bluuebunny/crossref_metadata_2025 huggingface dataset:
Post‐psychiatry: paradigm shift or wishful thinking? A speculative review of future possibles for psychiatry
Authors: KEEN T. M.
Published: March 2003

Psychiatric‐mental health nurses have yet to arrive at a consensus definition and agreed operational summary of their roles and responsibilities. Although the craft seems often disunited and uneasy in its traditional alliances with general nursing and psychiatry, it remains subordinate to both. This paper identifies some actual or possible developments in social values, science and technology, workplace economics and management that could impact upon the nature and practice of psychiatry, and thereby influence the possible future scope and practice of psychiatric‐mental health nursing.
Story‐like organization of dream experience in different periods of REM sleep
Authors: CIPOLLI CARLO , BOLZANI ROBERTO , TUOZZI GIOVANNI
Published: March 2003

Four dream reports, collected from each of 16 subjects in an experimental night, were analysed using the criteria of Mandler and Johnson's story grammar. The experimental night was the first of the four nights where subjects had spontaneously given a dream report after each of the four awakenings planned in REM sleep. A multivariate analysis of covariance, taking the order of the nights where the experimental night occurred and the order of reports as factors, the number of stories per report as covariate and the number of statements in the setting, the number of statements in the event structure and number of episodes per story as dependent variables, showed that the greater length and complexity of reports collected in the second half of the night depends on a greater effectiveness of the dream production system rather than on a greater accuracy of recall. This increase concerns the organization of individual stories rather than the number of stories developed in a given time. These findings raise the issue of how dream production is re‐triggered during REM sleep. To cast light on this issue, it seems important to establish whether and how the themes of the various stories developed in a given dream experience are interrelated.
Different nocturnal body temperatures and sleep with forced‐air warming in men and in women taking hormonal contraceptives
Authors: BAKER FIONA C. , SELSICK HUGH , DRIVER HELEN S. , TAYLOR SHEILA R. , MITCHELL DUNCAN
Published: March 2003

We studied how forced‐air warming, conventionally used to control body temperature during and after anaesthesia, affected the nocturnal rectal temperatures and sleep composition of young men and women. Seven healthy women who were taking oral or injection contraceptives, and six healthy men spent 3 nights in a controlled environment: an adaptation night followed by 2 nights when they slept under either a down duvet (baseline) or a quilt perfused with warm air (hot). Repeated analysis of variance (ANOVA) revealed significant gender differences in the body temperature responses. On the baseline night, despite sleeping under the same conditions, the women did not show a nocturnal drop in body temperature as shown by the men. Forced‐air warming increased body temperature to a similar extent in the men and the women, and resulted in enhanced hyperthermia in the women, and blunted the drop in body temperature in the men, compared to their baseline nights. The significant increases in body temperature had no consequences, however, for the subjective sleep quality of either the men or women, and only minor consequences for objective sleep composition. Both men and women had increased amounts of Stage 2 sleep on the hot night ( P
<0.04). In addition, the women had reduced rapid eye movement (REM) sleep when compared to their baseline night (
P <0.04). Our results confirm that in a passive thermal environment, women who are taking oral or injection contraceptives have higher nocturnal body temperatures than men. Also, as sleep architecture was minimally affected by the increases in body temperature of between 0.2 and 0.3°C on the hot night in the men and women, and subjective sleep quality was unaffected, our results question the existence of a tight association between sleep and body temperature.
Bright light treatment used for adaptation to night work and re‐adaptation back to day life. A field study at an oil platform in the North Sea
Authors: Bjorvatn BjØRn , Kecklund GÖRan , Åkerstedt TorbjÖRn
Published: March 2003

Night workers complain of sleepiness, reduced performance and disturbed sleep due to lack of adjustment of the circadian rhythm. In simulated night‐work experiments scheduled exposure to bright light has been shown to reduce these complaints. Here we studied the effects of bright light treatment on the adaptation to 14 days of consecutive night work at an oil platform in the North Sea, and the subsequent re‐adaptation to day life at home, using the Karolinska sleep/wake diary. Bright light treatment of 30 min per exposure was applied during the first 4 nights of the night‐shift period and the first 4 days at home following the shift period. The bright light exposure was scheduled individually to phase delay the circadian rhythm. Bright light treatment modestly facilitated the subjective adaptation to night work, but the positive effect of bright light was especially pronounced during the re‐adaptation back to day life following the return home. Sleepiness was reduced and the quality of day was rated better after exposure to bright light. The modest effect of bright light at the platform was, possibly, related to the finding that the workers seemed to adapt to night work within a few days even without bright light. These results suggest that short‐term bright light treatment may help the adaptation to an extended night‐work period, and especially the subsequent re‐adaptation to day life.
Morningness/eveningness and the need for sleep
Authors: Taillard Jacques , Philip Pierre , Bioulac Bernard
Published: March 2003

