bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of light exposure and sleep displacement on dim light melatonin onset
Authors: Gordijn M. C. M. , Beersma D. G. M. , Korte H. J. , VAN DEN Hoofdakker R. H.
Published: March 2003

The purpose of the study was to induce in two different ways, a phase‐angle difference between the circadian pacemaker and the imposed sleep–wake cycle in humans, we intended to: (i) shift the circadian pacemaker by exposure to bright light and keep the timing of the sleep–wake cycle fixed; and (ii) keep the timing of the circadian pacemaker fixed by a constant light–dark cycle and displace sleep. We monitored dim light melatonin onset (DLMO), core body temperature and sleep. DLMO was delayed significantly after 3 days of a 3‐h delayed sleep‐phase when compared with 3 days of sleep at a normal or 3‐h advanced sleep‐phase. The shifts in DLMO were not accompanied by shifts in body temperature, changes in waking‐up time or by a change in the duration of the first rapid eye movement (REM) sleep episode. Three days of light exposure in the morning or evening resulted in shifts in DLMO of similar magnitude, but this was accompanied by shifts in the rhythm of body temperature, changes in waking‐up time and in the duration of the first REM sleep episode. We conclude that the changes observed after light exposure reflect shifts in the circadian pacemaker. In contrast, we propose that the changes observed in DLMO after sleep displacement are not mediated by the circadian pacemaker. These results raise some doubts about the reliability of DLMO as a marker of circadian phase in cases of sleep disturbances. Finally, we initiate a search for changes in sleep that might be responsible for the unexpected effects on DLMO.
EEG arousals and awakenings in relation with periodic leg movements during sleep
Authors: Karadeniz  , Ondze  , Besset  , Billiard
Published: March 2003

It is known that periodic leg movements are frequently accompanied by full awakenings or by signs of EEG arousals. The time relationship of these EEG arousals with leg movements varies from patient to patient. They may precede or follow leg movements or occur simultaneously. It is not clear whether these arousals trigger leg movements or, alternatively, whether both EEG arousals and leg movements are separate expressions of a common pathophysiological mechanism. We investigated the temporal relationship of five EEG arousals, such as alpha activity, K‐complexes, spindles, K‐alpha, K‐spindle activities and awakenings, with leg movements in 10 periodic leg movement patients. These EEG arousals were considered to be associated with leg movements if they occurred 10 s before/after or simultaneously with the onset of right or left tibialis muscle EMG potentials. It was found that 49.19% of EEG arousals occurred before leg movements, 30.61% occurred simultaneously and 23.18% occurred just after leg movements. The number of EEG arousals was significantly higher in the 10 s preceding leg movement than simultaneously or in the 10 s following. Alpha activity was the phenomenon associated most frequently with leg movements, irrespective of its temporal organization and was significantly higher during the 10 s preceding movement. Spindle and K‐spindle activities were significantly higher before leg movement, whereas K‐complex activity was significantly more frequent during leg movements. The number of awakenings was significantly higher after leg movements than simultaneously. These results indicated that leg movements are not primary, but rather are a phenomenon associated with an underlying arousal disorder.
Diurnal variations in the waking EEG: comparisons with sleep latencies and subjective alertness
Authors: Lafrance  , Dumont
Published: March 2003

Daytime measures of sleep latency and subjective alertness do not correlate with one another, suggesting that they assess different aspects of alertness. In addition, their typical diurnal variations show very different time courses. Quantitative analysis of the waking electroencephalogram (EEG) has been proposed as an objective measure of alertness, but it is not clear how it compares with other measures. In this study, the waking EEG was measured in the daytime to determine the presence of diurnal variations in the activity of standard frequency bands and to compare these variations with the temporal patterns typical of sleep propensity and subjective alertness. Alertness was evaluated in four men and 12 women, aged 19–33 y. Assessments were conducted every 2 h, from 10.00 to 24.00, in the following order: a visual analogue scale of alertness, a waking EEG recording and a sleep latency test. The waking EEG was recorded with eyes open. For each recording session, 32–60 s of artefact‐free signals were selected from the C3/A2 derivation, then subjected to amplitude spectral analysis. Four EEG frequency bands showed significant diurnal variations: delta, theta, sigma and beta1. None of these variations showed a significant correlation with the temporal patterns of sleep latencies or subjective alertness. At the individual level, however, theta band activity increased when subjective alertness decreased, suggesting that the theta band can be used to monitor variations in alertness in a given individual, even at the moderate levels of sleepiness experienced during the daytime.
Excessive daytime sleepiness in patients suffering from different levels of obstructive sleep apnoea syndrome
Authors: Sauter  , Asenbaum  , Popovic  , Bauer  , Lamm  , Klösch  , Zeitlhofer
Published: March 2003

