bluuebunny/crossref_metadata_2025 huggingface dataset:
Prostaglandin D2 and sleep – a molecular genetic approach
Authors: Hayaishi
Published: March 2003

Prostaglandin (PG) D2 is the major prostanoid in the mammalian brain, and is the endogenous sleep‐promoting substance in mice, rats, and monkeys, and probably in humans as well. When PGD synthase (PGDS), the enzyme responsible for the biosynthesis of PGD2 in the brain, was inhibited in vivo by its selective inhibitors, tetravalent selenium compounds, both slow‐wave sleep and rapid‐eye‐movement sleep were reduced almost completely but reversibly, indicating that PGDS is a key enzyme in sleep regulation. Experiments with transgenic mice also support this contention. Insitu hybridization, immunoperoxidase staining, and direct enzyme assay of tissue samples revealed that PGDS is mainly, if not exclusively, localized in the arachnoid membrane and choroid plexus, from which it is secreted into the cerebrospinal fluid to become β‐trace protein. PGD2 exerts its somnogenic activity by binding with PGD2 receptors, exclusively localized at the ventro‐rostral surface of the basal forebrain. CGS21680, an adenosine A2a agonist, mimicked the somnogenic activity of PGD2 when applied to the PGD2‐sensitive zone. This effect was dose‐dependently and selectively abolished by the prior i.p. application of the adenosine A2a antagonist KF 17837. Furthermore, the somnogenic activity of PGD2 was also dose‐dependently and selectively attenuated by KF17837, indicating the possibility that the sleep induction by PGD2 may be mediated by adenosine through A2a receptors under these conditions. When PGD2 was infused into the subarachnoid space below the rostral basal forebrain, concurrent with sleep induction, striking expression of Fos immunoreactivity was observed in the ventro‐lateral preoptic area. Fos expression in the ventrolateral preoptic area was positively correlated with the preceding amount of sleep and negatively correlated with Fos expression in the tuberomammillary nucleus. PGD2 also increased Fos IR in the basal leptomeninges and several regions implicated in autonomic regulation. These observations suggest that PGD2 may induce sleep via leptomeningeal PGD2 receptors with subsequent activation of the ventrolateral preoptic area neurons.
Slow release caffeine and prolonged (64‐h) continuous wakefulness: effects on vigilance and cognitive performance
Authors: Beaumont M. , Batejat D. , Pierard C. , Coste O. , Doireau P. , Van Beers P. , Chauffard F. , Chassard D. , Enslen M. , Denis J. B. , Lagarde D.
Published: March 2003

Some long work or shift work schedules necessitate an elevated and prolonged level of vigilance and performance but often result in sleep deprivation (SD), fatigue and sleepiness, which may impair efficiency. This study investigated the effects of a slow‐release caffeine [(SRC) at the daily dose of 600 mg] on vigilance and cognitive performance during a 64 h continuous wakefulness period. Sixteen healthy males volunteered for this double‐blind, randomised, placebo controlled, two‐way crossover study. A total of 300‐mg SRC or placebo (PBO) was given twice a day at 21:00 and 9:00 h during the SD period. Vigilance was objectively assessed with continuous electroencephalogram (EEG), the multiple sleep latency tests (MSLT) and wrist actigraphy. Cognitive functions (information processing and working memory), selective and divided attention were determined with computerised tests from the AGARD‐NATO STRES Battery (Standardised Tests for Research with Environmental Stressors). Attention was also assessed with a symbol cancellation task and a Stroop’s test; alertness was appreciated from visual analogue scales (VAS). Tests were performed at the hypo (02:00–04:00 h, 14:00–16:00 h) and hypervigilance (10:00–12:00 h, 22:00–00:00 h) periods during SD. Central temperature was continuously measured and safety of treatment was assessed from repeated clinical examinations. Compared with PBO, MSLT showed that SRC subjects were more vigilant from the onset (P=0.001) to the end of SD (P < 0.0001) whereas some cognitive functions were improved till the thirty third of SD but others were ameliorated through all the SD period and alertness was better from the thirteenth hour of SD, as shown by Stroop’s test (P=0.048). We showed that 300‐mg SRC given twice daily during a 64‐h SD is able to antagonize the impairment produced on vigilance and cognitive functions.
Pharmacokinetics of ceftiofur sodium in exotic and domestic avian species
Authors: Tell L. , Harrenstien L. , Wetzlich S. , Needham M. , Nappier J. , Hoffman G. , Caputo J. , Craigmill A.
Published: March 2003

The pharmacokinetics of ceftiofur sodium were determined in domestic chicks, turkey poults, adult cockatiels (Nymphicus hollandicus), and adult orange‐winged Amazon parrots (Amazona amazonica) after subcutaneous (chicks and turkey poults) and intramuscular (i.m.) dosing (cockatiels and Amazon parrots). Turkey poult data were best fit to a single exponential model with disappearance half‐lives (t1/2) of 8.6, 7.4 and 5.6 h after doses of 0.12, 0.24 and 0.48 mg ceftiofur free acid equivalents (CFAE)/poult, respectively. Data from chicks were best fit to a biexponential model with primary and secondary half‐lives of 2.2 and 7.5, 3.7 and 6.8, and 3.8 and 5.3 h after doses of 0.04, 0.08 and 0.16 mg CFAE/chick, respectively. Cockatiel and Amazon parrot data were best fit to a biexponential model with primary and secondary half‐lives of 0.28 and 2.5, and 0.93 and 7.9 h, respectively, after doses of 10 mg CFAE/kg body weight. The maximum concentration (Cmax) and area under the concentration time curve (AUC) in chicks and poults were dose‐proportional. TheCmaxfor cockatiels was 5.2 μg/mL and for Amazon parrots was 11 μg/mL. Clearance in cockatiels and Amazon parrots were 11.3 and 3.8 mL/min/kg, respectively, and reflected the much greaterAUCseen in Amazon parrots. Clearance values of ceftiofur were similar in chicks and Amazon parrots, slightly greater in turkey poults and greatest in cockatiels. These results indicate that pharmacokinetic differences must be considered when establishing dosage regimens for different avian species.
Pharmacokinetic studies of flunixin meglumine and phenylbutazone in plasma, exudate and transudate in sheep
Authors: Cheng Z. , McKeller Q. , Nolan A.
Published: March 2003