The purpose of this study was to determine, in a large sample of adults of all ages (17–80 years), the effect of morningness/eveningness on sleep/wake schedules, sleep needs, sleep hygiene and subjective daytime somnolence. A total of 617 subjects (219 subjects per chronotype group) matched for age, sex and employment status, completed an abridged morningness/eveningness questionnaire, a questionnaire on sleep habits and the quality of sleep, and the Epworth Sleepiness Scale. Eveningness was associated with a greater need for sleep, less time in bed during the week compared to ideal sleep needs, more time in bed at the weekend, a later bedtime and waking‐up time especially at the weekend, more irregular sleep/wake habits and greater caffeine consumption. These subjects built up a sleep debt during the week and extended their duration of sleep at the weekend. They did not, however, rate themselves more sleepy than other types, despite the fact that our results showed a clear link between subjectively evaluated daytime somnolence and sleep debt. Why they were less affected by sleep deprivation is not clear. This raises the question of individual susceptibility to the modification of sleep parameters.
Transient cardiorespiratory events during NREM sleep: A feline model for human microarousals
Authors: Quattrochi James J. , Shapiro Jonathan , Verrier Richard L. , Hobson J. Allan
Published: March 2003

Microarousals (MAs) are brief transient events that occur during normal sleep in humans and with increased frequency in disordered sleep, especially in association with sleep apnoea. In a feline model, we discovered transient cardiorespiratory events during nonrapid eye movement (NREM) sleep that exhibited consistent features with similarities to human MAs. It was observed that MAs have two distinct phases. Phase I (MAI) is characterized by an abrupt increase in electromyogram (EMG) amplitude (> 50%), increased electrooculogram (EOG) activity and accelerated frequency of hippocampal electroencephalographic (EEG) activity. MAI lasts 4.1 ± 0.3 s. Phase II (MAII), lasting 9.8 ± 0.8 s, is characterized by high frequency EEG activity, but EMG, EOG and hippocampal activity remain at baseline levels. Mean inspiratory rate begins to increase 15 s before the onset of the MA, followed 10 s later by the increase in mean heart rate. Mean respiratory rate decreases sharply through MAII, and returns to baseline levels 15 s after the MA. During MAII mean heart rate decreases quickly; there is increased respiratory irregularity, followed by a prolonged ventilatory overshoot. The abrupt shift in heart rate is coincident with the change in breath timing seen during MAII. Heart rate returns to baseline levels 10 s following the MA. Integrating our findings with those described previously in humans, we propose that MAs may serve as a homeostatic mechanism which is designed to restore cardiorespiratory function allowing the continuity of sleep.
Computerized endopharyngeal myotonometry (CEM): A new method to evaluate the tissue tone of the soft palate in patients with obstructive sleep apnoea syndrome
Authors: Veldi  , Vasar  , Vain  , Hion  , Kull
Published: March 2003

This study compared the tissue tone of the soft palate in nonsnoring subjects and patients with obstructive sleep apnoea syndrome (OSAS) during wakefulness. Here, tissue tone means the biomechanical property of the tissue which can be characterized by two main parameters: stiffness and elasticity. Tissue tone includes both structural and neural components. A new method to evaluate the tissue tone of the soft palate was used – computerized endopharyngeal myotonometry (CEM). This method records and analyses the response of the soft palate tissues to a brief mechanical impact. The method enabled us to evaluate the most important parameters of tissue tone: stiffness, which is expressed as a frequency; and elasticity, expressed as a logarithmic decrement of the damped oscillation. First, a self‐reported questionnaire was completed about the medical history of the subjects. Subjects then underwent a physical examination of the oropharynx and polysomnography with overnight pulse oximetry. The results of the CEM method indicated that patients with OSAS show an increased stiffness of the soft palate tissues (20.3, SD 4.7 Hz) compared with nonsnoring subjects (12.2, SD 1.8 Hz). In patients with sleep apnoea, elasticity is not increased in a similar way to stiffness. Thus, the disproportion between tissue stiffness and elasticity of the soft palate is a measure of the pathological changes in patients with sleep apnoea.
Rest and activity states in a gray whale
Authors: Lyamin  , Manger  , Mukhametov  , Siegel  , Shpak
Published: March 2003

The behaviour of a female gray whale (Eschrichtius robustus) that had been rescued 14 months previously was recorded continuously on a video‐recorder for 9 days at ‘Sea World’ in San Diego. On average, during the first six recording days, active wakefulness accounted for 37.9 ± 1.7% of each 24 h; transitional stage for 17.4 ± 1.4% and rest for 41.2 ± 1.7%. In the rest stage the whale was lying on the bottom of the pool (13.2 ± 1.7%) or hanging on the surface (28.0 ± 1.7%). During the rest stage, it was immobile most of the time and moved only for respiration. In the rest stage both eyes could be open, one eye could be open while the other was closed or, more rarely, both eyes could be closed. Characteristic jerks of the head, neck and sometimes of the whole body were observed in the whale during the rest stage. Most jerks were single and only 10% of all jerks were serial (occurring within 10 s of a prior jerk). Eyelid movements accompanied 40% of jerks. In two episodes, intense jerks followed each other continuously for 3 and 4 s and were accompanied by eyelid movements. These jerks resembled the twitches characteristic of paradoxical sleep in terrestrial mammals. During these episodes the whale was falling slowly onto its side and subsequently started to swim in the pool.
Development of sleep patterns in early adolescence
Authors: Laberge L. , Petit D. , Simard C. , Vitaro F. , Tremblay R.E. , Montplaisir J.
Published: March 2003

