bluuebunny/crossref_metadata_2025 huggingface dataset:
Sequential activation of Rap1 and Rac1 small G proteins by PDGF locally at leading edges of NIH3T3 cells
Authors: Takahashi Motonori , Rikitake Yoshiyuki , Nagamatsu Yuichi , Hara Tetsuya , Ikeda Wataru , Hirata Ken‐ichi , Takai Yoshimi
Published: April 2008

Moving cells form protrusions, such as filopodia and lamellipodia, and focal complexes at leading edges, which eventually enhance cell movement. The Rho family small G proteins, Rac1, Cdc42 and RhoA, are involved in the formation of these leading edge structures. We investigated the role of another small G protein Rap1 in the platelet‐derived growth factor (PDGF)‐induced formation of leading edge structures and cell movement. Upon stimulation of NIH3T3 cells by PDGF, leading edge structures were formed and Necl‐5, integrin αVβ3, and PDGF receptor were accumulated at leading edges. Rap1, upstream regulators of Rap1 such as Crk and C3G, and a downstream effector RalGDS, were accumulated at peripheral ruffles over lamellipodia. Over‐expression of Rap1GAP, which inactivates Rap1, and knockdown of Rap1 inhibited the PDGF‐induced formation of leading edge structures, accumulation of these molecules, and cell movement. In addition, Rap1 activation subsequently induced accumulation of Rac1, Vav2 and PAK at peripheral ruffles, which was inhibited by Rap1GAP and knockdown of Rap1. These results indicate that Rap1, activated by PDGF, is recruited to leading edges and that Rac1 is thereby activated locally at peripheral ruffles. This process is pivotal for the PDGF‐induced formation of leading edge structures and cell movement.
Elevated activity of the oxidative and non‐oxidative pentose phosphate pathway in (pre)neoplastic lesions in rat liver
Authors: Frederiks Wilma M. , Vizan Pedro , Bosch Klazina S. , Vreeling‐Sindelárová Heleen , Boren Joan , Cascante Marta
Published: April 2008

(Pre)neoplastic lesions in livers of rats induced by diethylnitrosamine are characterized by elevated activity of the first irreversible enzyme of the oxidative branch of the pentose phosphate pathway (PPP), glucose‐6‐phosphate dehydrogenase (G6PD), for production of NADPH. In the present study, the activity of G6PD, and the other NADPH‐producing enzymes, phosphogluconate dehydrogenase (PGD), isocitrate dehydrogenase (ICD) and malate dehydrogenase (MD) was investigated in (pre)neoplastic lesions by metabolic mapping. Transketolase (TKT), the reversible rate‐limiting enzyme of the non‐oxidative branch of the PPP, mainly responsible for ribose production, was studied as well. Activity of G6PD in (pre)neoplastic lesions was highest, whereas activity of PGD and ICD was only 10% and of MD 5% of G6PD activity, respectively. Glucose‐6‐phosphate dehydrogenase activity in (pre)neoplastic lesions was increased 25 times compared with extralesional parenchyma, which was also the highest activity increase of the four NADPH‐producing dehydrogenases. Transketolase activity was 0.1% of G6PD activity in lesions and was increased 2.5‐fold as compared with normal parenchyma. Transketolase activity was localized by electron microscopy exclusively at membranes of granular endoplasmic reticulum in rat hepatoma cells where G6PD activity is localized as well. It is concluded that NADPH in (pre)neoplastic lesions is mainly produced by G6PD, whereas elevated TKT activity in (pre)neoplastic lesions is responsible for ribose formation with concomitant energy supply by glycolysis. The similar localization of G6PD and TKT activity suggests the channelling of substrates at this site to optimize the efficiency of NADPH and ribose synthesis.
Endocannabinoids, Blood Pressure and the Human Heart
Authors: Sarzani R.
Published: April 2008

The effects of exogenous and endogenous cannabinoids on the cardiovascular system have been the focus of extensive research. The direct and indirect effects of cannabinoids on heart and blood vessels depend upon experimental conditions, animal species, and, in humans, clinical background. Cannabinoids decrease blood pressure in hypertensive rodents primarily because of decrease cardiac contractility, leading researchers to postulate a role in the treatment of hypertension and cardiac hypertrophy. Rimonabant, the CB1 receptor blocker in clinical use in many countries, induced a marked and sustained increase in cardiac contractility and blood pressure in hypertensive rats but, on the contrary, contributed to decrease blood pressure in weight‐loss clinical trials especially in obese patients with hypertension.