Flunixin meglumine (FM, 1.1 mg/kg) and phenylbutazone (PBZ, 4.4 mg/kg) were administered intravenously (i.v.) as a single dose to eight sheep prepared with subcutaneous (s.c.) tissue‐cages in which an acute inflammatory reaction was stimulated with carrageenan. Pharmacokinetics of FM, PBZ and its active metabolite oxyphenbutazone (OPBZ) in plasma, exudate and transudate were investigated. Plasma kinetics showed that FM had an elimination half‐life (t½β) of 2.48 ± 0.12 h and an area under the concentration – time curve (AUC) of 30.61 ± 3.41 μg/mL.h. Elimination of PBZ from plasma was slow (t½β = 17.92 ± 1.74 h,AUC = 968.04 ± μg/mL.h.). Both FM and PBZ distributed well into exudate and transudate although penetration was slow, indicated by maximal drug concentration (Cmax) for FM of 1.82 ± 0.22 μg/mL at 5.50 ± 0.73 h (exudate) and 1.58 ± 0.30 μg/mL at 8.00 h (transudate), andCmaxfor PBZ of 22.32 ± 1.29 μg/mL at 9.50 ± 0.73 h (exudate) and 22.07 ± 1.57 μg/mL at 11.50 ± 1.92 h (transudate), and a high mean tissue‐cage fluids:plasmaAUClastratio obtained in the FM and PBZ groups (80–98%). These values are higher than previous reports in horses and calves using the same or higher dose rates. Elimination of FM and PBZ from exudate and transudate was slower than from plasma. Consequently the drug concentrations in plasma were initially higher and subsequently lower than in exudate and transudate.
Chronic phenobarbital therapy reduces plasma benzodiazepine concentrations after intravenous and rectal administration of diazepam in the dog
Authors: Wagner  , Sams  , Podell
Published: March 2003

Disposition of diazepam (DZ) 2 mg/kg after single bolus intravenous (i.v.) and rectal (p.r.) administration before and after 30 day oral phenobarbital therapy was investigated in normal dogs. Adverse cardiovascular and neurologic effects for each drug, dosage and route of administration were evaluated. Plasma benzodiazepine concentrations were determined by fluorescence polarization immunoassay. This assay measured DZ and its active metabolites, oxazepam and nordiazepam to provide a total benzodiazepine concentration. Mean peak plasma concentrations after i.v. administration were 5963 and 5565 ng/mL, before and after phenobarbital treatment, respectively. After p.r. administration, mean peak concentrations were 629 ng/mL and 274 ng/mL and were reached within 30 min before and after phenobarbital treatment, respectively. The target concentration for potential seizure control (i.e. 150 ng/mL) was attained in five dogs in the post phenobarbital p.r. group with a median time to attainment of target concentration of 8 min. The administration of phenobarbital resulted in significantly lower areas under the plasma concentration vs. time curves (AUC) for both i.v. and p.r. administration. Similarly, there was a reduction in maximal plasma concentration, bioavailability (F), mean residence time, and time to target and peak concentrations in the postphenobarbital p.r. group, as compared to the prephenobarbital p.r. group. Adverse cardiovascular and neurologic effects were short‐lived and were considered of minor clinical significance. Overall, chronic phenobarbital therapy in the dog reduces total benzodiazepine concentration after i.v. and p.r. administration presumably due to increased hepatic clearance of DZ and its metabolites oxazepam and nordiazepam. Despite this finding, administration of DZ rectally at 2 mg/kg may be a clinically useful alternative to i.v. administration to treat emergency seizures when i.v. therapy is not possible in dogs on chronic phenobarbital therapy.
Pharmacokinetics of phenylbutazone in plasma and milk of lactating dairy cows
Authors: De Veau  , Pedersoli  , Cullison  , Baker
Published: March 2003

Phenylbutazone was administered intravenously (i.v.) to a group of four lactating cows at a dosage of 6 mg/kg body weight. Whole plasma, protein‐free plasma and milk were analysed for phenylbutazone residues. Pharmacokinetic parameters of total and free phenylbutazone in plasma were calculated using a non compartmental method. In regards to whole plasma data, the mean volume of distribution at steady state (Vss), was 147 mL/kg body weight, with a mean (± SEM) terminal elimination half‐life (t1/2) of 40 ± 6 h. The mean clearance (Cl) was 3 mL/h/kg body weight. TheVssas determined from the protein‐free plasma fraction was 50 021 mL/kg body weight. This largerVssof free phenylbutazone compared to 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 39 ± 5 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. Meant1/2as determined from milk, applying a urinary excretion rate model, was 47 ± 4 h. Milk clearance of phenylbutazone was 0.009 mL/h/kg body weight, or about 0.34% of total body clearance. Furthermore, evidence suggests that phenylbutazone either binds to milk proteins, or is actively transported into milk, as its concentration in milk was greater than that predicted due to a simple partitioning from plasma into milk.
Moxidectin: persistence and efficacy against drug‐resistantOstertagia circumcincta
Authors: Sutherland  , Leathwick  , Brown
Published: March 2003