This study examines the developmental changes of sleep patterns as a function of gender and puberty and assesses the prevalence of sleep habits and sleep disturbances in early adolescence. It also investigates the relationship between sleep patterns, sleep habits and difficulty falling asleep and nocturnal awakenings. The present analyses are based on results available for 588 boys and 558 girls for whom mothers completed questions concerning demographics and sleep at annual intervals when their child was aged 10–13 years. The results indicated that nocturnal sleep times decreased, bedtimes were delayed and differences between weekend and school day sleep schedules progressively increased with age. Gender and puberty were both associated with the timing of sleep on weekends. Girls presented longer weekend time in bed (TIB) and later weekend wake time than boys. Similarly, subjects with higher pubertal status showed longer weekend TIB and later weekend wake time than subjects with lower pubertal status. Difficulty falling asleep was associated with later weekend wake time and with sleeping with a night light. In conclusion, the gender differences commonly reported in adolescents’ sleep patterns are most likely explained by girls’ higher pubertal status. This study emphasizes the link between puberty and a putative physiological need for more sleep, in presence of a general reduction of sleep times during adolescence. From age 10–13 years, the delay and lengthening of the sleep period on weekends in comparison to schooldays is associated with difficulty falling asleep.
The effects of levetiracetam on objective and subjective sleep parameters in healthy volunteers and patients with partial epilepsy
Authors: Bell Caroline , Vanderlinden Hilde , Hiersemenzel Reinhard , Otoul Christian , Nutt David , Wilson Sue
Published: March 2003

Levetiracetam is a novel antiepileptic drug which has recently been released as an adjunctive treatment for partial epilepsy. In the two studies reported here we examined the objective and subjective effects of levetiracetam on sleep in 12 healthy volunteers and 17 patients [16 who could be evaluated for electroencephalogram (EEG) recordings] with a history of partial epilepsy on stable carbamazepine monotherapy. The studies were of a similar double‐blind crossover placebo‐controlled design with subjects' sleep being recorded in their own homes. The results from the two studies showed considerable similarities. In both, levetiracetam produced an increase in the time spent in stage 2 sleep, which in the patient study was accompanied by a decrease in the time spent in stage 4 sleep and in the volunteer study an increase in rapid eye movement (REM) latency. The subjective changes included reports that sleep was of a better quality with fewer awakenings and patients also reported that their sleep was more restful. Volunteers and patients did, however, feel less alert on waking in the morning. Therefore, both groups reported a decrease in awakenings after levetiracetam despite the finding from the EEG of no change in the actual number of awakenings. It may be concluded from both studies that levetiracetam does affect some indicators of subjective sleep perception, but does not influence objective sleep measures of sleep continuity. The results from the patient study during placebo add‐on treatment also showed that patients on carbamazepine had a marked increase in SWS, an increase in stage 2 sleep and an increase in REM latency compared with healthy volunteers. Interestingly, levetiracetam also reduced bilateral epileptiform EEG activity, particularly in patients with more discharges.
Copulatory activity increases slow‐wave sleep in the male rat
Authors: Vazquez‐Palacios G. , Bonilla‐Jaime H. , Retana‐Marquez S. , Velazquez‐Moctezuma J.
Published: March 2003

It is believed that sexual activity increases the need to sleep in many species. However, the relationship between copulatory activity and sleep has been poorly studied. Several studies have observed variations in the sleep of female rats and women as a function of their reproductive state. These effects have been correlated with the effects of female steroid hormones, but not with sexual activity. The aim of the present study was to evaluate the sleep–wake pattern of male rats immediately after different conditions of copulatory activity. Sexually experienced male rats were chronically implanted with a standard set of electrodes for sleep recording. After a control sleep recording of 8 h, the males were randomly assigned to one of the following experimental conditions: 30 min in the presence of an ovariectomized (OVX) rat; 30 min in the presence of an intact non‐receptive female (NRF); with a receptive female until reaching one ejaculation (1E); and with a receptive female until reaching three ejaculations (3E). In addition, after 10 days, males were randomly exposed to one of the following copulatory conditions during 4 h: to remain in the presence of an OVX rat; to remain in the presence of an NRF female, and with receptive females until reaching sexual satiety (SS). Male sexual behavior was assessed just after the onset of the dark period, and sleep recordings were obtained during 8 h immediately after experimental testing. Both the three ejaculations group (3E) in the first experiment and the sexual satiety group (SS) in the second experiment showed enhanced percentages of time spent in slow wave sleep (SWS) II and a shorter latency to the first SWS II episode than in the control group or under basal conditions. In addition, neither the presence of a non‐receptive female or an OVX female, nor sexual behavior until reaching one ejaculation induced any effect on the sleep stages. These findings suggest that the increase in SWS II induced by both 3E and SS may be governed by some specific mechanism that is essentially independent of physical exercise or stress. Copulatory activity might be the source of neurohormonal processes that induce sleep and may involve the participation of gamma‐aminobutyric acid, serotonin or other endogenous regulators of sleep and wakefulness. Nevertheless, the precise mechanism by which the sexual behavior increases SWS is still to be determined.
Characterization of vasodilatory adenosine receptors in equine digital veins
Authors: ELLIOTT  , BRADY
Published: March 2003

