bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics, metabolism and urinary detection time of flunixin after intravenous administration in camels
Authors: Wasfi I.A. , Boni N.S. , Abdel Hadi A.A. , ElGhazali M. , Zorob O. , Alkatheeri N.A. , Barezaiq I.M.
Published: March 2003

The pharmacokinetics of flunixin were determined after an intravenous dose of 1.1 mg/kg body weight in six camels and 2.2 mg/kg body weight in four camels. The data obtained (mean ±  SEM) for the low and high dose, respectively, were as follows:

 The elimination half‐lives (t½β) were 3.76 ± 0.24 and 4.08 ± 0.49 h, the steady state volumes of distribution (Vdss) were 320.61±38.53 and 348.84 ± 35.36 mL/kg body weight, total body clearances (ClT) were 88.96 ± 6.63 and 84.86±4.95 mL/h/kg body weight and renal clearances (Clr) were 0.52 ± 0.09 and 0.62 ± 0.18 mL/h/kg body weight. A hydroxylated metabolite of flunixin was identified by gas chromatography/mass spectrometry (GC/MS) under electron and chemical ionization and its major fragmentation pattern was verified by tandem mass spectrometry (GC/MS/MS) using neutral loss, daughter and parent scan modes. The detection times for flunixin and its hydroxylated metabolite in urine after an intravenous (i.v.) dose of 2.2 mg/kg body weight were 96 and 48 h, respectively.
Adrenocortical and metabolic responses to dobutamine infusion during halothane anaesthesia in ponies
Authors: TAYLOR
Published: March 2003

The study investigated whether hypotension in halothane‐anaesthetised ponies is the stimulus inducing an endocrine stress response by assessing the effect of maintenance of normotension with a dobutamine infusion. Groups of six ponies were studied. After premedication with acepromazine (0.04 mg/kg) anaesthesia was induced with thiopentone (10 mg/kg) and maintained for 120 min with halothane (group AN). Dobutamine was infused to effect (1.1–4.4 μg/kg/min) to maintain arterial pressure at pre anaesthetic levels. The conscious group (CON) were prepared as for AN and then received only dobutamine infusion 1.0 μg/kg/min for 120 min. Arterial blood pressure, pH, oxygen and carbon dioxide tension, pulse rate, haematocrit, and plasma cortisol, glucose and lactate concentrations were measured before, at 20 min intervals during anaesthesia, and 20 and 120 min after anaesthesia ceased. Blood pressure remained close to control in both groups. The AN group became hypercapnic and acidotic, pulse rate and haematocrit increased, cortisol increased more than twofold and plasma glucose and lactate did not change. All values remained at control in the CON group except for small increases in haematocrit and decreases in pulse rate. Maintenance of normotension during halothane anaesthesia did not blunt the adrenocortical response to anaesthesia nor did the same dose of dobutamine alone increase plasma cortisol. Hypotension appears not to be the sole stimulus to equine adrenocortical activity during halothane anaesthesia.
The effects of hyperoxia on the biosynthesis of cyclooxygenase products and haemodynamic response to nitric oxide synthase inhibition with L‐NAME in endotoxaemic pigs
Authors: Hellyer  , Wright  , Mallinckrodt  , Gaynor  , Mama  , Wagner
Published: March 2003

The interaction between constitutive nitric oxide and oxygen may depend on the degree of tissue oxygenation and may play a critical role in the pathophysiological response to endotoxaemia. We investigated if hyperoxia (100% O2) attenuated the systemic and pulmonary vasoconstriction and increased biosynthesis of thromboxane B2(TXB2) and 6‐keto‐prostaglandin (PG) F1αinduced by inhibition of nitric oxide synthase with NG‐nitro‐l‐arginine‐methyl‐ester (L‐NAME) in a porcine model of endotoxaemia. Twenty‐two domestic, random source pigs, weighing 15.4 ± 2.7 kg (mean ± standard deviation) were the subjects of this study. Pigs were anaesthetized with isoflurane in 100% O2, orotracheally intubated and ventilated to maintain normocapnia, and then instrumented for haemodynamic monitoring. Following instrumentation, pigs were maintained at an end‐tidal isoflurane concentration of 2%. Pigs were randomly assigned to treatment groups: saline + 30% O2(Control,n = 6);Escherichia colilipopolysaccharide (5 μg/kg/h from 1 to 2 h followed by 2 μg/kg/h from 2 to 5 h) + 30% O2(LPS,n = 4); L‐NAME (0.5 mg/kg/h, from 0 to 5 h) + LPS + 100% O2(n = 6); and L‐NAME + LPS + 30% O2(n = 6). L‐NAME and endotoxin significantly (P < 0.05) increased mean arterial pressure, mean pulmonary arterial pressure, and systemic and pulmonary vascular resistance index beginning at 90 min. When results were pooled across all time periods, mean arterial pressure and mean pulmonary arterial pressure were significantly higher in the L‐NAME + LPS + 30% O2group than all other groups, reflecting pulmonary and systemic vasoconstriction. Hyperoxia attenuated the L‐NAME + LPS‐induced increases in TXB2and 6‐keto‐PGF1αconcentrations at 90 and 120 min and 120 min, respectively, although the differences were not statistically significant. These results support the observation that nitric oxide synthase inhibition with L‐NAME has deleterious haemodynamic effects in this model of endotoxaemia. The temporal attenuation of L‐NAME‐induced pulmonary and systemic vasoconstriction by hyperoxia suggested that the haemodynamic effects of acute endotoxaemia were in part influenced by the relative amounts of nitric oxide and oxygen present.
Pharmacokinetic parameters and milk concentrations of ketoprofen after administration as a single intravenous bolus dose to lactating goats
Authors: Musser  , Anderson  , Tyczkowska
Published: March 2003