In order to determine whether the efficacy of moxidectin againstOstertagia circumcinctais enhanced by its persistency, therapeutic efficacy was compared at intervals after treatment and with that of ivermectin, a closely related but more transient endectocide. Groups of 7‐month‐old New Zealand Romney lambs were infected with a strain ofO. circumcinctaknown to be resistant to moxidectin. At patency of the infections, groups of lambs were treated with either moxidectin or ivermectin at the manufacturer’s recommended dosages, or left untreated. At 3, 6 and 10 days post‐treatment, faecal egg count was measured and groups of lambs were slaughtered for estimation of adult worm burden. Drug‐resistant worm burdens were significantly reduced in those animals treated with moxidectin but not in those treated with ivermectin. No effect of time of slaughter on worm burden was observed with either drug, demonstrating that the higher therapeutic efficacy of moxidectin against this parasite was not due to an increased period of drug exposure. Faecal egg counts in the moxidectin treated animals increased with time after treatment indicating a temporary suppression of egg output by surviving worms. The implications of these findings on selection for anthelmintic resistance are discussed.
Pharmacokinetics of amoxycillin in normal horses and horses with experimental arthritis
Authors: Errecalde J. O. , Carmely D. , Mariño E. L. , Mestorino N.
Published: March 2003

The serum and synovial pharmacokinetics of amoxycillin (AMX) were studied after i.v. administration at a dosage of 40 mg/kg to normal horses and horses with induced aseptic carpal arthritis. The best estimates of serum and synovial pharmacokinetic parameters were calculated by mono or bivariable non‐linear regression analysis. A biexponential equation was used to describe the concentration vs. time profiles in both normal and arthritic horses. There were no serum kinetic differences between normal and arthritic horses. There were, however, major synovial kinetic changes between these groups. The rate of penetration from serum to synovial fluid was larger in arthritic animals, indicating better penetration in this case. On the other hand, the rate of disappearance from synovial fluid was larger in normal horses, indicating more persistence of the drug in the diseased joint. Synovial AMX availability increased from 21% in normal horses to 79% in arthritic horses. These findings support the use of AMX for the treatment of infectious synovial joint disease produced by susceptible organisms in horses.
Pharmacokinetics and pharmacodynamics of antiulcer agents in llama
Authors: Christensen J. M. , Limsakun T. , Smith B. B. , Hollingshead N. , Huber M.
Published: March 2003

Plasma concentration time curves following intravenous (i.v.) administration of 1.5 mg/kg of ranitidine, 0.2 mg/kg, 0.4 mg/kg and 0.8 mg/kg of omeprazole, respectively, were analysed in six llamas. Plasma profiles after i.v. administration of both drugs showed plasma concentrations declining in a biexponential manner with a rapid distribution phase. Pharmacokinetics parameters after ranitidine administration to six llamas showed a mean elimination half‐life of 1.53 ± 0.26 h. The mean volume of distribution (Vdss) in llamas was 1.77 ± 0.31 L/kg, and mean body clearance in llamas was 0.778 ± 0.109 L/kg/h. Ranitidine produced only a small transitory (<1 h) decline in acid production when administered i.v. at a dose of 1.5 mg/kg. Omeprazole showed dose‐dependent nonlinear pharmacokinetics. The mean half‐life of 0.2 mg/kg i.v. omeprazole was shorter than that of 0.4 and 0.8 mg/kg i.v. omeprazole, i.e. 0.61, 0.72 and 1.07 h, respectively. The area under the curve (AUC) and mean residence time (MRT) increased with increasing dose, while clearance decreased as dose increased. The decline in acid production following 0.2 mg/kg i.v. omeprazole was highly variable and did not produce a clinically useful suppression of third compartment acid production. In contrast, both 0.4 mg/kg and 0.8 mg/kg omeprazole i.v. administration significantly reduced third compartment acid production. The reduction in acid production following 0.8 mg/kg omeprazole was not significantly greater than the reduction observed following 0.4 mg/kg dosage. Misoprostol (10 μg/kg) was administered i.v. in an absolute alcohol solution. Two animals collapsed following drug administration. While the side‐effects could have been produced by either misoprostol or the alcohol vehicle, the clinical changes were more consistent with an adverse drug reaction. Unfortunately, the limitation of UV detection did not provide the sensitivity needed to quantify the amount of misoprostol in llama plasma, and the pharmacokinetics could not be evaluated.
Pharmacokinetic profile andin vitroselective cyclooxygenase‐2 inhibition by nimesulide in the dog
Authors: Toutain P. L. , Cester C. C. , Haak T. , Metge S.
Published: March 2003

The pharmacokinetic properties andin vitropotency of nimesulide, a nonsteroidal anti‐inflammatory drug (NSAID) were investigated in 8 or 10 dogs after intravenous (i.v.), intramuscular (i.m.) and oral (single and multiple dose) administrations at the nominal dose of 5 mg/kg. After i.v. administration, the plasma clearance was 15.3 ± 4.2 mL/kg/h, the steady‐state volume of distribution was low (0.18 ± 0.011 L/kg) and the elimination half‐life was 8.5 ± 2.1 h. After i.m. administration, the terminal half‐life was 14.0 ± 5.3 h indicating a slow process of absorption with a maximum plasma concentration (6.1 ± 1.5 μg/mL) at 10.9 ± 2.1 h postadministration and the systemic bioavailability was 69 ± 22%. After oral administration in fasted dogs, the maximal plasma concentration (10.1 ± 2.7 μg/mL) was observed 6.1 ± 1.6 h after drug administration, the plasma half‐life was 6.2 ± 1.9 h and the mean bioavailability was 47 ± 12%. After daily oral administrations for 5 days, the average plasma concentration during the fifth dosage interval was 8.1 ± 2.9 μg/mL and the overall bioavailability was 58 ± 16%. The mean accumulation ratio was 1.27 ± 0.4.In vitronimesulide inhibitory potencies for cyclooxygenase (COX)‐1 and COX‐2 isoenzymes were determined using a whole blood assay. Canine clotting blood was used to test for inhibition of COX‐1 activity and whole blood stimulated by lipopolysaccharide (LPS) was used to test for inhibition of COX‐2 activity. The inhibitory concentration (IC50) for inhibition of COX‐2 and COX‐1 were 1.6 ± 0.4 μM(0.49 ± 0.12 μg/mL) and 20.3 ± 2.8 μM(6.3 ± 0.86 μg/mL) giving a nimesulide COX‐1/COX‐2 ratio of 12.99 ± 3.41. It was concluded that at the currently recommended dosage regimen (5 mg/kg), the plasma concentration totally inhibits COX‐2 and partly inhibits COX‐1 isoenzyme.
Inadequacy of low‐volume resuscitation with hemoglobin‐based oxygen carrier hemoglobin glutamer‐200 (bovine) in canine hypovolemia
Authors: Driessen B. , Jahr J. S.; , Lurie F. , Gunther R. A.
Published: March 2003