Isolated equine digital veins (EDVs) which had been denuded of their endothelium were used to study adenosine receptors causing vasodilation. When the blood vessel wall tension was raised with the thromboxanemimetic, U44069 (30 nm), the order of vasodilator potency of adenosine receptor agonists was: 5′‐N‐ethylcarboxamidoadenosine (NECA) > 2‐p‐(2‐carboxyethyl)phenyl amino‐5′‐N‐ethylcarboxamido‐adenosine (CGS 21680) > 5′‐N‐methylcarboxamido‐adenosine (MECA) > > N6‐cyclohexyladenosine (CHA) > N6‐cyclopentyladenosine (CPA) > N6–2‐(4‐Aminophenyl)ethyladenosine (APNEA) > adenosine. Removal of the endothelium had no significant effect on the responses to NECA. The adenosine receptor antagonists, 8‐cyclopentyl‐1,3‐dipropylxanthine (DPCPX; A1‐selective) and xanthine amine cogener (XAC; non‐selective antagonist) inhibited responses to NECA and CHA in a competitive manner and XAC proved to be 8–25 times more potent than DPCPX against both agonists. These data support the presence of A2adenosine receptors in EDVs, located on the vascular smooth muscle cells, which are most likely to be of the A2A‐adenosine receptor subtype. A direct comparison between the potency and efficacy of NECA and adenosine as vasodilators of EDV and equine digital arteries was made and both agonists proved to be significantly more potent and efficacious as vasodilators of EDVs. These data suggest that adenosine may be an important local mediator regulating blood flow through the digital circulation and that its generation under hypoxic conditions would lead to selective venodilation.
Contribution of α1‐acid glycoprotein to species difference in lincosamides‐plasma protein binding kinetics
Authors: Son  , Osabe  , Shimoda  , Kokue
Published: March 2003

Protein binding kinetics of lincomycin (LM) and clindamycin (CM) were studied using plasma, albumin and α1‐acid glycoprotein (AGP) derived from humans, dogs, cattle and sheep. Based on Rosenthal plots of LM and CM, drug‐binding property in plasma presented specific and non‐specific binding, except for LM in cattle and sheep and for CM in sheep, where only non‐specific binding was demonstrated. Dissociation constant (Kd) and binding capacity (Bmax) for specific binding and proportionality constant (PC) for non‐specific binding were as follows: Kd = 3.14 μmol/L, Bmax = 15.28 μmol/L, PC = 0.19 for humans; Kd = 3.84 μmol/L, Bmax = 6.55 μmol/L, PC = 0.14 for dogs; PC = 0.12 for cattle; PC = 0.16 for sheep in LM and Kd = 0.94 μmol/L, Bmax = 12.24 μmol/L, PC = 4.98 for humans; Kd = 1.48 μmol/L, Bmax = 9.52 μmol/L, PC = 2.91 for dogs; Kd = 1.22 μmol/L, Bmax = 4.45 μmol/L, PC = 2.40 for cattle; PC = 1.48 for sheep in CM. The specific binding for each species was different, showing more difference in Bmax compared with Kd. The non‐specific binding of LM was similar among species whereas that of CM was different, implying species difference. The drug‐binding property of AGP for each species was all specific binding and the Kd was comparable to that obtained from plasma, indicating that AGP is a major specific binder in plasma. The lack of detection of specific binding for LM in cattle and sheep and for CM in sheep plasma could be attributable to a higher Kd and lower plasma AGP concentration compared with other species. The drug‐binding property of albumin was characterized as all non‐specific, without a great difference among species. Except for CM in sheep, the lower PC in albumin solution compared with that in plasma suggested the presence of another non‐specific binder in plasma, i.e. lipoprotein. From the simulation of drug‐binding percentage to AGP concentrations, AGP could be a major contributor to drug‐plasma protein binding in pathological states. The degree of AGP‐drug binding for each species could vary according to the degree of increase of AGP concentrations from a healthy to a pathological state, inducing a decrease in the unbound fraction (fp): 6.1 fold for dogs, 4.6 fold for humans, 1.8 fold for sheep and 1.4 fold for cattle in LM; 5.8 fold for dogs, 5.7 fold for cattle, 4.0 fold for humans and 1.5 fold for sheep in CM. Therefore, the disposition and efficacy of lincosamides affected byfpcan be modified differently by the change offpattributable to the alteration of plasma AGP concentration in each species.
Population pharmacokinetics in veterinary medicine: Potential use for therapeutic drug monitoring and prediction of tissue residues
Authors: MARTÍN‐JIMÉNEZ T. , RIVIERE J.E.
Published: March 2003

Population pharmacokinetics can be defined as a study of the basic features of drug disposition in a population, accounting for the influence of diverse pathophysiological factors on pharmacokinetics, and explicitly estimating the magnitude of the interindividual and intraindividual variability. It is used to identify subpopulations of individuals that may present with differences in drug kinetics or in kinetic/dynamic responses. Rooted in procedures used in engineering systems, population pharmacokinetics methods were conceived as a means to determine the pharmacokinetic profile in populations in which a sparse number of samples were obtained per individual, such as those in late stage human clinical trials. This is the situation commonly encountered in all aspects of veterinary medicine. The exploratory nature of this technique allows one to probe relationships between clinical factors (such as age, gender, renal function, etc.) and drug disposition and/or effect. Similarly, the utilization of these techniques in the clinical research phases of drug development optimize the determination of efficacy and safety of drugs. Given the observational nature of most studies published so far, statistical methods to validate the population models are necessary. Simulation studies may be conducted to explore data collection designs that maximize information yield with a minimum expenditure of resources. The breadth of this approach has allowed population studies to be more commonly employed in all areas of drug therapy and clinical research. Finally, in veterinary medicine, there is an additional field in which population studies are potentially ideally suited: the application of this methodology to the study of tissue drug depletion and drug residues in production animals, and the establishment of withdrawal times tailored to the clinical or production conditions of populations or individuals. Such application would provide a major step toward assuring a safe food supply under a wide variety of dose and off‐label clinical uses. Population pharmacokinetics is an ideal method for generating data in support of the implementation of flexible labelling policies and extralabel drug use recently approved under AMDUCA (Animal Medicinal Drug Use Clarification Act. 21 CFR Part 530).
Review of furosemide in horse racing: its effects and regulation
Authors: Soma L.R. , Uboh C.E.
Published: March 2003

