infused intravenously, 5 g (7.7–11.7 mg/kg) VCV delivered intragastrically (IG) and 15 g (22.7–34.1 mg/kg) VCV administered IG. Serum samples were obtained at predetermined times for acyclovir assay using high‐performance liquid chromatography. Following the administration of 5 g VCV, the mean observed maximum serum ACV concentration (Cmax) was 1.45 ± 0.38 (SD) μg/mL, at 0.74 ± 0.43 h. At a dose of 15 g VCV, the meanCmaxwas 5.26 ± 2.82 μg/mL, at 1 ± 0.27 h. The mean bioavailability of ACV from oral VCV was 60 ± 12% after 5 g of VCV and 48 ± 12% after 15 g VCV, and did not differ significantly between dose rates (P > 0.05). Superposition suggested that a loading dose of 27 mg/kg VCV every 8 h for 2 days, followed by a maintenance dose of 18 mg/kg every 12 h, will maintain effective serum ACV concentrations.
Trends in stillbirths, early and late neonatal mortality in rural Bangladesh: the role of public health interventions
Authors: Ronsmans Carine , Chowdhury Mahbub Elahi , Alam Nurul , Koblinsky Marge , Arifeen Shams El
Published: April 2008

Trends were examined in a cohort study of stillbirths and early and late neonatal deaths in Matlab, a rural area of Bangladesh between 1975 and 2002, using routinely collected demographic surveillance data. Main outcome measures were stillbirths per 1000 births, early neonatal deaths per 1000 livebirths, and late neonatal deaths per 1000 children surviving after 1 week. We performed a logistic regression examining trends over time and between two areas in the three outcome measures, controlling for the effects of parental education, religion, time, geography, parity, maternal age and birth spacing.

There was a marked decline in stillbirths, early and late neonatal mortality over time in both areas, though the pace of decline was somewhat faster in the ICDDR,B (International Centre for Diarrhoeal Disease Research, Bangladesh) service area. Stillbirths declined by 24% overall in the ICDDR,B service area (crude OR comparing 1996–2002 with 1975–81: 0.76 [95% CI 0.68, 0.84]), compared with 15% in the Government service area (crude OR comparing 1996–2002 with 1975–81: 0.85 [0.76, 0.94]). The overall reduction in early and late neonatal mortality comparing the same periods was 39% and 73%, respectively, in the ICDDR,B area, compared with 30% and 63%, respectively, in the Government service area. Adjusting for socio‐economic or demographic factors did not substantially alter the time or area differentials. The dramatic decline in neonatal mortality was, in large part, due to a fall in deaths from neonatal tetanus. The pace of decline was faster in the area receiving intense maternal and child health and family planning interventions, but stillbirths, early and late neonatal deaths also declined in the area not receiving such intense attention, suggesting that factors outside the formal health sector play an important role.
Measuring dietary sodium intake in infancy: a review of available methods
Authors: Sutton Eileen , Emmett Pauline , Lawlor Debbie A.
Published: April 2008

It has been hypothesised that infancy may be a particularly sensitive period with respect to the effect of dietary sodium (salt) intake on later blood pressure. If this is the case, interventions to reduce dietary sodium intake in infancy could have major public health impact by reducing cardiovascular disease in the future. However, research in this area is hampered by difficulties of how to measure dietary sodium intake in infancy. Here we review the literature with an aim to describe different methods that have been used for research purposes, how these have been used and their relative strengths and limitations.

We identified five studies that were relevant to our aim. In epidemiological and intervention studies sodium intake in infancy has been assessed via parents using diet diaries, which appear to be feasible and acceptable to parents. In these studies, sodium concentration in breast milk is assumed not to vary from one woman to the next, which may not be correct but has been poorly studied. The gold standard method – 24 h urinary excretion of sodium – was used in only one study and there is debate about the most appropriate way to collect urine for research purposes in infants. None of the studies directly compared different methods for determining infant dietary sodium intake. We conclude that research is required to determine the best methods of estimating dietary sodium intake in infants in different research contexts.
Phosphatidylinositol 4‐phosphate accumulates extracellularly upon xylanase treatment in tomato cell suspensions
Authors: GONORAZKY GABRIELA , LAXALT ANA M. , TESTERINK CHRISTA , MUNNIK TEUN , DE LA CANAL LAURA
Published: April 2008

Various phosphoinositides have been implicated in plant defence signalling. Until now, such molecules have been exclusively related to intracellular signalling. Here, evidence is provided for the detection of extracellular phosphatidylinositol 4‐phosphate (PI4P) in tomato cell suspensions. We have analysed and compared the intracellular and extracellular phospholipid profiles of [32Pi]‐prelabelled tomato cells, challenged with the fungal elicitor xylanase. These phospholipid patterns were found to be different, being phosphatidylinositol phosphate (PIP) the most abundant phospholipid in the extracellular medium. Moreover, while cells responded with a typical increase in phosphatidic acid and a decrease in intracellular PIP upon xylanase treatment, extracellular PIP level increased in a time‐ and dose‐dependent manner. Using two experimental approaches, the extracellular PIP isoform was identified as PI4P. Addition of PI4P to tomato cell suspensions triggered the same defence responses as those induced by xylanase treatment. These include production of reactive oxygen species, accumulation of defence‐related gene transcripts and induction of cell death. We demonstrate that extracellular PI4P is accumulated in xylanase‐elicited cells and that exogenous application of PI4P mimics xylanase effects, suggesting its putative role as an intercellular signalling molecule.
Large shear zones with no relative displacement
Authors: Nicolas Adolphe , Boudier Françoise
Published: April 2008