Stroma‐free hemoglobin‐based oxygen carriers (HBOC) have been developed to overcome problems associated with transfusion of allogeneic blood. We have studied the efficacy of the first licensed veterinary blood substitute, hemoglobin glutamer‐200 bovine (Oxyglobin®; Biopure, Cambridge, MA, USA, Hb‐200), in a canine model of acute hypovolemia and examined whether clinically commonly used criteria are adequate to guide fluid resuscitation with this product. Twelve anesthetized dogs were instrumented for measurements of physiological variables including hemodynamic, oxygenation, and blood gas and acid–base parameters. Dogs were bled to a mean arterial pressure (MAP) of 50 mmHg for 1 h followed by resuscitation with either shed blood (controls) or Hb‐200 until heart rate (HR), MAP and central venous pressure (CVP) returned to baseline. Recordings were repeated immediately and 3 h after termination of fluid resuscitation. Hemorrhage (average 32 mL/kg) caused significant decreases in total hemoglobin (Hb), mean pulmonary arterial pressure (PAP), cardiac output (CO) and oxygen delivery (DO2I), increases in HR and systemic vascular resistance (SVRI), and lactic acidosis. In controls, only re‐transfusion of all shed blood returned HR, MAP and CVP to prehemorrhage values, whereas in other dogs this endpoint was reached with infusion of 10 mL/kg Hb‐200. Unlike blood transfusion, Hb‐200 infusion failed to return CI and DO2I to baseline and to increase arterial oxygen content (CaO2) and total Hb; SVRI further increased. Thus, commonly used criteria (HR, MAP, CVP) to guide transfusion therapy in patients posthemorrhage prove insufficient when HBOCs with pronounced vasoconstrictive action are used and lead to inadequate volume repletion.
Comparison of cefepime pharmacokinetics in neonatal foals and adult dogs
Authors: Gardner S. Y. , Papich M. G.
Published: March 2003

The pharmacokinetics of cefepime, a new fourth generation cephalosporin with enhanced antibacterial activity, was examined in neonatal foals and adult dogs. Cefepime was administered intravenously (i.v.) at a dose of 14 mg/kg to five neonatal foals and six adult dogs. Blood samples were collected in both groups of animals and plasma cefepime concentrations measured by reverse‐phase high‐performance liquid chromatography (HPLC). Cefepime concentrations in both groups of animals were described by a two‐compartment pharmacokinetic model with elimination half‐lives of 1.65 and 1.09 h for the foal and dog, respectively. We tested whether or not pharmacokinetic parameters for cefepime could be scaled across species using principles of allometry. The parameters of elimination half‐life (t½β), apparent volume of distribution (VDarea), and systemic clearance (CL) were scaled linearly to body weight on a double logarithmic plot with allometric exponents for body weight of 0.26, 1.08 and 0.72, respectively. This study further determined doses for cefepime, a potentially useful antibiotic for neonatal foals and dogs, from the pharmacokinetic values. An i.v. dose of cefepime estimated from this study for treating sensitive bacteria was 11 mg/kg every 8 h for neonatal foals and 40 mg/kg every 6 h for dogs.
Effects of dopaminergic drugs on inflammatory bowel disease induced with 2,4‐dinitrofluorbenzene in BALB/c mice
Authors: Herak‐Perković V. , Grabarević Ž. , Banić M. , Anić B. , Novosel V. , Pogačnik M.
Published: March 2003

Herak‐Perković, V., Grabarević, Ž., Banić, M., Anić, B., Novosel, V., Pogačnik, M. Effects of dopaminergic drugs on inflammatory bowel disease induced with 2,4‐dinitrofluorbenzene in BALB/c mice. J. Vet. Pharmacol. Therap.24, 267–273.

The aim of the study was to demonstrate the effects of dopaminergic drugs on 2,4‐dinitrofluorbenzene (DNFB) induced experimental inflammatory bowel disease (IBD) in previously sensitized BALB/c mice. The number and extent of ulcerations and erosions, the intensity of haemorrhages, oedema, and accumulation of neutrophils and eosinophils within colonic lamina propria and submucosa were scored and statistically evaluated. The 180 BALB/c mice, were allocated into three equal groups. The mice in the first experimental group were treated with domperidone (DP), a peripheral dopamine (DA) antagonist. The mice from the second experimental group were treated with bromocriptine (BC), a dopamine agonist. The mice from the control group were treated with an equivalent volume of normal saline in the same manner. Ten animals from each group were killed on days 1, 2, 3, 5 and 10, subsequent to the challenge enema of DNFB solution. Gross and microscopic examination of the colon was performed. Treatment with BC resulted in clinical improvement and decreased mortality rate by 2 of 60 (3%), while domperidone treatment increased mortality rate to 12 of 60 (20%) compared with the controls [4 of 60 (6%)]. The analysis of the microscopic lesions indicated that the beneficial effects of BC were the result of maintenance of vascular integrity.
Pharmacokinetic behavior of marbofloxacin after intravenous and intramuscular administrations in adult goats
Authors: Waxman S. , Rodríguez C. , González F. , De Vicente M. L. , San Andrés M. I. , San Andrés M. D.
Published: March 2003