In the midst of the obesity pandemic and from the cardiometabolic point of view, the overactivation of the endocannabinoid system present in intra‐abdominal obesity appears to be very harmful. Moreover, novel human findings suggest a relationship between CB1‐mediated overactive endocannabinoid system and nephrovascular damage. Overall, it appears that CB1 blockade in obese patients behaves as a ‘multiplier’ of the many beneficial effects of body weight loss induced by a hypocaloric diet and increased physical activity (the ‘lifestyle changes’ that are so difficult to start and maintain). Thus, the concept − based mostly on experimental results using in vitro or animal models − that CB1‐mediated endocannabinoid effects are beneficial for the cardiovascular system should be revised at least in obese patients.

The results of long‐term clinical trials such as the STRADIVARIUS and the CRESCENDO trials will tell whether the improvement in the cardiometabolic risk profile induced by Rimonabant translates into vascular changes, reducing the risk of myocardial infarction, stroke and cardiovascular death in patients with abdominal obesity. Time (and much more work) will tell us much more about cannabinoids and the human heart.
Interplay Between Endocannabinoids, Steroids and Cytokines in the Control of Human Reproduction
Authors: Battista N. , Pasquariello N. , Di Tommaso M. , Maccarrone M.
Published: April 2008

The use of marijuana, which today is the most used recreational drug, has been demonstrated to affect adversely reproduction. Marijuana smokers, both men and women, show impaired fertility, owing to defective signalling pathways, aberrant hormonal regulation, or wrong timing during embryo implantation. Anandamide (N‐arachidonoylethanolamine, AEA) and 2‐arachidonoylglycerol (2‐AG) mimic Δ9‐tetrahydrocannabinol (THC), the psychoactive principle ofCannabis sativa, by binding to both the brain‐type (CB1) and the spleen‐type (CB2) cannabinoid receptors. These ‘endocannabinoids’ exert several actions either in the central nervous system or in peripheral tissues, and are metabolised by specific enzymes that synthesise or hydrolyse them. In this review, we shall describe the elements that constitute the endocannabinod system (ECS), in order to put in a better perspective the role of this system in the control of human fertility, both in females and males. In addition, we shall discuss the interplay between ECS, sex hormones and cytokines, which generates an endocannabinoid−hormone−cytokine array critically involved in the control of human reproduction.
Endocannabinoids and Nutrition
Authors: Hansen H. S. , Artmann A.
Published: April 2008

The endocannabinoids anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) are bioactive lipids derived from the n‐6 family of polyunsaturated fatty acids that are essential fatty acids. Symptoms of essential fatty acid deficiency in rats – growth retardation, scaly skin, and increased transepidermal water loss – can mainly be attributed to lack of linoleic acid as a structural element of the epidermis. Arachidonic acid, however, also serve essential functions, particularly in cellular signalling via its precursor role for numerous oxygenated derivatives such as prostaglandins, leukotrienes, hepoxilins and other eicosanoids. Furthermore, arachidonic acid is also a structural part of endocannabinoids that have signalling functions in relation to modulation of neurotransmitter release, which might involve physiological and pathophysiological phenomena such as regulation of appetite, energy metabolism, pain perception, memory and learning. Furthermore, along with AEA formation other acylethanolamides are always formed – e.g., oleoylethanolamide (OEA), that can inhibit food intake, and palmitoylethanolamide, that is anti‐inflammatory – possibly through activation of peroxisome proliferator activated receptor α (PPAR α) and/or GPR119. As all these unsaturated fatty acids are ingested daily in smaller or larger amounts, one can ask whether different dietary fats can affect the levels of these fatty acids in the tissues and thereby the quantitative formation of these bioactive signalling molecules. Generally, in vivo arachidonic‐acid‐derived eicosanoid production can be increased and decreased by prolonged feeding with pharmacological levels of arachidonic acid and long‐chain (n‐3) fatty acids (fish oil), respectively. Changes in levels of these two fatty acids within the traditional human diet hardly affects the eicosanoid production, however. Moreover, preliminary data suggest that dietary intake of arachidonic acid and fish oil also doesn’t easily affect endocannabinoid formation; however, dietary fat in terms of saturated, polyunsaturated and monounsaturated seems to affect tissue levels of AEA, 2‐AG and OEA.
Drug residues in food animals II. Plasma and tissue kinetics of oxytetracycline in young cross‐bred swine
Authors: MERCER H. DWIGHT , TESKE RICHARD H. , LONG PATRICIA E. , SHOWALTER DAVID H.
Published: April 2008