Excessive daytime sleepiness (EDS) is a frequent symptom of patients with obstructive sleep apnoea (OSA). EDS is a high‐risk factor for accidents at work and on the road. Thirty untreated patients with different levels of severity of OSA were studied concerning night sleep and EDS. The criterion for severity was the respiratory disturbance index (RDI): 15 patients were classified as ‘moderately’ apnoeic (RDI < 40), 15 as ‘severely’ apnoeic (RDI > 40). Following night‐time polysomnography, objective and subjective aspects of EDS were studied. To assess objective EDS the Maintenance of Wakefulness Test (MWT) and a computer‐based vigilance performance test were used. Subjective EDS was determined using the Stanford Sleepiness Scale (SSS), the Epworth Sleepiness Scale (ESS) and the Visual Analogue Scales for Performance (VAS‐P) and Tiredness (VAS‐T). Well‐being was assessed using the Scale of Well‐Being by von Zerssen (Bf‐S/Bf‐S′). Severe apnoea patients spent more time in stage 1 and less in slow‐wave sleep. MWT latencies tended to be shorter in the severe apnoea group. Vigilance testing revealed no group differences. Patients with moderate apnoea described themselves as more impaired in all subjective scales, but only SSS scores reached statistical significance. Our results suggest that there is no simple correlation between polysomnographic and respiratory sleep variables at night on the one hand, and the extent of EDS on the other hand. Furthermore, subjective and objective evaluation of EDS does not yield the same results. New approaches which allow a more detailed analysis of night sleep and daytime function are required to identify high‐risked patients.
Illumination levels in nursing home patients: effects on sleep and activity rhythms
Authors: Shochat Tamar , Martin Jennifer , Marler Matthew , Ancoli‐Israel Sonia
Published: March 2003

Studies examining levels of illumination in adult populations have demonstrated that the level and amount of light exposure are lower in the elderly compared with younger adults, particularly in institutionalized patients with dementia. Although insufficient light exposure has been implied as a cause of sleep fragmentation, evidence for such a relationship is scant. Sixty‐six institutionalized elderly had their activity and light exposure monitored for a 3‐day period. Mean and median light levels, minutes spent over 1000 and over 2000 lux, percent sleep and wake, and number of naps were computed for daytime intervals, defined as 07.00–18.59. Percentages of sleep and wake, number of awakenings and mean duration of wake periods were computed for night‐time intervals, defined as 22.00–05.59. Mesor, amplitude and acrophase of activity and of light were determined by cosinor analysis. A mixed linear model was used to assess the effects of daytime Actillume measures on subsequent night‐time measures, and vice versa. Spearman correlations were computed, and multiple regression analyses were carried out with light variables and dementia level as predictors and sleep–wake and activity measures as dependent variables. The median light level was 54 lux and a median of only 10.5 min were spent over 1000 lux. Higher light levels predicted fewer night‐time awakenings, and severe dementia predicted more daytime sleep and lower mean activity. Increased bright light exposure predicted later activity acrophase. There was an association between the acrophases of light and of activity, with maximum illumination preceding peak activity. These results suggest that daytime light exposure has an impact on both night‐time sleep consolidation and timing of peak activity level.
Sleep deprivation blunts the night time increase in aldosterone release in humans
Authors: Charloux Anne , Gronfier Claude , Chapotot Florian , Ehrhart Jean , Piquard François , Brandenberger Gabrielle
Published: March 2003

The aim of this study was to determine the effect of sleep deprivation on the 24‐h profile of aldosterone and its consequences on renal function. Aldosterone and its main hormonal regulatory factors, ACTH (evaluated by cortisol measurement) and the renin‐angiotensin system [RAS, evaluated by plasma renin activity (PRA) measurement] were determined every 10 min for 24 h in eight healthy subjects in the supine position, once with nocturnal sleep and once during total 24‐h sleep deprivation. Plasma Na+ and K+ were measured every 10 min in four of these subjects. In an additional group of 13 subjects under enteral nutrition, diuresis, natriuresis and kaliuresis were measured once during the sleep period (23.00–07.00 h) and once during a 23.00–07.00 hours sleep deprivation period. During sleep deprivation, aldosterone displayed lower plasma levels and pulse amplitude in the 23.00–07.00‐hour period than during sleep. Similarly, PRA showed reduced levels and lower pulse frequency and amplitude. Plasma cortisol levels were slightly enhanced during sleep deprivation. Overnight profiles of plasma K+ and Na+ were not affected. Diuresis and kaliuresis were not influenced by sleep deprivation. In contrast, natriuresis significantly increased during sleep deprivation. This study demonstrates that sleep deprivation modifies the 24‐h aldosterone profile by preventing the nocturnal increase in aldosterone release and leads to altered overnight hydromineral balance.
Sleep during Ramadan intermittent fasting
Authors: Roky Rachida , Chapotot Florian , Hakkou Farid , Benchekroun Majda Taoudi , Buguet Alain
Published: March 2003

During the month of Ramadan intermittent fasting, Muslims eat exclusively between sunset and sunrise, which may affect nocturnal sleep. The effects of Ramadan on sleep and rectal temperature (Tre) were examined in eight healthy young male subjects who reported at the laboratory on four occasions: (i) baseline 15 days before Ramadan (BL); (ii) on the eleventh day of Ramadan (beginning of Ramadan, BR); (iii) on the twenty‐fifth day of Ramadan (end of Ramadan, ER); and (iv) 2 weeks after Ramadan (AR). Although each session was preceded by an adaptation night, data from the first night were discarded. Polysomnography was taken on ambulatory 8‐channel Oxford Medilog MR‐9000 II® recorders. Standard electroencephalogram (EEG), electro‐oculogram (EOG) and electromyogram (EMG) recordings were scored visually with the PhiTools ERA© software. The main finding of the study was that during Ramadan sleep latency is increased and sleep architecture modified. Sleep period time and total sleep time decreased in BR and ER. The proportion of non‐rapid eye movement (NREM) sleep increased during Ramadan and its structure changed, with an increase in stage 2 proportion and a decrease in slow wave sleep (SWS) duration. Rapid eye movement (REM) sleep duration and proportion decreased during Ramadan. These changes in sleep parameters were associated with a delay in the occurrence of the acrophase of Tre and an increase in nocturnal Tre during Ramadan. However, the 24‐h mean value (mesor) of Tre did not vary. The nocturnal elevation of Tre was related to a 2–3‐h delay in the acrophase of the circadian rhythm. The amplitude of the circadian rhythm of Tre was decreased during Ramadan. The effects of Ramadan fasting on nocturnal sleep, with an increase in sleep latency and a decrease in SWS and REM sleep, and changes in Tre, were attributed to the inversion of drinking and meal schedule, rather than to an altered energy intake which was preserved in this study.
Circadian preference, sleep and daytime behaviour in adolescence
Authors: Giannotti Flavia , Cortesi Flavia , Sebastiani Teresa , Ottaviano Salvatore
Published: March 2003