The pharmacokinetic behavior of marbofloxacin was studied in goats after single‐dose intravenous (i.v.) and intramuscular (i.m.) administrations of 2 mg/kg bodyweight. Drug concentration in plasma was determined by high performance liquid chromatography (HPLC) and the data collected were subjected to compartmental and noncompartmental kinetic analysis. This compound presented a relatively high volume of distribution (Vss=1.31 L/kg), which suggests good tissue penetration, and a total body clearance (Cl) of 0.23 L/kg·h, which is related to a long elimination half‐life (t1/2β=7.18 h and 6.70 h i.v. and i.m., respectively). Pharmacokinetic parameters were not significantly different between both routes of administration. Marbofloxacin was rapidly absorbed after i.m. administration (Tmax=0.9 h) and had high bioavailability (F=100.74%).
Morphine, pethidine and buprenorphine disposition in the cat
Authors: Taylor P. M. , Robertson S. A. , Dixon M. J. , Ruprah M. , Sear J. W. , Lascelles B. D. X. , Waters C. , Bloomfield M.
Published: March 2003

Pharmacokinetics of morphine, buprenorphine and pethidine were determined in 10 cats. Six cats received morphine (0.2 mg/kg) intravenously and four intramuscularly. Five received buprenorphine (0.01 mg/kg) intravenously and six intramuscularly. Six received pethidine (5 mg/kg) intramuscularly. Jugular venous blood samples were collected at time points to 24 h, and plasma morphine concentrations were measured by high performance liquid chromatograpy (HPLC), buprenorphine by radioimmunoassay (RIA) and pethidine by gas chromatography. Our data for morphine show elimination half‐life (t1/2el) 76.3 min intravenous (i.v.) and 93.6 min intramuscular (i.m.); mean residence time (MRT) 105.0 and 120.5 min; clearance (Clp) 24.1 and 13.9 mL/kg/min; and volume of distribution (V(dss)) 2.6 and 1.7 L/kg, respectively. Comparable data for buprenorphine aret1/2el416.8 and 380.2 min;MRT417.6 and 409.8 min;Clp16.7 and 23.7 mL/kg/min; andV(dss)7.1 and 8.9 L/kg. For i.m. pethidine,t1/2el216.4 min;MRT307.5 min;Clp20.8 mL/kg/min andV(dss)5.2 L/kg. For i.m. dosing, thetmaxfor morphine, buprenorphine and pethidine were 15, 3 and 10 min, respectively. The pharmacokinetics of the three opioids in cats are broadly comparable with those of the dog, although there is a suggestion that the cat may clear morphine more slowly.
Pharmacokinetics of ceftiofur in plasma and uterine secretions and tissues after subcutaneous postpartum administration in lactating dairy cows
Authors: OKKER H. , SCHMITT E. J. , VOS P. L. A. M. , SCHERPENISSE P. , BERGWERFF A. A. , JONKER F. H.
Published: March 2003

A study was conducted to measure concentrations of potentially active ceftiofur derivatives, in plasma, in uterine tissues (endometrium and caruncles) and in uterine secretions at different time points after a single subcutaneous administration of ceftiofur hydrochloride (Excenel®RTU Sterile Suspension) at the dose of 1 mg/kg body weight in Holstein–Friesian dairy cows. The animals (n=4) were injected within 24 h of calving, after expulsion of the foetal membranes. Plasma, lochial fluid, caruncles and endometrium were collected before ceftiofur hydrochloride administration and at 1, 2, 4, 8, 12 and 24 h after treatment. For each cow the concentrations of ceftiofur in the biological matrices were quantified using an high‐performance liquid chromatography (HPLC) assay. The limit of quantification of the method was 0.1 μg/mL for plasma and 0.1 μg/g for lochial fluid, caruncles and endometrium. The concentrations of potentially active ceftiofur derivatives detected in plasma reached a maximum of 2.85 ± 1.11 μg/mL at 2 h and decreased to 0.64 ± 0.14 μg/mL at 24 h after administration. In lochial fluid, these concentrations reached a maximum of 0.97 ± 0.25 μg/g at 4 h and decreased to 0.22 ± 0.21 μg/g at 24 h after administration. In endometrium, these concentrations reached a maximum of 2.23 ± 0.82 μg/g at 4 h and decreased to 0.56 ± 0.14 μg/g at 24 h following the injection, whereas these levels in caruncles were 0.96 ± 0.45 and 0.60 ± 0.39 μg/g obtained at 8 and 24 h, respectively. At the dose of 1 mg/kg body weight in healthy dairy cows, subcutaneous administration of ceftiofur (as ceftiofur hydrochloride) after parturition results in concentrations of ceftiofur derivatives in uterine tissues and in lochial fluid that exceed the reported minimal inhibitory concentrations (MICs) for the common pathogens (Escherichia coli,Fusobacterium necrophorum, Bacteroides spp., andArcanobacterium pyogenes) associated with acute puerperal metritis.
Cisapride reverses the anticholinergic effect of disopyramide on the isolated guinea‐pig urinary bladder
Authors: KOUTSOVITI‐PAPADOPOULOU M. , NIKOLAIDIS E. , BATZIAS G. C. , KOUNENIS G.
Published: March 2003