Furosemide has been used empirically and has been legally approved for many years by the US racing industry for the control of exercise‐induced pulmonary haemorrhage (EIPH) or bleeding. Its use in horses for this purpose is highly controversial and has been criticized by organizations outside and inside of the racing industry. This review concentrates on its renal and extra‐renal actions and the possible relationship of these actions to the modification of EIPH and changes in performance of horses. The existing literature references suggest that furosemide has the potential of increasing performance in horses without significantly changing the bleeding status. The pulmonary capillary transmural pressure in the exercising horse is estimated to be over 100 mmHg. The pressure reduction produced by the administration of furosemide is not of sufficient magnitude to reduce transmural pressures within the capillaries to a level where pressures resulting in rupture of the capillaries, and thus haemorrhage, would be completely prevented. This is substantiated by clinical observations that the administration of furosemide to horses with EIPH may reduce haemorrhage but does not completely stop it. The unanswered question is whether the improvement of racing times which have been shown in a number of studies are due to the reduction in bleeding or to other actions of furosemide. This review also discusses the difficulties encountered in furosemide regulation, in view of its diuretic actions and potential for the reduction in the ability of forensic laboratories to detect drugs and medications administered to a horse within days or hours before a race. Interactions between nonsteroidal anti‐inflammatory drugs (NSAIDs) and furosemide have also been examined, and the results suggest that the effects of prior administration of NSAID may partially mitigate the renal and extra‐renal effects which may contribute to the effects of furosemide on EIPH.
Effect of cephapirin and mecillinam on the phagocytic and respiratory burst activity of neutrophil leukocytes isolated from bovine blood
Authors: Dosogne  , Hoeben  , Burvenich  , Lohuis
Published: March 2003

Antimicrobial therapy is the most commonly used treatment of bacterial infections in dairy cows. Polymorphonuclear neutrophil leukocytes (PMN) play an important role in the first line defence against invading bacteria and it is important that the function of PMN is not compromised by antibiotics. We investigated thein vitroeffect of cephapirin, a first generation cephalosporin, and mecillinam, an amidinopenicillin with activity against mainly Gram‐negative bacteria, on phagocytosis and respiratory burst activity of PMN isolated from bovine blood. Afterin vitroincubation of PMN with different concentrations of the antibiotics, phagocytosis was evaluated by flow cytometry and respiratory burst activity was evaluated by registration of chemiluminescence (CL) with a luminometer. None of the investigated concentrations of cephapirin and mecillinam had an effectin vitroon phagocytosis ofEscherichia coliby PMN. At high concentrations (100 and 1000 μg/mL), cephapirin and mecillinam reduced the respiratory burst activity of PMN. Part of these suppressive effects could be ascribed to oxidant scavenging. Inhibitory effects of cephapirin were stronger than mecillinam. In conclusion, cephapirin and mecillinam did not seem to affect antibacterial activity of PMN isolated from bovine bloodin vitroat therapeutic concentrations.
The determination of the cellular volume of avian, porcine and bovine phagocytes and bovine mammary epithelial cells and its relationship to uptake of tilmicosin
Authors: Scorneaux  , Shryock
Published: March 2003

In order to compare the intracellular concentration of antimicrobial agents in phagocytic and nonphagocytic cells, the knowledge of their cell volume is essential. For the first time, the determination of the avian, porcine, and bovine polymorphonuclear neutrophils (PMN), monocyte‐derived macrophages, macrophages, and bovine mammary epithelial cell volume was performed using [3H]‐water and [14C]‐carboxyinulin. The comparison of all the cells showed that the PMN have a size range between 3.58 and 4.04 μL per mg of protein, and are smaller than the monocyte‐derived macrophages and mammary epithelial cells (4.32–5.01 μL per mg of protein). The macrophages show the largest size (5.84–6.57 μL per mg of protein). The cellular uptake of tilmicosin in these cells was then determined. The examination of the intracellular/extracellular concentration ratios (Ci/Ce) after 4 h of incubation with 10 mg/mL of [14C]‐labelled tilmicosin revealed that tilmicosin was well accumulated and showed a ratio of 137, 169 and 193 in avian PMN, porcine PMN, and bovine alveolar macrophages, respectively. The cellular uptake data also demonstrated that tilmicosin accumulated in nonphagocytic bovine mammary epithelial cells. The importance of the use of the appropriate species and cell type specific cell volume values for calculations was exemplified by calculating the Ci/Ceof tilmicosin using cell volume data found in the literature for human and mouse cells. The subsequent comparison of these data with the Ci/Cecalculated with the actual cell volume appropriate for the species tested revealed an under evaluation of 3–13% in monocyte‐macrophages, an over evaluation of 7–18%, 16–31% and 69% in PMN, macrophages, and epithelial cells, respectively. This study highlights the importance of the proper cell volume in order to determine the Ci/Ce. Moreover, the cell volumes determined here for avian, porcine and bovine cells should facilitate furtherin vitroandin vivocellular studies by veterinary researchers.
The suppressive effects of lipopolysaccharide‐induced acute phase response on hepatic cytochrome P450‐dependent drug metabolism in rabbits
Authors: Saitoh  , Kokue  , Shimoda
Published: March 2003