The aim of this study was to determine the relationship between circadian preferences, regularity of sleep patterns, sleep problems, daytime sleepiness and daytime behaviour. As a part of an epidemiological survey on sleep in a representative sample of Italian high‐school students, a total of 6631 adolescents, aged 14.1–18.6 years, completed the School Sleep Habits Survey, a comprehensive questionnaire including items regarding sleep, sleepiness, substance use, anxiety and depressed mood, use of sleeping pills, school attendance and a morningness/eveningness scale. The sample consisted of 742 evening‐types (315 males and 427 females; mean age 17.1 years) and 1005 morning‐types (451 males and 554 females; mean age 16.8 years). No significant sex differences were found for morningness/eveningness score. Eveningness was associated with later bedtime and wake‐up time, especially on weekends, shorter time in bed during the week, longer weekend time in bed, irregular sleep–wake schedule, subjective poor sleep. Moreover, evening types used to nap more frequently during school days, complained of daytime sleepiness, referred more attention problems, poor school achievement, more injuries and were more emotionally upset than the other chronotype. They referred also greater caffeine‐containing beverages and substances to promote sleep consumption. Our results suggest that circadian preference might be related not only to sleep pattern, but also to other adolescent behaviours.
Lactation is associated with an increase in slow‐wave sleep in women
Authors: Blyton D. M. , Sullivan C. E. , Edwards N.
Published: March 2003

Major physiological changes occur following parturition and the onset of lactation, including the withdrawal of oestrogen and progesterone, with a consequent increase in circulating prolactin (PRL). Changes in other circulating hormones are well known to alter sleep architecture in other circumstances. We therefore aimed to assess whether sleep architecture is altered in fully lactating women as a result of hormonal changes associated with lactation. A descriptive comparison study was undertaken on 12 fully breastfeeding women (B/F), 12 age‐matched control women (CTRL), and seven postnatal women who had chosen to bottle‐feed their infants (BOTTLE). Maternal age, infant age and body mass index (BMI) were similar between all three groups. We performed overnight polysomnography utilizing the Portable Compumedics P‐series. The total sleep time (TST) and rapid eye movement (REM) sleep time were similar in the three groups of women. However, B/F women demonstrated a marked increase in slow wave sleep (SWS), 182 ± 41 min compared with CTRL (86 ± 22 min, P < 0.001 compared with B/F) and BOTTLE subjects (63 ± 29 min, P < 0.001 compared with B/F). There was a compensatory reduction in light non‐rapid eye movement (NREM) sleep in B/F when compared with CTRL and BOTTLE. The most likely explanation for the altered sleep architecture noted to occur in women who are fully breastfeeding their infants is an increase in circulating PRL, which occurs in lactating women. Enhanced SWS may be another important factor to support breastfeeding in the postnatal period.
Sleep in seasonal affective disorder patients in forced desynchrony: an explorative study
Authors: Koorengevel Kathelijne M. , Beersma Domien G. M. , Den Boer Johan A. , Van Den Hoofdakker Rutger H.
Published: March 2003

The majority of winter‐type seasonal affective disorder (SAD) patients complain of hypersomnia and daytime drowsiness. As human sleep is regulated by the interaction of circadian, ultradian and homeostatic processes, sleep disturbances may be caused by either one of these factors. The present study focuses on homeostatic and ultradian aspects of sleep regulation in SAD. Sleep was recorded polysomnographically in seven SAD patients and matched controls subjected to a 120‐h forced desynchrony protocol. In time isolation, subjects were exposed to six 20‐h days, each comprising a 6.5‐h period for sleep. Patients participated while being depressed, while remitted after light therapy and in summer. Controls were studied in winter and in summer. In each condition, the data of each subject were averaged across all recordings. Thus, the influence of the effects of the circadian pacemaker on sleep was excluded mathematically. The comparison of patients with controls and with themselves in the various conditions revealed no abnormalities in homeostatic parameters: sleep stage variables, relative power spectra and time courses of power in various frequency bands across the first three non‐rapid eye movement–rapid eye movement (NREM–REM) cycles showed no differences. The data suggest that homeostatic processes are not involved in the disturbance of sleep in SAD.
The use of microbiological end‐points in the safety evaluation and elaboration of maximum residue limits for veterinary drugs intended for use in food producing animals
Authors: WOODWARD
Published: March 2003