Six clinically normal lactating does were administered ketoprofen (2.2 mg/kg intravenously (i. v.)). Blood and milk samples were collected prior to and for 24 h after drug administration. Drug concentrations in serum and milk were determined by high performance liquid chromatography. Pharmacokinetic parameters from each goat were combined to obtain mean estimates (mean ± SD) of half‐life of elimination (t½β) of 0.32 ± 0.14 h, systemic clearance (Cl) of 0.74 ± 0.12 L/kg· h, and volume of distribution at steady state (Vss) of 0.23 ± 0.051 L/kg. In milk, ketoprofen was unmeasurable by the method employed (level of detection 25 ng/mL) for all samples.
Characterization of the antinociceptive and sedative effect of amitraz in horses
Authors: Queiroz‐Neto  , Zamur  , Gonçalves  , Carregaro  , Mataqueiro  , Harkins  , Tobin
Published: March 2003

Amitraz, an acaricide used to control ectoparasites in animals has a complex pharmacological activity, including α2‐adrenergic agonist action. The purpose of this research was to investigate the possible antinociceptive and/or sedative effect of amitraz in horses. The sedative effect of the intravenous (i.v.) injection of dimethylformamide (DMF, 5 mL, control) or amitraz (0.05, 0.10, 0.15 mg/kg), was investigated on the head ptosis test. The participation of α2‐adrenergic receptors in the sedative effect provoked by amitraz was studied by dosing yohimbine (0.12 mg/kg, i.v.). To measure the antinociception, xylazine hydrochloride (1 mg/kg, i.v., positive control) and the same doses of amitraz and DMF were used. A focused radiant light/heat directed onto the fetlock and withers of a horse were used as a noxious stimulus to measure the hoof withdrawal reflex latency (HWRL) and the skin twitch reflex latency (STRL). The three doses of amitraz used (0.05, 0.10 and 0.15 mg/kg) provoked a dose‐dependent relaxation of the cervical muscles. The experiments with amitraz and xylazine on the HWRL showed that after i.v. administration of all doses of amitraz there was a significant increase of HWRL up to 150 min after the injections. Additionally, there was a significant difference between control (DMF) and positive control (xylazine) values up to 30 min after drug injection. On the other hand, the experiments on the STRL show that after administration of amitraz at the dose of 0.15 mg/kg, a significant increase in STRL was observed when compared with the control group. This effect lasted up to 120 min after injection. However, no significant antinociceptive effect was observed with the 0.05 and 0.10 mg/kg doses of amitraz or at the 1.0 mg/kg dose of xylazine.
A comparison between clenbuterol, salbutamol and terbutaline in relation to receptor binding and in vitro relaxation of equine tracheal muscle
Authors: Törneke  , Ingvast Larsson
Published: March 2003

Beta2‐adrenoceptor agonists are used as bronchodilators in both humans and horses. Of these drugs, clenbuterol is the one most frequently used when treating chronic obstructive pulmonary disease in the horse, while salbutamol and terbutaline are used in the treatment of human asthma. Little is known of the properties of the latter two drugs in equine medicine.

 We have compared salbutamol and terbutaline with clenbuterol in relation to their ability to relax muscle strips from equine tracheal muscle, pre‐ contracted with 40 nm carbachol, in tissue chambers. The affinities of these drugs to the β2‐adrenoceptors in homogenates of the same muscle tissue were also examined. These experiments were performed with radioligand binding studies using the very potent β‐adrenoceptor antagonist 125I‐cyanopindolol.

 The three drugs were almost equipotent in relaxing the muscle strips. The EC50‐values for salbutamol, terbutaline and clenbuterol were 5.6, 13.8 and 2.1 nm, respectively, and all three drugs relaxed the preparations completely. In the competitive binding study, however, the Kd‐value of clenbuterol was much lower (24 nm) than that of salbutamol and terbutaline (1100 nm and 3900 nm, respectively). The amount of receptors bound at the EC50‐value of clenbuterol was 8% compared to less than 1% for salbutamol and terbutaline. This indicates a lower intrinsic efficacy of clenbuterol than of the other two drugs. The β‐adrenoceptor density was 45 ± 14.3 fmol/mg protein (mean ± SD) and the Kd‐value of 125I‐cyanopindolol was 11.4 ± 3.3 pm.
Pharmacokinetics, bioavailability and dosage regimen of sulphadiazine (SDZ) in camels (Camelus dromedarius)
Authors: Kumar  , Singh  , Kapoor  , Rai
Published: March 2003

The pharmacokinetics of sulphadiazine (SDZ) (100 mg/kg, body weight) were investigated in six camels (Camelus dromedarius) after intravenous (i.v.) and oral (p.o.) administration. Following i.v. administration, the overall elimination rate constant (β) was 0.029±0.001/h and the half‐life (t½β) was 23.14±1.06 h. The apparent volume of distribution (Vd(area)) was 0.790±0.075 L/kg and the total body clearance (ClB) was 23.29±2.50 mL/h/kg. After p.o. administration, SDZ reached a peak plasma concentration (Cmax(cal.)) of 62.93±2.79 μg/mL at a post injection time of (Tmax(cal.)) 22.98±0.83 h. The elimination half‐life was 19.79±1.22 h, not significantly different from that obtained by the i.v. route. The mean absorption rate constant (Ka) was 0.056±0.002 h−1 and the mean absorption half‐life (t½Ka) was 12.33±0.37 h. The mean availability (F) of sulphadiazine was 88.2±6.2%.