The acute phase response (APR) was induced by five separate intravenous (i.v.) injections ofEscherichia colilipopolysaccharide (LPS, 17 μg/kg each time) in rabbits, with intervals of 1 h. This model was used to study the effects of APR on the activities of hepatic microsomal cytochrome P450 (CYP)‐dependent enzyme including drug metabolism. Five female rabbits were included in each of four groups, a control group and three LPS‐treated groups (group I, II and III). The rabbits of the control, group I, II and III were killed at 1, 1, 3 and 7 days after saline (control only) or the LPS injection, respectively. The APR was confirmed by increases in rectal body temperature, plasma concentrations of interleukin‐6 and C‐reactive protein (CRP). Pharmacokinetics of antipyrine before death were examined in every group. Antipyrine was administered (5 mg/kg) at 24 h (control and group I), 3 days (group II) and 7 days (group III) after the first LPS injection. Total body clearance (Cltot) of antipyrine tended to decrease in group I. All the livers were excised for measuring CYP‐dependent activities. Total CYP content and several CYP‐dependent activities (aminopyrine N‐demethylation, aniline 4‐hydroxylation and caffeine 3‐demethylation) decreased in group I. The maximum velocity (Vmax) values of those enzymes, and the amount of CYP1A1/1A2 and CYP2E1 apoproteins appeared to decrease. Michaelis constant (Km) values of those enzymes were not affected by the APR. Rectal body temperature recovered to normal at 3 days after the first LPS injection in group II and III. The concentration of CRP, albumin, total CYP content and the plasma clearance of antipyrine returned to the control levels at 7 days after the first LPS injection. These results suggest that the metabolism of drugs, including CYP‐dependent drug metabolizing activity, is suppressed markedly in incipient APR induction in rabbits, and the drug metabolizing capacity is returned to normal at 7 days after APR induction.
Enantiospecific pharmacokinetics and pharmacodynamics of ketoprofen in sheep
Authors: Landoni  , Comas  , Mucci  , Anglarilli  , Bidal  , Lees
Published: March 2003

Pharmacokinetic and pharmacodynamic parameters were established for the enantiomers of the 2‐arylpropionic acid (APA) nonsteroidal anti‐inflammatory drug (NSAID), ketoprofen (KTP). Each enantiomer was administered separately (1.5 mg/kg) and in a racemic mixture (3 mg/kg) intravenously (i.v.) to a group of eight sheep in a four‐way, four‐period cross‐over study using a tissue cage model of inflammation. Plasma disposition of each KTP enantiomer was similar following separate administration of the pure compounds compared to administration of the racemic mixture. S(+)KTP volume of distribution (Vdarea) was higher and clearance (ClB) faster than those of R(–)KTP. S(+) and R(–) KTP achieved relatively low concentrations in exudate and transudate. Unidirectional limited chiral inversion of R(–) to S(+)KTP was demonstrated. After R(–)KTP administration S(+)KTP was detected in plasma, but not in either exudate or transudate.

Pharmacokinetic/pharmacodynamic (PK/PD) modelling of the data could not be undertaken following R(–)KTP administration because of chiral inversion to S(+)KTP, but the pharmacodynamic parameters, calculated maximum effect (Emax), concentration producing 50% effect (EC50), Hill’s coefficient (N), rate constant of elimination of drug effect from the compartment (KeO) and mean equilibration half‐life (t½Ke0) were determined for S(+)KTP after administration of the racemic mixture as well as the pure compound.
Airflow and device effects on aerosol delivery for large animals
Authors: Davis M. S. , Foster Wm. F.
Published: March 2003

Aerosol delivery of medications has recently gained acceptance in large animal veterinary medicine. However, delivery of therapeutic aerosols currently relies on equipment modified from human use and delivery of medical aerosols may be adversely affected by the equipment design. In this study, we demonstrate the effect of typical large animal inspiratory flow rates on aerosol delivery characteristics. A benchtop system was assembled to simulate aerosol delivery to large animals. Phasic airflow was generated using a large animal anesthesia machine set to deliver 6 bpm (7 L/breath) at 100, 150 and 180 L/min mean inspiratory airflow. Aerosol from a DeVilbis ultrasonic nebulizer was delivered to a simulated facemask using standard 22 mm tubing and fittings. Total mass, delivery efficiency and mass median aerosol diameter (MMAD) was measured with and without an inspiratory one‐way valve on the facemask. Delivered aerosol mass ranged from 0.26 to 0.08 g/min and delivery efficiency ranged from 30 to 6%. Both parameters were significantly reduced by both increasing flow rates and the presence of a one‐way valve between the nebulizer and the facemask. Average MMAD was 0.7 μm and was not affected by any experimental variable. These results demonstrate that current aerosol equipment used on large animals has a substantial adverse effect on aerosol delivery. Elimination of one‐way valves between the aerosol source and the patient is expected to improve delivery of the aerosol in these patients.
Inflammatory mediators induce endothelium‐dependent adherence of equine eosinophils to cultured endothelial cells
Authors: Bailey S. R. , Cunningham F. M.
Published: March 2003