The safety evaluation of veterinary drugs intended for use in food producing animals relies heavily on the results of toxicity studies in laboratory animals, supported where possible by any data resulting from human exposure. The general approach involves the calculation of an acceptable daily intake which in turn can be used to elaborate maximum residue limits. It is an approach used in the European Union, in other countries and at the international level. In recent years, concern has been expressed over the presence of microbiologically active residues of veterinary drugs in food and their possible effects on the human gastrointestinal microflora. Methodologies for conducting microbiological safety studies have been investigated and approaches to microbiological safety assessments have been debated. The whole approach has proved to be controversial, partly because there are considerable doubts over the ability of low concentrations of antibiotic substances to produce adverse effects on the human gut flora and partly because there are no validated methods for testing for these attributes. This paper reviews the problems in some detail and discusses the regulatory consequences.
The regulatory status of xylazine for use in food‐producing animals in the United States
Authors: Chamberlain  , Brynes
Published: March 2003

Xylazine is commonly used in veterinary medicine as a tranquillizer or adjunct to surgical anaesthesia. Although its use is approved in companion animals and certain species of deer, xylazine remains unapproved for use in food‐producing animals in the United States. This paper reviews existing toxicological and residue chemistry information on xylazine in food animals, particularly cattle, and discusses the regulatory status of the drug in the US, as well as the conclusions reached by the Joint FAO/WHO Expert Committee on Food Additives in its recent evaluation of xylazine.
Ceftiofur distribution in plasma and joint fluid following regional limb injection in cattle
Authors: Navarre  , Zhang  , Sunkara  , Duran  , Kompella
Published: March 2003

The objective of this study was to evaluate the efficacy of regional intravenous (i.v.) injection of ceftiofur in delivery of this drug to joint fluid and plasma in a limb distal to a tourniquet in five, healthy, adult, mixed breed beef cattle. A tourniquet was positioned in the mid‐metacarpal region, and 500 mg of ceftiofur was administered through a catheter in the dorsal common digital vein (DCDV). Plasma samples were collected from the catheter at 15, 30 and 45 min postinjection, and from the abaxial proper palmar vein (APPV) at 15 min postinjection. Synovial fluid was collected from the metacarpal phalangeal joint at 45 min postinjection. Ceftiofur concentrations were estimated in plasma and synovial fluid using high‐pressure liquid chromatography (HPLC) and a microbiological assay utilizingPasteurella haemolyticaas the test organism. Both assays indicated highest plasma concentrations of ceftiofur at 15 min, with the concentrations declining with time. Concentrations of ceftiofur in plasma obtained from the DCDV were not significantly different from APPV levels, indicating rapid distribution of ceftiofur within the limb. Microbiological assay always demonstrated higher concentrations of ceftiofur compared with HPLC assay, because the former probably also detected the active metabolites of ceftiofur as well as the parent compound. At 45 min, ceftiofur concentrations determined by HPLC were 251 ± 97 and 15 ± 5 μg/mL in plasma and synovial fluid, respectively. Regional intravenous injection appears to be a feasible technique to produce rapid distribution of ceftiofur within the limb well above therapeutic concentrations.
Enrofloxacin serum bioactivity in bottlenose dolphins, Tursiops truncatus, following oral administration of 5 mg/kg in whole fish
Authors: Linnehan R.M. , Ulrich R.W. , Ridgway S.
Published: March 2003

Eight adult bottlenose dolphins Tursiops truncatus (six male, two female) were employed in a single‐dose study of orally administered enrofloxacin dosed at 5 mg/kg body weight. Blood samples were obtained from all animals at 0, 2, 4, 8, 12 and 24 h following administration of the dose in the animals morning ration of fish. Serum antimicrobial activity concentrations (SAAC) were determined using bioassay.

 The mean elimination half‐life (t½) of enrofloxacin and its major metabolites was 6.4 ± 2.0 h with a range of 3–9.4 h. The time of maximal serum concentration (tmax) occurred at approximately 4 h with a range of 2–8 h following a single oral dose of 5 mg/kg. This variation in tmax most likely resulted from individual differences in absorption because of variations in the storage and digestion of the fish ration containing the drug dose within the compartmentalized cetacean stomach.
Moxidectin in cattle: correlation between plasma and target tissues disposition
Authors: Lifschitz  , Virkel  , Imperiale  , Sutra  , Galtier  , Lanusse  , Alvinerie
Published: March 2003

The time of parasite exposure to active drug concentrations determines the persistence of the antiparasitic activity of endectocide compounds. This study evaluates the disposition kinetics of moxidectin (MXD) in plasma and in different target tissues following its subcutaneous (s.c.) administration to cattle. Eighteen male, 10‐month old Holstein calves weighing 120–140 kg were subcutaneously injected in the shoulder area with a commercially available formulation of MXD (Cydectin 1%, American Cyanamid, Wayne, NJ, USA) at 200 μg/kg. Two treated calves were killed at each of the following times post‐treatment: 1, 4, 8, 18, 28, 38, 48, 58 and 68 days. Abomasal and small intestine mucosal tissue and fluids, bile, faeces, lung, skin and plasma samples were collected, extracted, derivatized and analysed to determine MXD concentrations by high performance liquid chromatography (HPLC) with fluorescence detection. MXD was extensively distributed to all tissues and fluids analysed, being detected (concentrations > 0.1 ng/g; ng/mL) between 1 and 58 days post‐treatment. MXD peak concentrations were attained during the first sampling day. MXD maximum concentration (Cmax) values ranged from 52.9 (intestinal mucosa) up to 149 ng/g (faeces). The mean residence time (MRT) in the different tissues and fluids ranged from 6.8 (abomasal mucosa) up to 11.3 (bile) days. MXD concentrations in abomasal and intestinal mucosal tissue were higher than those detected in plasma; however, there was a high correlation between MXD concentrations observed in plasma and those detected in both gastrointestinal mucosal tissues. MXD concentrations were markedly greater in the mucosa than in its respective digestive fluid (P < 0.01). MXD concentrations in skin were higher than those found in plasma (P < 0.01). Drug concentrations recovered in the dermis were greater than those detected in the hypodermal tissue (P < 0.05). Large concentrations of MXD were excreted in bile and faeces. These findings may contribute to an understanding of the relationship between the kinetic behaviour and the persistence of the antiparasite activity of MXD against different ecto‐endoparasites in cattle.
Pharmacokinetics of ketorolac after intravenous and oral single dose administration in dogs
Authors: Pasloske  , Renaud  , Burger  , Conlon
Published: March 2003