 To achieve and maintain therapeutically satisfactory plasma SDZ levels of 50 μg/mL, the priming and maintenance doses would be 80 mg/kg and 40 mg/kg intravenously and 90 mg/kg and 45 mg/kg orally, respectively, to be repeated at 24 h intervals.
Lack of local anaesthetic efficacy of fentanyl in the abaxial sesamoid block model
Authors: Harkins  , Tobin
Published: March 2003

Fentanyl and other opioid drugs have their effect in the central nervous system; however, activity at peripheral sites has also been demonstrated. Pain‐suppression activity at peripheral sites raises the possibility of skilled individuals producing local anaesthetic effects with small doses of opioid drugs that would be difficult to detect forensically and could be used to affect the outcome of a race. Therefore, the local pain‐suppression effect (peripheral nerve inhibition) of fentanyl was tested using an abaxial sesamoid block/hoof withdrawal model. With this model, fentanyl did not produce significant anaesthesia when tested in eight Thoroughbred horses. This suggests that fentanyl at this or lower doses is unlikely to reduce pain perception when applied directly to sensory neurons. However, the effect of fentanyl and other opioids on joint pain perception of horses, especially inflamed joints, is unknown.
In vivo and ex vivo uptake of albendazole and its sulphoxide metabolite by cestode parasites: relationship with their kinetic behaviour in sheep
Authors: Alvarez  , Sánchez  , Lanusse
Published: March 2003

The current experiments correlate the disposition kinetics of albendazole (ABZ) following its intravenous (i.v.) and intraruminal (i.r.) administrations to Moniezia spp.‐infected sheep, with the pattern of drug/metabolite uptake by tapeworms collected from treated animals. The ex vivo uptake pattern of ABZ and albendazole sulphoxide (ABZSO) by the same cestode parasite was also investigated. Naturally infected (Moniezia spp.) Corriedale lambs were treated with ABZ by either i.v. (Group A, n = 15) or i.r. (Group B, n = 15) administration at 7.5 mg/kg. Plasma and abomasal fluid samples were obtained over a 120‐h period. Two animals per group were killed at 0.5, 1, 2, 4 and 6 h post‐treatment; parasite material (tapeworms), bile and intestinal fluid samples were recovered. Furthermore, Moniezia spp. tapeworms obtained from sheep killed at the local abattoir were incubated with either ABZ or ABZSO for different time periods in a Kreb's Ringer Tris buffer (ex vivo experiments). Samples were analysed by high performance liquid chromatography for ABZ, ABZSO and albendazole sulphone (ABZSO2). ABZ plasma concentrations decreased rapidly and were not detectable beyond 10 h following i.v. administration. ABZSO and ABZSO2 were the metabolites recovered in plasma after both treatments. ABZ and its metabolites were extensively distributed to the digestive tract, mainly into the abomasal fluid, after the i.v. and i.r. administrations. The parent drug and its active ABZSO metabolite were recovered in tapeworms collected from both i.v. and i.r. treated lambs. However, the availability of both ABZ and ABZSO was higher in parasite material recovered from i.v. treated animals. The uptake of ABZ by the cestode parasite, both in vivo and ex vivo, was significantly greater than that of its sulphoxide metabolite, which agrees with the higher lipophilicity of the parent drug.
In vitrobiotransformation of anabolic steroids in canines
Authors: Williams  , Kind  , Hill
Published: March 2003

Forensic drug testing of anabolic steroids in racing animals is required because of the potential for steroid abuse. Often when the metabolic products of an administered compound have not been identified, the analysis and verification of the administered compound is difficult. The objective of this study was to qualitatively identify thein vitrophase I biotransformation products of anabolic steroids that have a high potential for abuse in canines. The investigated steroids included testosterone, methyltestosterone, mibolerone and boldenone. Steroid biotransformation products were generated using beagle liver microsomes and analysed by high performance liquid chromatography (HPLC)/mass spectrometry (MS) with an electrospray ionization source. Characterization of steroid metabolites was based on HPLC retention, UV and mass spectra. The major testosterone metabolites were identified as androstenedione and 6β‐ and 16α‐hydroxytestosterone. 6β‐Hydroxymethyltestosterone was identified as a major metabolite in the methyltestosterone microsomal incubations. Several mibolerone metabolites were identified as monohydroxylated mibolerones as well as an oxidized mibolerone metabolite. Boldenone metabolites were identified as monohydroxylated boldenones, oxidized boldenone, and testosterone. This information should assist in the determination of anabolic steroid use in canines through the correlation of the urinary metabolites to the administered drug.
Pulmonary vascular pressures of Thoroughbred horses exercised 1, 2, 3 and 4 h after furosemide administration
Authors: Magid  , Manohar  , Goetz  , Baker  , Ulbricht  , Bontkowski  , Ghantous
Published: March 2003