Accumulation of equine eosinophils at sites of parasite infestation or allergic inflammation depends upon their adherence to vascular endothelial cells and subsequent migration through the endothelium and extracellular matrix. This study has examined whether cytokines, which cause endothelial cell‐dependent eosinophil adherence in other species, and histamine and substance P, which increase adherence of equine eosinophils to protein coated plastic, induce equine eosinophil adherence to cultured equine digital vein endothelial cell (EDVEC) monolayers. The EDVEC monolayers were stimulated with recombinant human (rh) interleukin (IL)‐1β, rhTNFα, substance P or histamine for different times and with a range of concentrations of mediators and the adherence of blood eosinophils from normal horses examined. All four mediators caused time‐ and concentration‐dependent increases in adherence. However, neither the response to substance P, nor that to histamine, reached a maximum at the highest concentration tested (10–3 M: 10.6 ± 2.6% and 4.5 ± 0.6% adherent cells vs. background adherence of 1.9 ± 0.4% and 1.1 ± 0.2%; values for substance P and histamine, respectively, expressed as a percentage of total cells added initially;n=4). These data suggest that, as in other species, cytokines induce endothelial cell‐dependent eosinophil adherence and mediators released during allergic inflammation may play a role in eosinophil recruitment by this mechanism.
Mixed effects modeling of the disposition of gentamicin across domestic animal species
Authors: Martín‐Jiménez T. , Riviere J. E.
Published: March 2003

An interspecies pharmacokinetic model for gentamicin was developed using the mixed effects modeling approach and serum disposition data obtained from the Food Animal Residue Avoidance Databank (FARAD). Data that meta prioriquality criteria was obtained from the database and analysed using the traditional double logarithmic analysis and the mixed effects modeling approach. Body weight, brain weight and fever were the covariates of interest in our study. Population pharmacokinetic models across species were developed and validated with swine data. The parameter volume of distribution was modeled as a function of body weight. The total clearance was initially modeled as a function of body weight. The predictability performance of the model improved dramatically when the parameter brain weight was included in the covariate model for clearance. This was a surprising finding worthy of further study. The covariate fever seemed to influence the magnitude of the volume of distribution, although the scarcity of data pertaining to diseased animals makes this finding uncertain. We conclude that the pharmacokinetic characteristics of drugs such as gentamicin, can be predicted across species using a population pharmacokinetics modeling approach, and that clinical features that affect species in a similar manner can be also explored in this fashion.
Plasma achiral and chiral pharmacokinetic behaviour of intravenous oxfendazole co‐administered with piperonyl butoxide in sheep
Authors: SÁNCHEZ S. , SMALL J. , JONES D. G. , MCKELLAR Q. A.
Published: March 2003

Co‐administration of piperonyl butoxide (PB) potentiates fenbendazole (FBZ) in small ruminants. The resultant increase in bioavailability of FBZ and its metabolite oxfendazole (OFZ) has important implications for the efficacy of these drugs against benzimidazole (BZD)‐resistant strains of Teladorsagia circumcincta. This study evaluated the racemic (achiral) and enantiomeric (chiral) plasma disposition kinetics of OFZ and its metabolites after the co‐administration of PB and OFZ in sheep. Six 6–8‐month‐old, parasite‐free, female Dorset sheep (30–40 kg) were used in a two‐phase crossover experiment. In phase I, three sheep received 30 mg/kg PB orally, followed by a single intravenous (i.v.) injection of OFZ at 5 mg/kg. The other three animals were treated similarly except that 5 mL of water replaced PB. In phase 2, treatments for the two groups were reversed and were given 14 days after the initiation of phase I. Three analytes OFZ, FBZ and fenbendazole sulphone (FBZSO2) were recovered in plasma up to 48 h post‐treatment in both experimental groups. Achiral and chiral pharmacokinetic (PK) profiles for OFZ, after the co‐administration of PB, were characterized by a significantly greater area under the concentration–time curve (AUC) and a longer mean residence time (MRT). Chiral OFZ distribution ratios were comparable in both treatment groups. Piperonyl butoxide treatment markedly influenced the plasma PK profiles for FBZ and FBZSO2 following OFZ administration. Production of FBZ was enhanced as reflected by increased (> 60%) AUC, delayed Tmax and a significantly delayed (> 45%) elimination (t½el). Although AUC values for FBZSO2 were not significantly different between groups, this metabolite was depleted more slowly from plasma (t½el > 60% and MRT > 42%) following PB treatment. This study demonstrated that PB co‐administration is associated with an inhibition of OFZ biotransformation, as evidenced by the significantly higher plasma concentrations of OFZ and FBZ, and this could have important implications in terms of antiparasite therapy against BZD‐resistant parasite strains.
In vitroruminal biotransformation of benzimidazole sulphoxide anthelmintics: enantioselective sulphoreduction in sheep and cattle
Authors: VIRKEL G. , LIFSCHITZ A. , PIS A. , LANUSSE C.
Published: March 2003