The pharmacokinetics of ketorolac (ToradolTM), a human non‐narcotic, nonsteroidal anti‐inflammatory drug (NSAID) of the pyrrolo‐pyrrole group, was studied in six mixed breed dogs of varying ages (1–5 years). The study was performed using a randomized crossover design, with each dog initially assigned to one of two groups (intravenous (i.v.) or oral (p.o.)). Each group of three dogs received either the injectable or oral formulation of ketorolac tromethamine at 0.5 mg/kg. Serial blood samples were collected before and over 96 h following treatment. Samples were analysed by reverse phase HPLC. Individual ketorolac plasma concentration–time curves were initially evaluated by computerized curve stripping techniques followed by nonlinear least squares regression. Following i.v. administration mean (± SD) pharmacokinetic parameters were: elimination half‐life (t1/2β) = 4.55 h, plasma clearance (Clp) = 1.25 (1.13) mL/kg/min, and volume of distribution at steady state (Vss) = 0.33 (0.10) L/kg. Mean (± SD) p.o. pharmacokinetic values were: t1/2β = 4.07 h, time to reach maximum concentration (tmax) = 51.2 (40.6) min, and p.o. bioavailability (F) = 100.9 (46.7)%. These results suggest that the pharmacodisposition characteristics of a clinically effective 0.5 mg/kg i.v. or p.o. single dose of ketorolac tromethamine administered to dogs is fairly similar to that observed in humans.
The pharmacokinetics and effects of intravenously administered carprofen and salicylate on gastrointestinal mucosa and selected biochemical measurements in healthy cats
Authors: Parton  , Balmer  , Boyle  , Whittem  , Machon
Published: March 2003

The pharmacokinetics of carprofen, a propionic acid‐derived nonsteroidal anti‐inflammatory (NSAID), and its effect on gastrointestinal mucosa, complete blood counts (CBC) and biochemical indicators of liver and renal function were investigated in healthy cats using a randomized crossover design. A single dose of 4 mg/kg of carprofen (Zenecarp® Injection), normal saline, or 20 mg/kg of DL‐lysine acetyl salicylate (Vetalgine®) was given intravenously (i.v.) to each of five cats with a washout period of 2 weeks between treatments. Endoscopy of the stomach and duodenum 8 h postinjection revealed one acetyl salicylate‐(aspirin)‐treated cat with minor pinpoint erosions. None of the other cats in the three treatment groups had evidence of bleeding or ulceration. Serum biochemistry measurements of blood urea nitrogen (BUN), alanine transferase (ALT) and alkaline phosphatase (ALP) and complete blood counts (CBC) were not significantly altered from pretreatment values by the single dose of salicylate or carprofen (P< 0.05). Early and extended sample time points suggest that the pharmacokinetics of carprofen in the cat fit a 2‐compartment model, with a long elimination half‐life (t1/2) of 20.1 ± 16.6 h, an area under the plasma concentration–time curve (AUC) of 637 (± 237) μg.mL/h and a volume of distribution (Vdss) of 0.14 ± 0.05 L/kg. Intravenously administered aspirin fit a 2‐compartment model and had a long elimination half‐life (t1/2) of 22.2 ± 3.1 h, anAUCof 3824.2 ± 506.7 μg.mL/h and a volume of distribution (Vdss) of 0.17 ± 0.01 L/kg.
Effects of endotoxin‐induced fever and probenecid on disposition of enrofloxacin and its metabolite ciprofloxacin after intravascular administration of enrofloxacin in goats
Authors: RAO G. S. , RAMESH S. , AHMAD A. H. , TRIPATHI H. C. , SHARMA L. D. , MALIK J. K.
Published: March 2003

Pharmacokinetics of enrofloxacin and its active metabolite ciprofloxacin were investigated in normal, febrile and probenecid‐treated adult goats after single intravenous (i.v.) administration of enrofloxacin (5 mg/kg). Pharmacokinetic evaluation of the plasma concentration–time data of enrofloxacin and ciprofloxacin was performed using two‐ and one‐compartment open models, respectively. Plasma enrofloxacin concentrations were significantly higher in febrile (0.75–7 h) and probenecid‐treated (5–7 h) goats than in normal goats. The sum of enrofloxacin and ciprofloxacin concentrations in plasma ≥0.1 μg/mL was maintained up to 7 and 8 h in normal and febrile or probenecid‐treated goats, respectively. Thet1/2β,AUC,MRTandClB of enrofloxacin in normal animals were determined to be 1.14 h, 6.71 μg.h/mL, 1.5 h and 807 mL/h/kg, respectively. The fraction of enrofloxacin metabolized to ciprofloxacin was 28.8%. TheCmax.,t1/2β,AUCandMRTof ciprofloxacin in normal goats were 0.45 μg/mL, 1.79 h, 1.84 μg.h/mL and 3.34 h, respectively. As compared with normal goats, the values oft1/2β (1.83 h),AUC(11.68 μg ? h/mL) andMRT(2.13 h) of enrofloxacin were significantly higher, whereas itsClB (430 mL/h/kg) and metabolite conversion to ciprofloxacin (8.5%) were lower in febrile goats. TheCmax. (0.18 μg/mL) andAUC(0.99 μg.h/mL) of ciprofloxacin were significantly decreased, whereas itst1/2β (2.75 h) andMRT(4.58 h) were prolonged in febrile than in normal goats. Concomitant administration of probenecid (40 mg/kg, i.v.) with enrofloxacin did not significantly alter any of the pharmacokinetic variables of either enrofloxacin or ciprofloxacin in goats.
Allometric analysis of thiamphenicol disposition among seven mammalian species
Authors: Castells G. , Capece B. P. S. , Pérez F. , Martí G. , Arboix M. , Cristòfol C.
Published: March 2003