Furosemide premedication of horses 4 h prior to exercise significantly attenuates exercise‐induced pulmonary capillary hypertension which may help diminish the severity of exercise‐induced pulmonary haemorrhage. As pulmonary hemodynamic effects of furosemide may be mediated via a reduction in plasma volume (which is most pronounced 15–30 min postfurosemide administration, with plasma volume recovering thereafter), we hypothesized that administration of furosemide at intervals shorter than 4 h before exertion may be more effective in attenuating the exercise‐induced rise in pulmonary capillary blood pressure. Thus, our objective was to determine whether furosemide‐induced attenuation of exercise‐induced pulmonary arterial, capillary and venous hypertension would be enhanced when the drug is administered at intervals shorter than 4 h before exercise. Using established techniques, right atrial, and pulmonary arterial, capillary and wedge (venous) pressures were ascertained in seven healthy, sound, exercise‐trained Thoroughbred horses in a randomized split‐plot experimental design. Measurements were made at rest and during exercise performed at maximal heart rate (217 ± 3 beats/min) in the control (no medications) experiments and following furosemide administration (250 mg intravenously (i.v.)) at 1, 2, 3 and 4 h before exercise. Sequence of treatments was randomized and 7 days were allowed between experiments on each horse. Although furosemide administration in the four treatment groups caused only insignificant changes in the pulmonary arterial, capillary and wedge pressures of standing horses, furosemide‐induced reduction in mean right atrial pressure achieved statistical significance in the 2 h postfurosemide experiments. In the control studies, exercise was attended by statistically significant increments in mean right atrial, as well as pulmonary arterial, capillary and wedge pressures. Although exercise in each of the four furosemide experiments was also attended by significant increments in right atrial as well as pulmonary vascular pressures, in the 1, 2 and 3 h postfurosemide experiments, mean right atrial pressure increased to a significantly lower value than in the control study. Exercise‐induced changes in pulmonary vascular pressures in the 1 h postfurosemide experiments were not different from the pressures in the control study. There was a significant attenuation of exercise‐induced pulmonary capillary and venous hypertension in the 2, 3 and 4 h postfurosemide experiments, but significant differences among these treatments were not found. Thus, these data did not support the contention that administration of furosemide at intervals shorter than 4 h before exercise is more effective in attenuating exercise‐induced pulmonary capillary or venous hypertension in Thoroughbred horses.
Enhanced plasma and target tissue availabilities of albendazole and albendazole sulphoxide in fasted calves: evaluation of different fasting intervals
Authors: SÁNCHEZ S. , ALVAREZ L. , SALLOVITZ J. , LANUSSE C.
Published: March 2003

The influence of different pre‐ and post‐treatment fasting periods on the plasma availability and disposition kinetics of albendazole (ABZ) and its sulphoxide metabolite (ABZSO) in cattle was investigated. The effect of fasting on the distribution of ABZ and ABZSO to different target tissues/fluids was also characterised. In Experiment I, 35 parasite‐free Holstein calves were divided into seven groups according to the following feeding conditions and treated intraruminally with ABZ (10 mg/kg): control group (fedad libitum), 24 h fasting either prior to (24 h pre‐) or post (24 h post‐) treatment, 24 h fasting with either 6 (6 h pre+18 h post) or 12 h (12 h pre+12 h post‐) of feed restriction prior to treatment, 12 h fasting either prior to (12 h pre‐) or post (12 h post) treatment. In Experiment II, calves from the same pool of animals were subjected to a 24 h fasting period prior to the same ABZ treatment and killed (two animals) at either 24, 36 or 48 h post‐administration to obtain samples of abomasal/intestinal mucosa and fluid contents, bile and lungs. Plasma (Experiment I) and tissues/fluids (Experiment II) samples were analysed by HPLC. All the fasting periods investigated induced marked changes to the plasma availability and disposition kinetics of the ABZSO metabolite. Enhanced plasma availability between 37 and 118%, delayed peak concentrations and extended mean residence times for ABZSO were observed in fasted compared to fed calves. The changes in plasma kinetics, reflecting an altered quantitative gastrointestinal absorption, were reflected in increased availability of ABZ and ABZSO in the target tissues/fluids of fasted calves. The availabilities of ABZ and ABZSO in the gastrointestinal mucosa and fluids in fasted calves were markedly greater than in those fedad libitum.
A pharmacokinetic/pharmacodynamic approach vs. a dose titration for the determination of a dosage regimen: the case of nimesulide, a Cox‐2 selective nonsteroidal anti‐inflammatory drug in the dog
Authors: Toutain P. L. , Cester C. C. , Haak T. , Laroute V.
Published: March 2003

The present experiment was designed to determine a dosage regimen (dose, interval of administration) in the dog for nimesulide, a nonsteroidal anti‐inflammatory drug within vitroselectivity for the inhibition of cyclo‐oxygenase 2 (Cox‐2), using a pharmacokinetic/pharmacodynamic (PK/PD) approach. The PK/PD results were compared with those obtained using a classical dose titration study. In the PK/PD experiment, 11 dogs were subjected to Freund’s adjuvant arthritis characterized by permanent hyperthermia. Nimesulide (5 mg/kg, oral route) was tested during the secondary phase of the inflammatory response. In the dose titration study, nimesulide (0, 3, 6 and 9 mg/kg, oral route) was tested in eight other dogs using a reversible urate crystal arthritis in a 4‐period crossover design. Different PD endpoints (including lameness assessed by force plate and hyperthermia) were regularly measured during the PK/PD experiment, and plasma samples were obtained to determine the plasma nimesulide concentration. The data were modeled using an indirect effect model. TheIC50of nimesulide for lameness was 6.26 ± 3.01 μg/mL, which was significantly higher than theEC50value obtained for antipyretic effect (2.72 ± 1.29 μg/mL). TheED50estimated from the classical dose titration study were 1.34 mg/kg (lameness) and 3.0 mg/kg (skin temperature). The PK/PD parameters were used to simulate different dosage regimens (dose, interval of administration). The antipyretic and anti‐inflammatory effects were calculated from the model for the recommended dosage regimen (5 mg/kg/24 h). It was apparent from this approach, that this dosage regimen enabled 76% of the theoretical maximal drug efficacy to be obtained for pyresis and 43% for lameness. It was concluded from the comparison ofin vivoandin vitro IC50, that nimesulide is a potent NSAID for which some Cox‐1 inhibition is required to obtain clinically relevant efficacy.
Chronobiological variations of indomethacin pharmacokinetic parameters in sheep
Authors: Boggio J. C. , Valtorta S. E. , Sánchez S. , Mckellar Q.
Published: March 2003

Boggio, J. C., Valtorta, S. E., Sánchez, S., McKellar, Q. Chronobiological variations of indomethacin pharmacokinetic parameters in sheep.J. vet. Pharmacol. Therap.24,261–265.