The present investigation aims to examine whether the prokinetic agent cisapride is able to reverse disopyramide's anticholinergic effect on the isolated guinea‐pig urinary bladder. Acetylcholine, at concentrations ranging from 10−7 to 10−3 M, produced a stimulatory effect on the urinary bladder (pEC50 value=5.1). Disopyramide competitively antagonized the contractile effect of acetylcholine with an ID50=4.4 × 10−6 M. Although cisapride by itself had either no intrinsic contractile action or a modest effect on the urinary bladder, at concentrations ranging from 3 × 10−7 to 10−6 M, it significantly reversed the above inhibitory effect of disopyramide, and produced a parallel leftward shift of the concentration–response curve for acetylcholine in the presence of disopyramide. The pEC50 values for acetylcholine in the presence of 3 × 10−6 M and 10−5 M disopyramide were 4.7 and 4.2, respectively, while in the presence of 10−5 M disopyramide, after pretreatment with 5 × 10−7 M cisapride, the pEC50 value for acetylcholine was 4.6. It is concluded that cisapride is effective in reversing the anticholinergic activity of disopyramide on the isolated guinea‐pig urinary bladder, probably by facilitating cholinergic neurotransmission.
Dose determination and confirmation of a long‐acting formulation of ceftiofur (ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory disease
Authors: HIBBARD B. , ROBB E. J. , CHESTER Jr. S. T. , DAME K. J. , BOUCHER J. F. , ALANIZ G. R.
Published: March 2003

Hibbard, B., Robb, E. J., Chester Jr., S. T., Dame, K. J., Boucher, J. F., Alaniz, G. R. Dose determination and confirmation of a long‐acting formulation of Ceftiofur (Ceftiofur crystalline free acid) administered subcutaneously for the treatment of bovine respiratory disease. J. vet. Pharmacol. Therap.25, 175–180.

The objective of this work was to determine and confirm an effective dose of ceftiofur crystalline free acid sterile oil suspension (CCFA‐SS, 100 mg ceftiofur equivalents (CE)/mL], a long‐acting single‐administration ceftiofur formulation, for the treatment of the bacterial component of bovine respiratory disease (BRD). Study 1 was a dose determination study that used an intratracheal Mannheimia haemolytica (Pasteurella haemolytica) challenge model to evaluate single‐administration doses of CCFA‐SS at 0.0, 1.1, 2.2, 3.3, 4.4 or 5.5 mg CE/kg body weight (BW) for the treatment of BRD. Data from this study were used to select doses for field testing in three multi‐location clinical studies. In Study 2, the efficacy of a single administration dose of CCFA‐SS at 4.4 mg CE/kg BW was compared with a negative control for the treatment of naturally occurring BRD in feedlot cattle. Treatments were administered when uniform clinical signs of BRD were present. Study 3 used a design similar to Study 2, and compared single‐administration doses of CCFA‐SS at 3.0 or 4.4 mg CE/kg BW with the positive‐control tilmicosin (Micotil® 300 Injection, Elanco Animal Health) at 10 mg/kg BW. Study 4 compared the efficacy of single doses of CCFA‐SS of 1.1–8.8 mg CE/kg BW with tilmicosin at 10 mg/kg BW. A total of 1176 cattle were included in these clinical studies. In Study 1, a dose of 4.55 mg CE/kg BW was determined to be effective. This was rounded to 4.4 mg CE/kg for field testing. In Study 2, a single dose of CCFA‐SS at 4.4 mg CE/kg BW had a higher treatment success rate on day 14 (61%) than negative controls (26%, P < 0.01). However, in Study 3 this dose was judged to be at the beginning of an efficacious dose range for the treatment of BRD when compared with tilmicosin. In Study 4, day 28 treatment success rates were higher for CCFA‐SS at 4.4–8.8 CE/kg BW than for tilmicosin (P=0.002) or the noneffective CCFA‐SS dose of 1.1 mg CE/kg BW (P < 0.001). Based on decision criteria for Study 4, the effective dose was determined to be 4.4–5.5 mg CE/kg BW. These clinical studies demonstrated that a single dose of CCFA‐SS (100 mg CE/mL) administered subcutaneously (s.c.) in the neck at 4.4–5.5 mg CE/kg BW is an effective treatment for BRD in feedlot cattle. However, this route of administration is no longer being considered for this formulation because of the ceftiofur residues that are present at the injection site for extended periods of time.
Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally inducedEscherichia colimastitis
Authors: Rantala M. , Kaartinen L. , Välimäki E. , Stryrman M. , Hiekkaranta M. , Niemi A. , Saari L. , Pyörälä S.
Published: March 2003

Efficacy and pharmacokinetics of enrofloxacin and flunixin meglumine for treatment of cows with experimentally inducedEscherichia colimastitis.J. vet. Pharmacol. Therap.25,251–258.

The efficacy of flunixin alone and together with enrofloxacin in treatment of experimentalEscherichia colimastitis was compared using six cows. The cross‐over study design was used. Pharmacokinetics of flunixin and enrofloxacin were also studied in these diseased cows. The response of each cow was similar after the first and second challenge and the individual reaction seemed to explain the severity of clinical signs. The most important predictive factor for outcome ofE. colimastitis was a heavy drop in milk yield. Treatment with enrofloxacin and flunixin enhanced elimination of bacteria, but the difference from those receiving flunixin alone was not significant. Two cows, which had received no antimicrobial treatment (Group 1), were killed on day 4 postchallenge. One cow was killed after the first and the other after the second challenge. Cows receiving combination therapy produced 0.9 L more milk per day during the study period than cows which had only received flunixin (P< 0.05). Based on our findings, antimicrobial treatment might be beneficial in the treatment of high‐yielding cows in early lactation. The absorption of enrofloxacin was delayed after subcutaneous administration, the mean apparent elimination half‐life being about 23 h, whereas after i.v. administration eliminationt1/2was only 1.5 h. The majority of the antimicrobial activity in milk originated from the active metabolite, ciprofloxacin, which could be measured throughout the 120‐h follow‐up period after the last subcutaneous administration. No differences were present in the pharmacokinetic parameters of flunixin between treatment groups: mean elimination half‐life was 5.7–6.2 h, volume of distribution 0.43–0.49 L/kg and clearance 0.13–0.14 L h/kg. No flunixin or merely traces were detected in milk: one of the three cows had a concentration of 0.019 mg/L 8 h after administration.
Pharmaco‐epidemiology and ‐economics should be developed more extensively in veterinary medicine
Authors: Chauvin C. , Madec F. , Guittet M. , Sanders P.
Published: March 2003