The pharmacokinetics of thiamphenicol (TAP), a broad‐spectrum antibiotic, was determined in male mice, rats, rabbits, dogs, pigs, sheep and calves. The relationship between the main pharmacokinetic parameters of TAP and body weight (W) was studied across these seven mammalian species, using double‐logarithmic plots. The experimental values of volume of distribution (Vss), clearance (Cl) and elimination half‐life (t½β) were plotted, and extrapolated values were determined from corresponding allometric equations. These parameters were fitted to the following equations:Vss=0.98W0.92,Cl=15.80W0.76andt½β=0.94W0.20, and present good correlation (Vss:r2=0.997,P < 0.001;Cl:r2=0.976,P < 0.001,t½β:r2=0.852,P < 0.005), that is expected of a drug eliminated primarily by renal glomerular filtration, with insignificant hepatic metabolism. For thet½β, the extrapolated and observed values were similar. The extrapolated values ofClwere close to the experimental values, except for the mouse and pig mean percent error [(M.E.) equal to 62 and 119%, respectively], while the extrapolated and observed values for theVsswere very similar. The comparison between experimental and extrapolated values suggests that it could be possible to extrapolate, with good prediction, the kinetic parameters of this drug for mammalian species, using allometric scaling, except for the species that eliminate the drug by a combination of renal excretion and hepatic metabolism.
Enantiospecific pharmacokinetics of ketoprofen in plasma and synovial fluid of horses with acute synovitis
Authors: Verde C. R. , Simpson M. I. , Frigoli A. , Landoni M. F.
Published: March 2003

Pharmacokinetic parameters were established for enantiomers of the nonsteroidal anti‐inflammatory drug (NSAID) ketoprofen (KTP) administered as the racemic mixture at a dose of 2.2 mg/kg and as separate enantiomers, each at a dose of 1.1 mg/kg to a group of six horses (five mares and one gelding). A four‐period cross‐over study in a LPS‐induced model of acute synovitis was used. After administration of the racemic mixture S(+)KTP was the predominant enantiomer in plasma as well as in synovial fluid. Unidirectional inversion of R(–) to S(+)KTP was demonstrated but the inversion was less marked than previously reported. It is suggested that this reduction could be because of the influence of the inflammatory reaction on hepatic metabolism. The disposition of KTP enantiomers after administration of the racemic mixture was similar to those observed after administration of S(+) and R(–)KTP. The S(+) and R(–)KTP concentrations in synovial fluid were low and short lasting. After administration of R(–)KTP significant concentrations of the optical antipode were detected in synovial fluid.
The effect of intravenous administration of variable‐dose flumazenil after fixed‐dose ketamine and midazolam in healthy cats
Authors: ILKIW J. E. , FARVER T. B. , SUTER C. , MCNEAL D. , STEFFEY E. P.
Published: March 2003

Ilkiw, J. E., Farver, T. B., Suter, C., McNeal, D., Steffey, E. P. The effect of intravenous administration of variable‐dose flumazenil after fixed‐dose ketamine and midazolam in healthy cats. J. vet. Pharmacol. Therap.25, 181–188.

The effects of intravenous administration of variable‐dose flumazenil (0, 0.001, 0.005, 0.01, and 0.1 mg/kg) after ketamine (3 mg/kg) and midazolam (0.0 and 0.5 mg/kg) were studied in 18 healthy unmedicated cats from time of administration until full recovery. End‐points were chosen to determine whether flumazenil shortened the recovery period and/or modified behaviors previously identified and attributed to midazolam. Overall, flumazenil administration had little effect on recovery or behaviors. One minute after flumazenil administration, all cats were recumbent but a greater proportion of cats which received the highest dose assumed sternal recumbency with head up than any other group. Although not significant, those cats that received the highest flumazenil dose also had shorter mean times for each of the initial recovery stages (lateral recumbency with head up, sternal recumbency with head up and walking with ataxia) than any of the other treatment groups that received midazolam. For complete recovery, flumazenil did decrease the proportion of the cats that was sedated, but did not shorten the time to walking without ataxia. Based on this study, the administration of flumazenil in veterinary practice, at the doses studied, to shorten and/or improve the recovery from ketamine and midazolam in healthy cats cannot be recommended.
Pharmacokinetics and bioavailability of trimethoprim‐sulfamethoxazole in alpacas
Authors: Chakwenya J. , Lakritz J. , Tyler J. , Fales W. H. , James‐Kracke M. , Smith K. , Holle J.
Published: March 2003