Tissue distribution and elimination kinetics of oxytetracycline in sixteen organs and body fluids were determined in young pigs following intravenous and oral administration. Seventeen non‐fasted pigs, 8–10 weeks of age, weight range 16.4–34.5 kg were dosed intravenously at a dose rate of 11 mg/kg bodyweight. An additional seventeen weaning pigs, 12–14 weeks of age, weight range 27.2–36.3 kg were dosed orally at a dose rate of 48–65 mg/kg bodyweight. Oxytetracycline was rapidly distributed (half‐life, 6.71 ± 1.13 min) in swine. The mean volume of distribution was 1.26 ± 0.18 l/kg and overall body clearance was 3.82 ± 0.59 ml/kg/min. The elimination half‐life of oxytetracycline in pigs was 3.87 ± 0.62 h, which is shorter than has been observed in other domestic animal species. Oxytetracycline became rapidly and efficiently involved in enterohepatic cycling, with as much as 70% of a total intravenous dose being available for reabsorption from the gastrointestinal tract within 1 h after administration. This high degree of enterohepatic recycling prolonged the half‐life, and the large amount of drug that entered the enteric tract contributed to the high volumes of distribution and high k12/k21 ratios. The excellent tissue penetration of this drug further contributed to the high volume of distribution and high k12/k21 ratios obtained. Relationships between plasma and tissue depletion for several major edible organs were found to be statistically significant. Blood plasma is proposed as a body fluid for monitoring oxytetracycline tissue residues.
Experimental production of porcine gastroesophageal ulcers by betazole and reserpine
Authors: KOKUE EI‐ICHI , NAKAMURA TAKASHI , HAYAMA TOYOAKI
Published: April 2008

The ulcerogenic and secretogenic properties of betazole, (an H2 agonist), and/or reserpine on pig stomachs were studied. (1) Betazole (50 mg/body) and reserpine (0.02 mg/kg) were successively injected (i.m.) for 5–10 days into starved animals. Gastroesophageal ulcers, pathologically similar to naturally occurring ulcers were observed in all pigs (10/10), whether a nutrient solution (5% glucose, 1 litre/day) was supplied or not. In the starved pigs given either betazole or reserpine, only a small ulcer or erosion was observed. (2) In four pigs which were given commercial mash at a rate of 3% of body weight per day and killed on the 6th or 10th day of successive injections of both drugs, the incidence of ulcers was 2/4. (3) The gastric secretogenic effect of betazole and/or reserpine was confirmed in pigs with Heidenhain gastric pouches. (4) From these data, a new method for the experimental induction of pig gastroesophageal ulcers, by means of simultaneous injections of betazole and reserpine for 5 days under the nutrient (glucose solution) drinking condition, is proposed. The authors consider that this method may be superior to the repository histamine method, with respect to the absence of adverse effects, practical convenience and pathological and etiological similarities with naturally occurring ulcers.
Drug residues in food animals. III. Plasma and tissue kinetics of potassium penicillin G in young cross‐bred swine
Authors: MERCER H. DWIGHT , TESKE RICHARD H. , LONG PATRICIA E. , SIIOWALTER DAVID II. , BRYANT HENRY H.
Published: April 2008