A two‐phase study to investigate the influence of administration time on pharmacokinetics of indomethacin in sheep was performed. In phase I, 12 animals were allocated to four groups, each corresponding to a different time: 08:00, 14:00, 20:00, 02:00 h. Sheep received an intravenous administration of 1 mg/kg indomethacin. In phase II, each group was administered indomethacin with a 12‐h difference compared to Phase I. The trial was performed in autumn, and animals were subjected to a natural light:dark cycle of 10:14 h. Blood samples were taken and processed by high performance liquid chromatography (HPLC) with ultraviolet detection. For each pharmacokinetic parameter, an analysis of variance was performed to outline the existence of chronobiological variations. Concentration at zero time (C0), hybrid constant for distribution and its half life, hybrid constant for elimination and its half‐life, volume of distribution (Vd), area under the curve (AUC∞) and clearance rate (Cl), presented chronobiological variations (P < 0.05) and were fitted to a cosine equation. The following parameters adjusted to circadian rhythms:C0(acrophase: 13.9788 h);AUC∞(acrophase: 13.4377 h);Vd(acrophase: 0.8245 h) andCl(acrophase: 1.4965 h). It was concluded that pharmacokinetic parameters of intravenously injected indomethacin in sheep would behave in a different, though predictable, manner according to the animal’s biological clock.
Bioequivalence of four preparations of enrofloxacin in poultry
Authors: Sumano L. H. , Gutiérrez O. L. , Zamora M. A.
Published: March 2003

In various parts of the world, many 10% enrofloxacin commercial preparations for water medication of chicken are being employed. To avoid the development of bacterial resistance to this agent, the original trademark and similar preparations must be bioequivalent. To assess whether or not bioequivalence exists among the pioneer vs. three commercial preparations of enrofloxacin, a controlled pharmacokinetic study was conducted. The following variables were compared: maximal plasma concentration (Cpeak), time toCpeak, bioavailability (expressed as the area under the concentration vs. time curve), elimination half‐life, and the shapes of the respective time‐serum concentrations of enrofloxacin profiles. Results indicate that all three similar commercial preparations had lowerCpeakvalues than the reference formulation, being 39.62 to 67.77% of the correspondingCpeakreference. Additionally, bioavailability of enrofloxacin in the pioneer product was statistically higher (P < 0.05). Based upon these results, we conclude that although all preparations were formulated as water‐soluble products, bioequivalence studies are mandatory for the analogue formulations to ensure product comparability. Lack of product bioequivalence could facilitate the development of bacterial resistance and limit the useful life span of the product.
An assessment of antimicrobial consumption in food producing animals in Kenya
Authors: Mitema E. S. , Kikuvi G. M. , Wegener H. C. , Stohr K.
Published: March 2003

Antimicrobial agents are useful for control of bacterial infections in food animals and man. Their prudent use in these animals is important to control any possible development and transfer of resistance between animals and man. The objective of this study was to generate quantitative information to evaluate antimicrobial usage patterns by animal species, route of administration, antimicrobial class and type of use from 1995 to 1999 in Kenya. Theses data are essential for risk analysis and planning and can be helpful in interpreting resistance surveillance data, and evaluating the effectiveness of prudent use efforts and antimicrobial resistance mitigation strategies. Data on quantities of active substance classes were collected from the official records of the Pharmacy and Poisons Board of the Ministry of Health and analysed in MS Excel 2000 program. The mean antimicrobial consumption for the 5‐year period was 14 594 ± 1457 kg per year. This was distributed in the various antimicrobial classes as follows: 7975 kg (54.65%) of tetracyclines, 3103.96 kg (21.27%) of sulfonamides and 954.5 kg (6.56%) of aminoglycosides, 905 kg (6.20%) of β‐lactams, 94 kg (0.64%) of quinolones, 35 kg (0.24%) of macrolides and 24 kg (0.16%) of others (tiamulin). Mean consumption per year among the various food animals was: 10 989 ± 357 kg in large animals (cattle, sheep, pigs and goats), 2906 ± 127 kg in poultry alone and 699 ± 427 kg in both large animals and poultry. These quantities represented 56.56% (8255 kg) consumption per year for parenteral use, 41.79% (6098 kg) for oral use and 1.65% (241 kg) for topical use (intramammary and eye ointments) in cattle. With respect to intended use in food producing animals, the mean consumption per year was: 13 178 kg (90.30%) for therapeutic use (ST), 4 kg (0.03%) for prophylactic treatment (PT) and 1411 ± 246 kg (9.67%) was used both for therapeutic and prophylactic purposes (GPT). The study confirmed that antimicrobials are not used for growth promotion in Kenya. There was no specific trend in the quantities of active antimicrobial classes. This study has revealed that the tetracyclines, sulfonamides and trimethoprim, nitrofurans aminoglycosides, β‐lactams and the quinolones are the most commonly used drugs in food‐producing animals in Kenya. Tetracyclines contributed approximately 55% of the total consumption, and there was an increasing trend in the consumption of quinolones from 1998.
Effects of carprofen (RandSenantiomers and racemate) on the production of IL‐1, IL‐6 and TNF‐α by equine chondrocytes and synoviocytes
Authors: ARMSTRONG S. , LEES P.
Published: March 2003