In the Oman ophiolite, the large scale Makhibiyah shear zone, in Wadi Tayin massif was generated with no or little relative motion between the two adjacent blocks, in contrast with what is reported from otherwise similar shear zones in deep crust and upper mantle. This shear zone is asymmetrical with, along one margin an asthenospheric mantle (∼1200 °C) and along the adjacent margin, a lithospheric mantle (∼1000 °C). Within the hotter side and with increasing shear strain, horizontal flow lines smoothly swing towards the shear zone direction before abutting against the wall of the lithosphere side. Profuse mafic melts issued from the hotter mantle are frozen in the shear zone by cooling along this lithospheric wall. Tectonic and magmatic activities are entirely localized within the asthenospheric compartment. Mantle flow lines were rotated, during their channelling along this NW‐SE shear zone, in the NW and SE opposite directions. Depending on whether the flow lines are deviated NW or SE, dextral or sinistral shear sense is recorded in the shear band mylonitic peridotites. This demonstrates that the shear zone was not generated by strike‐slip motion, a conclusion supported by regional observations.
Transcript profiling indicates that the absence of PsbO affects the coordination of C and N metabolism in Synechocystis sp. PCC 6803
Authors: Schriek Sarah , Aguirre‐von‐Wobeser Eneas , Nodop Anke , Becker Anke , Ibelings Bas W. , Bok Jasper , Staiger Dorothee , Matthijs Hans C. P. , Pistorius Elfriede K. , Michel Klaus‐Peter
Published: April 2008

Transcript profiling of nitrate‐grown Synechocystis sp. PCC 6803 PsbO‐free mutant cells in comparison to wild‐type (WT) detected substantial deviations. Because we had previously observed phenotypical differences between Synechocystis sp. PCC 6803 WT and its corresponding PsbO‐free mutant when cultivated with l‐arginine as sole N source and a light intensity of 200 μmol photons m−2 s−1, we also performed transcript profiling for both strains grown either with nitrate or with l‐arginine as sole N source. We observed a total number of 520 differentially regulated transcripts in Synechocystis WT because of a shift from nitrate‐ to l‐arginine‐containing BG11 medium, while we detected only 13 differentially regulated transcripts for the PsbO‐free mutant. Thus, the PsbO‐free Synechocystis mutant had already undergone a preconditioning process for growth with l‐arginine in comparison to WT. While Synechocystis WT suffered from growth with l‐arginine at a light intensity of 200 μmol photons m−2 s−1, the PsbO‐free mutant developed only a minor stress phenotype. In summary, our results suggest that the absence of PsbO in Synechocystis affects the coordination of photosynthesis/respiration and l‐arginine metabolism through complex probably redox‐mediated regulatory pathways. In addition, we show that a comparison of the transcriptomes of nitrate‐grown Synechococcus elongatus PCC 7942 WT cells and its corresponding PsbO‐free mutant cells resulted in only a few differentially regulated transcripts between both strains. The absence of the manganese/calcium‐stabilizing PsbO protein of PSII with an assigned regulatory function for photosynthetic water oxidation causes bigger changes in the transcriptome of the permissive photoheterotrophically growing Synechocystis sp. PCC 6803 than in the transcriptome of the obligate photoautotrophically growing S. elongatus PCC 7942.
Toxicity related to autologous peripheral blood haematopoietic progenitor cell infusion is associated with number of granulocytes in graft, gender and diagnosis of multiple myeloma
Authors: Bojanic I. , Cepulic B. Golubic , Mazic S. , Batinic D. , Nemet D. , Labar B.
Published: April 2008

Background and Objectives  We prospectively evaluated the infusion‐related toxicity of autologous peripheral blood progenitor cells (PBPC) in 215 patients with haematologic malignancies or solid tumours.

Materials and Methods  PBPCs were collected by apheresis after mobilization with chemotherapy and/or granulocyte–colony‐stimulating factor (G‐CSF). The grafts were cryopreserved in 10% dimethyl sulfoxide (DMSO) and stored in liquid nitrogen. Patients were monitored for vital signs and symptoms of the toxicity during and after infusion.

Results  The adverse reactions were reported during 149 (56·9%) infusions. During 21·0% infusions occurred just one symptom classified as grade 1, while during 35·9% occurred multiple symptoms classified as grade 2. Logistic regression analysis showed that female gender, diagnosis of multiple myeloma and number of granulocytes infused per kg body weight were significant predictors of occurrence of adverse reactions during infusion.

Conclusion  Our results indicate that beside the infused DMSO dose, the composition of graft as well as patient's diagnosis are also very important factors for infusion‐related toxicity.
Underwater germination potential of common ash seed (Fraxinus excelsiorL.) originating from flooded and non‐flooded sites
Authors: Dacasa Rüdinger M. C. , Dounavi A.
Published: April 2008

Oxygen availability is one of the main factors affecting seed germination capacity. On floodplains, oxygen supply is seasonally restricted because of flooding events. Seed ecotypes are able to cope with total submergence to different extents, depending on the species and its position in a given environmental gradient. This investigation tested three provenances of common ash (Fraxinus excelsiorL.), one from a lowland site and two from upland sites, for germination capacity and germination velocity under water. The final germination capacity of all provenances was unaffected, but the germination velocity was decreased for all provenances. The adaptational significance of these results is discussed.