The pharmacokinetics and bioavailability of trimethoprim‐sulfamethoxazole (TMP‐SMX) were studied in six healthy male‐castrate alpacas (Lama pacos) after intravenous (i.v.) or oral (p.o.) drug administration of 15 mg/kg TMP‐SMX using a crossover design with a 2‐week washout period. After 90 days one group (n = 3) was given a p.o. dose of 30 mg/kg TMP‐SMX and the other group (n = 3) was given a p.o. dose of 60 mg/kg TMP‐SMX. After i.v. administration of 15 mg/kg of TMP‐SMX the mean initial plasma concentration (C0) was 10.75 ± 2.12 μg/mL for trimethoprim (TMP) and 158.3 ± 189.3 μg/mL for sulfamethoxazole (SMX). Elimination half‐lives were 0.74 ± 0.1 h for TMP and 2.2 ± 0.6 h for SMX. The mean residence times were 1.45 ± 0.72 h for TMP and 2.8 ± 0.6 h for SMX. The areas under the respective concentration vs. time curves (AUC) were 2.49 ± 1.62 μg h/mL for TMP and 124 ± 60 μg h/mL for SMX. Total clearance (Clt) for TMP was 21.63 ± 9.85 and 1.90 ± 0.77 mL/min kg for SMX. The volume of distribution at steady state was 2.32 ± 1.15 L/kg for TMP and 0.35 ± 0.09 L/kg for SMX. After intragastric administration of 15, 30 and 60 mg/kg the peak concentration (Cmax) of SMX were 1.9 ± 0.8, 2.6 ± 0.4 and 2.8 ± 0.7 μg/mL, respectively. The AUC was 9.1 ± 5, 25.9 ± 3.3 and 39.1 ± 4.1 μg h/mL, respectively. Based upon these AUC values and correcting for dose, the respective bioavailabilities were 7.7, 10.5 and 7.94%. Trimethoprim was not detected in plasma after intragastric administration. These data demonstrate that therapeutic concentrations of TMP‐SMX are not achieved after p.o. administration to alpacas.
Effect of renal insufficiency on the pharmacokinetics and pharmacodynamics of benazepril in cats
Authors: King J. N. , Strehlau G. , Wernsing J. , Brown S. A.
Published: March 2003

The effect of renal insufficiency was studied on the pharmacokinetics (PK) and pharmacodynamics (PD) of the angiotensin‐converting enzyme (ACE) inhibitor benazepril in cats. The active metabolite of benazepril, benazeprilat, is eliminated principally (∼85%) via biliary excretion in cats. A total of 20 control animals and 32 cats with moderate renal insufficiency induced by partial nephrectomy were used. Assessments were made at steady state after treatment with placebo or benazepril (0.25–2 mg/kg) once daily for a minimum of 10 days. The PK endpoint was the AUC (0→24 h) of total plasma benazeprilat. The PD endpoints were systolic, diastolic and mean blood pressures (respectively SBP, DBP and MBP) measured by telemetry, and plasma ACE activity, assessed by an ex vivo assay. Renal function was assessed by glomerular filtration rate (GFR), measured by inulin clearance, and plasma creatinine concentrations (1/PCr). As compared with control animals, the renal insufficient cats had a 78% reduction in GFR (0.57 ± 0.41 mL/min kg), increased plasma creatinine (2.7 ± 1.0 mg/dL), urea (44.0 ± 11.9 mg/dL) and ACE activity, and moderately increased blood pressure (SBP 171.8 ± 5.1 mmHg) (all parameters P < 0.05). Renal insufficient cats receiving benazepril had significantly (P < 0.05) lower SBP, DBP, MBP and ACE, and higher GFR values as compared with placebo‐treated animals. There were no significant differences in SBP, DBP, MBP, benazeprilat or ACE values according to the degree of renal insufficiency in cats receiving benazepril. It is concluded that no dose adjustment of benazepril is necessary in cats with moderate renal insufficiency.
Pharmacokinetics and endometrial tissue concentrations of enrofloxacin and the metabolite ciprofloxacin after i.v. administration of enrofloxacin to mares
Authors: Papich M. G. , Van Camp S. D. , Cole J. A. , Whitacre M. D.
Published: March 2003

Enrofloxacin was administered i.v. to five adult mares at a dose of 5 mg/kg. After administration, blood and endometrial biopsy samples were collected at regular intervals for 24 h. The plasma and tissue samples were analyzed for enrofloxacin and the metabolite ciprofloxacin by high‐pressure liquid chromatography. In plasma, enrofloxacin had a terminal half‐life (t½), volume of distribution (area method), and systemic clearance of 6.7 ± 2.9 h, 1.9 ± 0.4 L/kg, and 3.7 ± 1.4 mL/kg/min, respectively. Ciprofloxacin had a maximum plasma concentration (Cmax) of 0.28 ± 0.09 μg/mL. In endometrial tissue, the enrofloxacinCmaxwas 1.7 ± 0.5 μg/g, and thet½was 7.8 ± 3.7 h. CiprofloxacinCmaxin tissues was 0.15 ± 0.04 μg/g and thet½was 5.2 ± 2.0 h. The tissue:plasma enrofloxacin concentration ratios (w/w:w/v) were 0.175 ± 0.08 and 0.47 ± 0.06 forCmaxandAUC, respectively. For ciprofloxacin, these values were 0.55 ± 0.13 and 0.58 ± 0.31, respectively. We concluded that plasma concentrations achieved after 5 mg/kg i.v. are high enough to meet surrogate markers for antibacterial activity (Cmax:MIC ratio, and AUC:MIC ratio) considered effective for most susceptible gram‐negative bacteria. Endometrial tissue concentrations taken from the mares after dosing showed that enrofloxacin and ciprofloxacin both penetrate this tissue adequately after systemic administration and would attain concentrations high enough in the tissue fluids to treat infections of the endometrium caused by susceptible bacteria.
Pharmacodynamics and enantioselective pharmacokinetics of racemic carprofen in the horse
Authors: Lees P. , Aliabadi F. S. , Landoni M. F.
Published: March 2003