Chondrocytes and synoviocytes harvested from the joints of healthy horses were maintained in tissue culture. Production of the cytokines interleukin‐1 (IL‐1), interleukin‐6 (IL‐6) and tumour necrosis factor‐α(TNF‐α) in response to lipopolysaccharide (LPS), and the effects of addition of carprofen (racemate andRandSenantiomers) were determined. Lipopolysaccharide failed to stimulate TNF‐αactivity in both cell types but concentrations of IL‐1 and IL‐6 were both increased in a concentration and time‐related manner. Both carprofen enantiomers and the racemic mixture attenuated the increase in IL‐6 induced by LPS in synoviocytes, and S carprofen exerted a similar effect on chondrocytes. Neither enantiomer nor the racemate of carprofen suppressed the increase in IL‐1 release produced by LPS in chondrocytes and synoviocytes. An action of carprofen to suppress IL‐6 release might contribute to the actions which occurin vivo.
Pharmacokinetics of phenylbutazone in beef steers
Authors: DE VEAU I. F. , PEDERSOLI W. , CULLISON R. , BAKER J.
Published: March 2003

De Veau, I. F., Pedersoli, W., Cullison R., Baker J. Pharmacokinetics of phenylbutazone in beef steers.J. vet. Pharmacol. Therap.25,195–200.

Phenylbutazone was administered intravenously to a group of 11 beef steers at a dosage of 6 mg/kg of body weight. Whole plasma and protein‐free plasma were analyzed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a noncompartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 140 mL/kg body weight, with a mean (±SEM) terminal elimination half‐life (t1/2) of 34 ± 9 h. The mean clearance was 3.2 mL/h/kg body weight. TheVss, as determined from the protein‐free plasma fraction, was 54093 mL/kg body weight. This largerVssof free phenylbutazone compared with total plasma phenylbutazone was attributed to a high degree of plasma protein binding, as well as the greater penetration of free phenylbutazone into tissues. The meant1/2of free phenylbutazone was 35 ± 12 h. This similarity to thet1/2estimated from total plasma phenylbutazone data is attributed to an equilibrium between free and plasma phenylbutazone during the terminal elimination phase. The pharmacokinetic parameters of free and total plasma phenylbutazone in beef steers are statistically similar to those previously reported for lactating dairy cows.
Distribution of orally administered trimethoprim and sulfadiazine into noninfected subcutaneous tissue chambers in adult ponies
Authors: Van Duijkeren E. , Ensink J. M. , Meijer L. A.
Published: March 2003

The distribution of trimethoprim (TMP) and sulfadiazine (SDZ) into subcutaneously implanted noninfected tissue chambers was studied in healthy adult ponies. Six ponies were given an oral TMP/SDZ paste formulation at a dose of 5 mg/kg TMP and 25 mg/kg SDZ at 12 h intervals for 2 days in order to reach steady‐state concentrations. Plasma concentrations and tissue chamber fluid (TCF) concentrations of both drugs were measured at regular intervals during a period commencing 24 h after the last oral administration. The peak concentration of TMP (mean ± SD) was 2.92 ± 0.86 μg/mL for plasma and 1.09 ± 0.25 μg/mL for TCF. For SDZ, the mean peak concentration was 40.20 ± 14.74 μg/mL for plasma and 23.48 ± 5.84 μg/mL for TCF. TMP peak concentrations in plasma were reached at 3.17 ± 03.48 h and those in TCF at 7.33 ± 03.72 h. SDZ peak concentrations in plasma were reached at 1.83 ± 02.04 h and those in TCF at 8.00 ± 03.10 h. Concentrations of TMP and SDZ in TCF remained above the generally accepted breakpoint for susceptibility (0.5/9.5 for the TMP/SDZ combination) for 12 h. Therefore, in ponies oral administration of TMP/SDZ at a dose rate of 30 mg/kg given twice daily in the form of a paste should be appropriate for effective treatment of infections caused by susceptible bacteria.
Pharmacodynamics and pharmacokinetics of phenylbutazone in calves
Authors: Arifah A. K. , Lees P.
Published: March 2003

Phenylbutazone (PBZ) was administered to six calves intravenously (i.v.) and orally at a dose rate of 4.4 mg/kg in a three‐period cross‐over study incorporating a placebo treatment to establish its pharmacokinetic and pharmacodynamic properties. Extravascular distribution was determined by measuring penetration into tissue chamber fluid in the absence of stimulation (transudate) and after stimulation of chamber tissue with the mild irritant carrageenan (exudate). PBZ pharmacokinetics after i.v. dosage was characterized by slow clearance (1.29 mL/kg/h), long‐terminal half‐life (53.4 h), low distribution volume (0.09 L/kg) and low concentrations in plasma of the metabolite oxyphenbutazone (OPBZ), confirming previously published data for adult cattle. After oral dosage bioavailability (F) was 66%. Passage into exudate was slow and limited, and penetration into transudate was even slower and more limited; area under curve values for plasma, exudate and transudate after i.v. dosage were 3604, 1117 and 766 μg h/mL and corresponding values after oral dosage were 2435, 647 and 486 μg h/mL. These concentrations were approximately 15–20 (plasma) and nine (exudate) times greater than those previously reported in horses (receiving the same dose rate of PBZ). In the horse, the lower concentrations had produced marked inhibition of eicosanoid synthesis and suppressed the inflammatory response. The higher concentrations in calves were insufficient to inhibit significantly exudate prostaglandin E2 (PGE2), leukotriene B4 (LTB4) andβ‐glucuronidase concentrations and exudate leucocyte numbers, serum thromboxane B2(TxB2), and bradykinin‐induced skin swelling. These differences from the horse might be the result of: (a) the presence in equine biological fluids of higher concentrations than in calves of the active PBZ metabolite, OPBZ; (b) a greater degree of binding of PBZ to plasma protein in calves; (c) species differences in the sensitivity to PBZ of the cyclo‐oxygenase (COX) isoenzymes, COX‐1 and COX‐2 or; (d) a combination of these factors. To achieve clinical efficacy with single doses of PBZ in calves, higher dosages than 4.4 mg/kg will be probably required.
Detection of hepatitis G virus RNA in patients with acute non‐A–E hepatitis
Authors: Frider B. , Sookoian S. , Castan˜o G. , González J. , Flichman D. , Viudez P. , Dawson G. J. , Schlauder G.G. , Mushahwar I. K.
Published: March 2003