Pharmaco‐epidemiology, which has emerged within the last 20 years as a new discipline in human medicine, deals with the quantities of drugs consumed and their effects on populations in terms of epidemiological concepts and tools. To a lesser extent, it is also practised in veterinary medicine. The applications presented in this review are illustrative of pharmaco‐epidemiological and ‐economical concepts. Assessment of drug consumption, the study of adverse drug effects, and the economic implications of drug use are the three main fields considered. Developments can be expected in veterinary medicine within the next few years relative to novel areas of interest such as antimicrobial resistance and new therapeutic class uses. These applications will require methodological progress and the elimination of current gaps. Pharmaco‐epidemiological methods need to be developed, which implies close co‐operation between statisticians, pharmacologists, veterinary practitioners and epidemiologists. A greater use of the term ‘pharmaco‐epidemiology’ as a keyword in literature would facilitate recognition of this domain which associates closely epidemiology and pharmacology.
Influence of Escherichia coli endotoxin‐induced fever on the pharmacokinetic behavior of marbofloxacin after intravenous administration in goats
Authors: Waxman S. , San Andrés M. D. , González F. , De Lucas J. J. , San Andrés M. I. , Rodríguez C.
Published: March 2003

The pharmacokinetic behavior of marbofloxacin was studied in seven healthy goats and in the same goats with induced fever after single‐dose intravenous (i.v.) administration of 2 mg/kg b.w. Fever was induced by the administration of Escherichia coli endotoxin. Drug concentration in plasma was determined by high‐performance liquid chromatography (HPLC). Drug distribution was somehow altered by fever as febrile goats showed a volume of distribution at steady‐state (Vss = 0.72 ± 0.15 L/kg) lower than normal goats (Vss = 1.19 ± 0.33 L/kg). The elimination of the drug was also modified. Total plasma clearance (Cl) decreased from 0.24 ± 0.12 L/kg/h in healthy animals to 0.13 ± 0.05 L/kg/h in animals with endotoxin‐induced fever, which is related to an increase in the area under the plasma concentration–time curve (AUC). Consequently, mean residence time (MRT) was also slightly increased in sick animals (MRT = 5.28 ± 00.99 and 6.09 ± 01.45 h, in healthy and febrile animals, respectively).
Evolution of the hypervariable region of hepatitis C virus
Authors: Smith D. B.
Published: March 2003

Despite being the most intensively studied part of the hepatitis C virus genome, our understanding of the function of the hypervariable region (HVR) at the NH2‐terminus of the E2 protein remains very limited. During chronic infection the HVR usually changes over time, with changes usually mirrored by those of HVR‐specific antibodies. Evidence is presented suggesting that the HVR is subject to constraint in its length, amino acid composition, and in the amino acid replacements that are tolerated at different positions. These constraints, and the pattern of HVR variation during chronic infection, suggest that it has an important role in virus infection. A causal relationship between HVR variation and persistence of HCV remains to be demonstrated.
A placebo‐controlled phase I/II study of adefovir dipivoxil in patients with chronic hepatitis B virus infection
Authors: Gilson R. J. C. , Chopra K. B. , Newell A. M. , Murray‐Lyon I. M. , Nelson M. R. , Rice S. J. , Tedder R. S. , Toole J. , Jaffe H. S. , Weller I. V. D.
Published: March 2003

Adefovir dipivoxil (bis‐POM PMEA) is an adenine nucleotide analogue with activity against retroviruses and herpesviruses, and in vitro activity against hepatitis B virus (HBV). This study was conducted to evaluate its safety and antiviral activity in patients with chronic HBV infection. Twenty patients (13 co‐infected with human immunodeficiency virus, HIV) were randomized in a phase I/II, double‐blind, placebo‐controlled study. Patients who had been hepatitis B surface antigen (HBsAg)/hepatitis B e antigen (HBeAg) positive for ≥ 6 months, with elevated hepatic transaminases and serum HBV DNA ≥ 50 pg ml–1, were randomized to adefovir dipivoxil 125 mg (n = 15) or placebo (n = 5) as a single, daily, oral dose for 28 days. Antiviral activity was assessed by changes in serum HBV DNA (using the Digene Hybrid Capture assay) and HBeAg/hepatitis B e antibody (HBeAb) status. HBV DNA levels fell rapidly by > 1 log10 in all active drug recipients (median fall 1.8 log10 pg ml–1) but increased by 0.01 log10 pg ml–1 in controls (P = 0.002). Reductions were sustained during treatment. HBV DNA returned to baseline over 1–6 weeks following discontinuation of active drug. HBeAg became transiently undetectable in one patient on treatment and, in another, sustained seroconversion to HBeAb occurred 12 weeks after treatment ended. Liver transaminase elevations > 300 U l–1 were observed in three patients during therapy (leading to protocol‐specified treatment discontinuation or dose reduction) and in four patients during follow‐up. On‐treatment transaminase elevations were associated with HIV status, occurring in three of six HIV‐uninfected patients compared with none of nine who were HIV infected. In addition, a slower return to baseline of serum HBV DNA levels was observed in the non‐HIV‐infected patients. Treatment for chronic hepatitis B as a once‐daily oral dose was well tolerated and associated with significant and sustained reductions in serum HBV DNA levels during treatment. Transaminase elevations, which may be related to the therapeutic effect, were observed during and after treatment. Further studies are warranted to investigate the safety, and optimum dose and duration, of adefovir dipivoxil treatment for chronic hepatitis B.
Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C
Authors: Vento S.
Published: March 2003