The comparativein vitrosulphoreduction of the (+) and (–) enantiomers of albendazole sulphoxide (ABZSO) and oxfendazole (OFZ) by ruminal fluid obtained from sheep and cattle, was investigated, under anaerobic conditions, in this study. Ruminal fluid samples were obtained from Holstein steers fitted with a permanent rumen fistula and from Corriedale lambs via an oesophageal tube. Albendazole sulphoxide, incubated as either the racemic (rac) mixture or as each individual enantiomeric form, was extensively sulphoreduced to form albendazole (ABZ) by ruminal fluid from both species. The concentrations of ABZ formed at different incubation times were between 55 and 158% greater after the incubation of cattle ruminal fluid with (+) ABZSO, compared with that produced when (–) ABZSO was the incubated substrate. Similarly, the concentrations of ABZ were 1.3–3.0‐fold higher when (+) ABZSO was incubated with sheep ruminal fluid. Significantly higher rates of depletion were observed for the (+) enantiomeric form when ABZSO was incubated with ruminal fluid from both species. The rates of ABZ formation from both ABZSO enantiomeric forms were significantly higher in sheep compared with cattle ruminal fluid. Fenbendazole (FBZ) was the metabolite formed after the incubation of the racemic form of OFZ with ruminal fluid obtained from both species. The metabolic profile of both OFZ enantiomers followed a similar pattern to that observed for ABZSO enantiomers. A bi‐directional chiral inversion of one enantiomer into its antipode was observed. The (+) enantiomer appeared in the incubation medium when (–) ABZSO was the incubated substrate, and also the (–) antipode was detected after (+) ABZSO incubation with ruminal fluid obtained from both species. The results reported here demonstrate an enantioselective ruminal sulphoreduction of ABZSO and OFZ (substrate enantioselectivity). These findings contribute to interpret the chiral behaviour of benzimidazole‐sulphoxide anthelmintics.
Comparative serum pharmacokinetics of the fluoroquinolones enrofloxacin, difloxacin, marbofloxacin, and orbifloxacin in dogs after single oral administration
Authors: HEINEN E.
Published: March 2003

The pharmacokinetics after oral application of the fluoroquinolones (FQs), enrofloxacin, difloxacin, marbofloxacin and orbifloxacin were compared in independent crossover studies in Beagle dogs. Commercially available tablet formulations were given at common dosage recommended by the manufacturers which were 2.0 mg/kg body weight (bw) for marbofloxacin, 2.5 mg/kg bw for orbifloxacin and 5.0 mg/kg bw for enrofloxacin and difloxacin. Analysis was performed by an agar diffusion assay. Pharmacokinetic parameters were calculated by noncompartmental methods. All FQs were rapidly absorbed and achieved average peak serum concentrations of 1.41, 1.11, 1.47 and 1.37 μg/mL for enrofloxacin, difloxacin, marbofloxacin and orbifloxacin, respectively. Enrofloxacin was eliminated at a terminal half‐life (t½) of 4.1 h, difloxacin at 6.9 h, orbifloxacin at 7.1 h and marbofloxacin at 9.1 h. While the area under the serum concentration–time curve of the 24‐h dosing interval (AUC0–24) for marbofloxacin and orbifloxacin were similar (approximately 13 μg · h/mL), enrofloxacin attained anAUC0–24of 8.7 and difloxacin of 9.3 μg · h/mL. Because of its favourable pharmacokinetics combined with excellentin vitroactivity, enrofloxacin exhibited superior pharmacodynamic predictors ofin vivoantimicrobial activity asCmax/MIC(maximum serum concentration/minimum inhibitory concentration) andAUC0–24/MIC(area under the 24‐h serum concentration–time curve/minimum inhibitory concentration) compared with other FQs.
Pharmacokinetics of azithromycin in foals after i.v. and oral dose and disposition into phagocytes
Authors: DAVIS J. L. , GARDNER S. Y. , JONES S. L. , SCHWABENTON B. A. , PAPICH M. G.
Published: March 2003

The properties of azithromycin suggest that it may be an alternative to erythromycin for treatment ofRhodococcus equipneumonia in foals. To investigate this possibility, the disposition of azithromycin in plasma, polymorphonuclear leukocytes (PMN), and alveolar cells was examined after a single administration in foals. Azithromycin suspension was administered orally (p.o.) at a dose of 10 mg/kg to five healthy 2–3‐month‐old foals. Two weeks later, azithromycin for injection was administered by intravenous (i.v.) infusion at a dose of 5 mg/kg to the same foals. Plasma samples were collected after p.o. and i.v. administration. Peripheral blood PMN and bronchoalveolar lavage fluid and alveolar cells were collected after p.o. administration. Azithromycin concentrations were determined by reverse‐phase high‐performance liquid chromatography (HPLC) with coulometric electrochemical detection. Azithromycin p.o. absorption was variable with a mean systemic availability of 39% (±20%). The plasma half‐life was 16 and 18.3 h after i.v. and p.o. administration, respectively. Azithromycin had a very large volume of distribution (Vd) of 11.6 L/kg [Vd(ss)] and 12.4 L/kg [Vd(area)]. The largeVdcan be attributed to high tissue and intracellular concentrations, exhibited by the high concentration of azithromycin in PMN and alveolar cells. The PMN half‐life was 49.2 h. Dosage of 10 mg/kg of azithromycin p.o. once daily for foals withR. equipneumonia is recommended for further study.