We investigated the possible role of hepatitis G virus (HGV or GBV‐C) in the aetiology of acute non‐A–E hepatitis in Argentina by detecting viral RNA in sera by reverse transcriptase–polymerase chain reaction (RT–PCR) using primers specific for the putative NS3 helicase region of HGV. Sixty two patients with acute hepatitis were included in this study. The absence of hepatitis A–E was confirmed by serological testing, and all patients were negative for HCV RNA and autoimmune markers. All patients denied alcohol intake and the use of hepatotoxic drugs. Their mean age was 35.3 years and 37 were males. HGV RNA was present in 19/62 (30.6%) of the patients with non‐A–E acute hepatitis. Among HGV‐positive patients, three had parenteral risk factors within 3 months of onset, one was a health care worker, one was sexually promiscuous, one had travelled to the Middle East and 13 (68.4%) had no history of parenteral exposure. Epidemiological, clinical and biochemical features between HGV‐positive and negative patients did not achieve statistical significance. Hence, HGV appears to play a role in the pathogenesis of acute viral hepatitis; however, the etiology of a significant number of hepatitis cases remains unclear, suggesting the existence of an additional agent(s). The absence of parenteral exposure in most of the HGV RNA‐positive patients in this study shows that routes of community‐acquired HGV infection are not yet completely understood.
Different responses of rat liver adenosine metabolizing enzymes during in vivo and in vitro treatment with interferon‐α2b
Authors: Koci´c G. , Koci´c R. , Vlahovi´c P. , Pavlovi´c D. , Jevtovi´c T.
Published: March 2003

Interferon‐α2b (IFN‐α2b) can exert antiproliferative activity in both normal and maligant liver tissue. To study mechanisms of its antiproliferative action, the activity of the enzymes of adenosine metabolism were investigated. We studied 5′‐nucleotidase (an adenosine‐producing enzyme) and adenosine deaminase (involved in adenosine degradation). Female Wistar rats (3 weeks old) were treated with IFN‐α2b for 48h, as were adult rats (3 months old) and adult rats subjected to partial hepatectomy. During IFN‐α2b administration, the activity of 5′‐nucleotidase increased in the liver of 3‐week‐old rats, proportionately more than in adult rats, but the greatest increase was seen in partially hepatectomised rats. The activity of adenosine deaminase decreased in the liver of 3‐week‐old rats, did not change significantly in 3‐month‐old rats, but was significantly lower in partially hepatectomised rats. As high adenosine concentrations are toxic for mammalian cells, especially during proliferation, the progressive increase of adenosine production, together with the progressive decrease of its degradation, could be one of the mechanisms of IFN‐α2b‐induced antiproliferative activity. In vitro studies were performed using collagenase‐isolated hepatocytes. They were exposed to IFN‐α2b, a cAMP analogue, or both. The incubation of hepatocytes with IFN‐α2b did not significantly change the activity of both enzymes, whereas incubation with the cAMP analogue decreased 5′‐nucleotidase activity and increased adenosine deaminase activity. The mechanism of IFN‐α2b‐induced alteration in adenosine metabolism is therefore unclear.
Hepatitis C antibody detection in dried blood spots
Authors: McCarron B. , Fox R. , Wilson K. , Cameron S. , McMenamin J. , McGregor G. , Pithie A. , Goldberg D.
Published: March 2003

In the UK, there have been few studies of the seroprevalence of antibodies to hepatitis C virus (anti‐HCV). As part of an ongoing prevalence study of HCV in injecting drug users, we have developed a technique for detecting anti‐HCV in blood spots dried on filter paper using a commercially available assay. Subjects with and without serum anti‐HCV were studied. The manufacturer’s recommended cut‐off (CO) for a positive anti‐HCV result is kit‐dependent, and therefore a ratio of test result (T) to kit CO was used to standardize results. T/CO values greater than 0.99 had a sensitivity of 100% and a specificity of 87.5% for anti‐HCV detection. T/CO values greater than 1.99 had a sensitivity of 97.2% and a specificity of 100%. Hence, testing dried blood spots may be useful for detecting anti‐HCV in epidemiological studies and as a diagnostic test in patients with poor peripheral venous access.
Failed adoptive immunity transfer: reactivation or reinfection?
Authors: Ireland J. , Hino K. , Lau G. K. K. , Cheng C. ‐C. , Carman W. F.
Published: March 2003

A 26‐year‐old female bone marrow transplant (BMT) recipient was hepatitis B surface antigen (HBsAg) and hepatitis B e antibody (HBeAb) positive. The donor, her human leucocyte antigen (HLA)‐compatible sister, was HBsAg negative but hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) positive. Twelve weeks post‐BMT the patient became HBsAg negative, as determined using a monoclonal antibody‐based assay. At 16 weeks post‐BMT, HBsAg became undetectable by monoclonal and polyclonal immunoassay with seroconversion to HBsAb; however, at 24 weeks post‐BMT the patient again became HBsAg positive. Both the recipient and the donor were retrospectively tested by hepatitis B virus (HBV) polymerase chain reaction (PCR) and found to be positive. The recipient displayed variants at amino acids 4 and 47 of the surface (S) gene prior to BMT. These mutations were not detected 32 weeks post‐BMT when the S gene sequence was identical to that of an adr prototype. The donor was
found to have four unique amino acid substitutions at positions 30, 98, 101 and 210
of the S gene. However, in vitro‐expressed HBsAg from the donor was detected by commercial kits and an immunofluorescence assay, indicating that antigenic alteration did not explain HBsAg negativity. This donor highlights the value of PCR as the gold standard test for current HBV infection. It also demonstrates that discordance between two commercial HBsAg assays may not always be caused by antigenic variants. The second episode of hepatitis may theoretically have been caused by reactivation, selection of an escape mutant by HBsAb, reinfection or recombination. We suggest it was reactivation because none of the donor variants was seen in the recipient post‐BMT.
Hepatitis C and the British Columbia experience with hepatitis A vaccination
Authors: Daly P.
Published: March 2003