There have been conflicting reports of the clinical outcome of acute hepatitis A virus (HAV) infection in patients with chronic hepatitis C virus (HCV) infection. A prospective study evaluated 432 patients with chronic hepatitis C (183 with cirrhosis) over a 7‐year period. Of the 17 patients with concurrent HAV infection, seven developed fulminant hepatitis and six died. None of these patients had cirrhosis; however, the HLA phenotype (A1; B8:DR3) appeared to be a significant factor in the development of fulminant hepatitis. Patients with this phenotype had high titres of antinuclear antibodies, antismooth muscle antibodies and antiasialoglycoprotein‐receptor antibodies, possibly reflecting the induction of autoimmune hepatitis in this group. The high frequency of fulminant hepatitis in patients with HAV/HCV coinfection contrasts with other surveys, although a large Centers for Disease Control and Prevention (CDC) survey demonstrated that HAV infection in patients with pre‐existing chronic liver disease (CLD) is associated with increased mortality. It is likely that CLD has some importance as an underlying factor in the development of fulminant hepatitis following HAV infection. Further prospective studies are needed to clarify this issue.
Frequent integration of precore/core mutants of hepatitis B virus in human hepatocellular carcinoma tissues
Authors: Zhong  , Chan  , Yeo  , Tam  , Johnson
Published: March 2003

The development of hepatitis B virus (HBV)‐associated hepatocellular carcinoma (HCC) frequently follows persistent HBV infection and may arise in individuals who are hepatitis B e antigen (HBeAg) negative, indicating the possible presence of precore/core mutants. It is unclear whether precore/core mutants are associated with tumour development or are selected for after chromosomal integration of the wild‐type viral DNA. We studied the status and sequence variation of the precore/core region of HBV in 56 patients with HBV‐associated HCC and in various corresponding non‐tumour tissues by Southern blot analysis, polymerase chain reaction and direct sequencing. Southern blot showed that integrated HBV DNA existed in 43 of 56 HCC tissues. Sequence analysis revealed mutations in 65% of the HCC (26/40) and 45% (14/31) of the corresponding non‐tumour tissues. The mutation at nucleotide (nt) 1896, known to prevent HBeAg synthesis, was detected in 40% (16/40) of the tumours and in 35.4% (11/31) of the non‐tumour tissues. Other mutations were found at nt 1899 (eight of 40 in HCC; three of 31 in non‐tumour tissues), nt 1898 (seven of 40 in HCC; two of 31 in non‐tumour tissues), nt 1912 (seven of 40 in HCC; none of 31 in non‐tumour tissues) and nt 1886 (three of 40 in HCC; none of 31 in non‐tumour tissues). To determine whether this finding merely reflected the prevalence of such mutants in this geographical region, HBV DNA from the sera of patients (also in this region) with acute and chronic hepatitis were sequenced. The nt 1896 mutant was found in 5.6% (one of 18) of patients with acute hepatitis B and in 22.8% (nine of 35) of patients with chronic hepatitis B. However, the nt 1898 mutation was not found in any of these sera. The precore/core mutant was observed with increasing frequency from acute hepatitis to chronic hepatitis, non‐tumour and HCC, and this difference in frequency was significant between HCC and acute hepatitis B groups (P < 0.01), suggesting that the precore/core mutant or hepatocytes harbouring this mutant may be under immune selection and that such mutations may facilitate integration and subsequent tumour development.
Evolution of hepatitis C virus genome in chronically infected patients receiving ribavirin monotherapy
Authors: Querenghi F. , Yu Qiang , Billaud G. , Maertens G. , Trépo C. , Zoulim F.
Published: March 2003

Recent results of clinical trials suggest that combination of interferon and ribavirin exhibits an enhanced antiviral effect in the treatment of chronic hepatitis C. To investigate the effect of ribavirin on hepatitis C virus (HCV) infection, we analysed the evolution of the genetic heterogeneity of HCV in relation to the anti‐HCV humoral response in patients treated by ribavirin alone. The study population included 35 patients with liver biopsy proven chronic hepatitis C infected with HCV genotype 1. Among them, 26 were treated with ribavirin for at least 12 months and nine untreated patients served as a control group. Serum samples were analysed before and at 6 and 12 months of therapy. Three regions of the HCV genome, i.e. HVR1, a domain of NS5A including part of the interferon sensitivity determining region (ISDR), and a segment of NS5B, were amplified by RT‐PCR using specific primers. The PCR products were then studied using single‐strand conformation polymorphism (SSCP) analysis followed by either direct sequencing, or cloning and sequencing. In parallel, the humoral anti‐E1 response was studied using an ELISA (Innotest HCV E1Ab, Innogenetics). The results of HCV genome analysis showed no significant effect on the amino acid sequence evolution of the HVR1, NS5A and NS5B regions of HCV. Analysis of a phylogenetic tree from the major quasispecies variants showed the absence of correlation with ribavirin response, and the absence of selection of viral strains during ribavirin treatment. A trend towards a decrease in the anti‐E1 Ab response was also observed. Altogether these results suggest that ribavirin may not exhibit a direct antiviral effect, but may trigger a favourable response to interferon by modulating the immune response against HCV.