Carprofen is a nonsteroidal anti‐inflammatory drug of the 2‐arylpropionate subclass. It contains a single chiral centre and exists in two enantiomeric forms. In this study rac‐carprofen, at two dosages, 0.7 and 4.0 mg/kg, and placebo were administered i.v. to six New Forest horses in a three period cross‐over study. The concentration–time profiles were established for R(–) and S(+)‐carprofen for plasma and both inflamed (exudate) and noninflamed (transudate) tissue cage fluids. R(–)‐carprofen was the predominant enantiomer in all three fluids, as indicated by plasma area under the curve (AUC) values for R(–) and S(+)‐carprofen of 117.4 and 22.6 μg h/mL (low dose carprofen) and 557.5 and 138.1 μg h/mL (high dose carprofen) respectively. Penetration of both enantiomers into exudate was slow and limited and passage into transudate was even lower. The pharmacodynamics of rac‐carprofen was investigated at both the molecular level and in terms of the ability to suppress components of the tissue cage inflammatory response. Low dose carprofen produced only moderate and transient inhibition of serum thromboxane (Tx)B2but failed to affect exudate prostaglandin (PG)E2concentrations, whilst suppression of exudate leukotriene (LT)B4and β‐glucuronidase was not significant. High dose carprofen produced greater and more persistent inhibition of serum TxB2and virtually abolished exudate PGE2synthesis. Some inhibition of LTB4and β‐glucuronidase in exudate was also obtained. At both dosages rac‐carprofen reduced the swelling produced by intradermal bradykinin injection but only high dose carprofen was anti‐inflammatory as indicated by suppression of temperature rise over exudate tissue cages and neither dose affected leucocyte numbers in exudate. When considered in conjunction with previous data on carprofen, the present findings indicate that carprofen is not a selective inhibitor of cyclooxygenase (COX) isoenzymes, COX‐1 and COX‐2 in the horse, although it may show some preference for COX‐2 inhibition. Because low dose carprofen, which is the clinically recommended dosage, produces minimal inhibition of COX, it is likely to achieve its therapeutic effects at least partially through other pathways, possibly including weak to moderate inhibition of 5‐lipoxygenase and of enzyme release. The good safety margin of carprofen in clinical use might also be explained by weak COX inhibition and by other actions at the molecular level.
Disposition of sodium salicylate, flunixin and meloxicam after intravenous administration in broiler chickens
Authors: Baert K. , De Backer P.
Published: March 2003

Three nonsteroidal anti‐inflammatory drugs (NSAIDs) [sodium salicylate, flunixin (FLU) and meloxicam (MEL)] were administered intravenously to broiler chickens. Plasma concentrations were determined by high‐performance liquid chromatography methods and pharmacokinetic parameters were calculated. After intravenous administration of sodium salicylate (50 mg/kg), FLU (1.1 mg/kg) and MEL (0.5 mg/kg), these drugs were eliminated from plasma with a mean half‐life of 04.04, 05.45 and 03.20 h, respectively. Apparent volumes of distribution (0.39, 0.08 and 0.12 L/kg, respectively) indicated that tissue distribution was limited for the three drugs. Total body clearance was 70 mL/h·kg for sodium salicylate and 10 and 25 mL/kg·h for FLU and MEL, respectively. Based on the pharmacokinetic parameters these NSAIDs may offer possibilities for treatment of various conditions in chickens.
Ribavirin monotherapy in patients with chronic hepatitis C: a retrospective study of 95 patients
Authors: Zoulim F. , Haem J. , Si Ahmed S. , Chossegros P. , Habersetzer F. , Chevallier M. , Bailly F. , Trépo C.
Published: March 2003

Ribavirin is a purine nucleoside that inhibits the replication of a variety of RNA viruses and was shown to have a transient efficacy in chronic hepatitis C during short‐term therapy. We have analysed retrospectively its efficacy in 95 patients with liver biopsy‐proven chronic hepatitis C. Patients received oral ribavirin (600–1200mg daily) for a mean duration of 11 months. Alanine aminotransferase (ALT) levels returned to normal values in 38 patients (40%) and decreased by more than 50% in 20 other patients (21%). HCV RNA clearance from serum was observed in seven patients (8%). The biochemical response rate was higher in patients with chronic hepatitis (54%) than in those with cirrhosis (24%) (P=0.003). Clearance of HCV RNA was observed in 10% of the patients with chronic hepatitis vs 4% of the patients with cirrhosis. In non‐responders to interferon (IFN) therapy, ALT levels returned to normal values in 11 (26%) and HCV RNA became negative in one (2%), as compared to 48% and 3%, respectively, in those contraindicated for IFN. In 17 patients in whom paired liver biopsy specimens were available, the histology activity index (HAI) improved in 12. Therapy was generally well tolerated although 11 patients had to stop therapy because of side‐effects, which were more common in cirrhotic patients. In conclusion, our results suggest that long‐term administration of ribavirin is well tolerated and may be beneficial in controlling the progression of chronic hepatitis C. This may represent an alternative therapy in patients who have contraindications for interferon therapy or as a palliative approach in non‐responders to IFN.