The prevalence of hepatitis C virus (HCV) infection in British Columbia is approximately 1.5%. Experience in this province has revealed that groups at high risk of HCV infection are also prone to outbreaks of hepatitis A virus (HAV). As hepatitis A infection can be fatal in HCV‐positive individuals, numerous strategies have been implemented to help minimize its spread. The importance of vaccinating individuals at high risk for hepatitis C infection against HAV has been recognized.
A virological perspective on the need for vaccination
Authors: Locarnini S.
Published: March 2003

Superinfecton of chronic carriers of hepatitis B virus (HBV) or hepatitis C virus (HCV) with hepatitis A virus (HAV) is often associated with more severe liver disease than infection with HAV alone. Superinfection commonly causes markers of HBV and HCV replication to fall to significantly lower levels. The pathogenesis of acute liver damage characteristic of viral hepatitis is thought to be mediated by host cytotoxic T‐lymphocytes (CTLs) directed against virus‐infected hepatocytes. It has been proposed that the more aggressive liver disease observed in individuals infected with HAV in addition to chronic HBV/HCV is a result of the induction of interferon (IFN)‐α during acute HAV infection. This accounts for the antiviral effect on the active markers of HBV/HCV replication, and the enhanced CTL response against HBV/HCV‐infected hepatocytes. Alternatively, HAV may indirectly stimulate the T helper 1 (Th1)‐type cytokine responses, such as interleukin (IL)‐2, IFN‐γ and tumour necrosis factor (TNF)‐α, which directly promote the antiviral CTL response. Clearance of HBV infection, and possible HAV and HCV, is associated with a specific CTL response, while viral persistence in chronic HBV and HCV infection has been attributed to an imbalance in the Th1–Th2 arms of the immune response. Vaccination against hepatitis A should be considered for patients with chronic HBV/HCV infection, to minimize the risk of exacerbating underlying liver disease.
Immunological and virological predictors of outcome during interferon‐α therapy of chronic hepatitis C
Authors: Saito  , Ebinuma  , Satoh  , Miyaguchi  , Tada  , Iwabuchi  , Kumagai  , Tsuchimoto  , Morizane  , Ishii
Published: March 2003

Results from a multicentre, clinical trial of interferon‐α2a (IFN‐α2a) for the treatment of chronic hepatitis C are reported. Serum hepatitis C virus (HCV) RNA levels were monitored as follows: before, and 2 days after, the first administration of IFN‐α2a; during and at the end of treatment; and 6 months after completion of therapy. Peripheral blood lymphocyte subpopulations were measured, by two‐colour flow cytometry, before and 3 h after the first intramuscular (i.m.) administration of 9 mega units (MU) of IFN‐α2a. Virological responders had a significantly lower pretreatment level of CD11+ CD8− lymphocytes. Biochemical responders had significantly lower pretreatment levels of CD11− CD8+, human leucocyte antigen (HLA) DR− CD4− and HLA DR− CD8+ populations, and a higher pretreatment HLA DR+ CD4− population. These pretreatment differences disappeared 3 h after the first i.m. administration of IFN‐α2a. CD11− CD8+ and HLA DR+ CD8+ cell populations became significantly lower in virological responders 3 h after the first i.m. administration of IFN‐α2a. HLA DR+ CD4+ cell populations were increased less in biochemical responders. Thus, T‐lymphocyte subpopulations were different between responders and non‐responders to IFN therapy and IFN‐modulated host immunity. Multivariate analysis showed that the pretreatment CD11+ CD8− cell population was an independent predictive factor of response to therapy. On the other hand, patients whose serum HCV RNA cleared or decreased within the first 2 days of IFN‐α2a therapy were more likely to achieve a virological response. This predictive factor, however, was not an independent factor by multivariate analysis. These results suggest that host immunity is an important factor in response to IFN therapy, and HCV clearance within the first 2 days is a good predictive factor of response.
Genotype and viral load as prognostic indicators in the treatment of hepatitis C
Authors: Trepo
Published: March 2003

Interferon‐α (IFN‐α), either alone or in combination with ribavirin, is the standard treatment for patients with hepatitis C. However, most patients do not achieve a sustained remission with this treatment regimen. A number of studies have demonstrated that genotype, baseline viral load and/or a decrease in viral load early after treatment induction are the major predictive factors for response to treatment with IFN. Patients with hepatitis C virus (HCV) genotype 1 are more resistant to treatment with IFN, whereas low viral load at baseline and a marked decline in the HCV RNA level during the first 2–12 weeks of IFN therapy are associated with enhanced treatment efficacy. These variables could potentially be used to develop treatment algorithms that tailor therapies for specific clinical situations. Continued development and refinement of such algorithms would facilitate both the selection of patients who are most likely to benefit from therapy and the development of optimal treatment regimens for different patient groups. Predictive factors will also enable clinicians to identify subsets of patients who are not expected to respond well to current treatment. The development of new delivery methods for IFN that produce sustained antiviral pressure may provide a means of treating these previously difficult‐to‐treat patient groups.