Twenty‐two young cross‐bred swine were treated either intravenously or orally with potassium penicillin G. The pharmacokinetics of penicillin G were determined in plasma and tissues. The plasma half‐life of penicillin G in swine was found to be 19.45±1.69 min, and the distribution and elimination kinetics were found to fit a classical two‐compartment model. The volume of distribution was found to be 0.53±0.12 1/kg, and the body clearance was found to be 19.06±5.06 ml/min/kg which exceeded the effective renal plasma flow of 16.50±2.73 ml/min/kg, suggesting that the drug was eliminated both by tubular excretion and glomerular filtration. The elimination rate constants (Beta) for the major organs were as follows: muscle, 0.00343 min‐1; lung, 0.0310 min‐1; fat, 0.0394 min‐1; and kidney, 0.0213 min‐1, which compared favorably with the elimination rate constant found in plasma (0.0320 min‐1). These values were found to be significantly similar at the level of P < 0.005 in muscle, spleen and fat, and at a level of P < 0.025 in lung tissue. The data indicates that blood plasma would be a satisfactory body fluid for estimating this drug in tissue.
5‐Hydroxytryptamine potentiates contraction mediated by the intramural cholinergic nerve in the longitudinal smooth muscle of the ruminant forestomach
Authors: TANEIKE T.
Published: April 2008

The effects of 5‐hydroxytryptamine (5‐HT) on the longitudinal smooth muscle from the rumen and reticulum of the bovine forestomach were investigated. 5‐HT (0.25–490 μM) caused a contraction and a relaxation of the ruminal strips while it produced only an excitatory effect on the reticular strips. These effects were not affected by tetrodotoxin, hexamethonium, atropine or morphine, but were blocked by methysergide, LSD‐25 or phenoxybenzamine. 5‐HT potentiated the contraction evoked by stimulation of the intramural cholinergic nerves but did not show any effect on the relaxation produced by the non‐adrenergic inhibitory nerves' excitation. The 5‐HT‐induced potentiation was not affected by morphine, LSD‐25, methysergide and hexamethonium or high concentration of nicotine. Nicotine and dimethylphenylpiperazinium also caused a transient augmentation of the nerve‐mediated contraction, but these effects were abolished by the competitive ganglionic blockers. The evoked contraction was depressed in high‐Mg2+ solution, but this depression was antagonized partly by 5‐HT. The affinity of the cholinomimetics to post‐synaptic muscarinic receptor was not affected by 5‐HT. It is concluded that contractions or relaxations of bovine forestomach strips induced by 5‐HT are mediated through activation of D‐receptors in the smooth muscle, and the 5‐HT‐induced potentiation of the evoked contraction may be elicited through presynaptic neural effects of 5‐HT on the cholinergic nerves.
A computer method for the calculation of pharmacokinetic parameters after repetitive drug administration, and its use in calculations of kinetic parameters of sulphadimethoxine in pigs and rabbits
Authors: LADEFOGED OLE , CHRISTIANSEN SVEND E.
Published: April 2008

A computer method for calculation of the pharmacokinetic parameters of drugs after multiple dosing is described. It is shown that the program can be used to calculate the pharmacokinetic parameters of sulphadimethoxine in pigs and rabbits. The program can be used in calculations of kinetic parameters even in cases where few blood samples are taken. This method for the calculation of pharmacokinetic parameters after repetitive dosing as a new approach in an endeavour to obtain more useful pharmacokinetic parameters is discussed.
Effect of ingesta on systemic availability of chloramphenicol from two oral preparations in cats
Authors: WATSON A. D. J.
Published: April 2008

On five separate occasions, five adult cats were dosed orally with 100 mg chloramphenicol tablets or chloramphenicol palmitate suspension. Each preparation was given once when the cats were fasted and once when fed ad lib. In addition, fasted cats were given the tablet preparation on one occasion with 10 ml water orally immediately afterwards. Chloramphenicol concentrations were determined at intervals after dosing, and all urine passed in 24 h after dosing was collected for chloramphenicol assay. The initial plasma antibiotic concentrations were lower with chloramphenicol palmitate suspension than with chloramphenicol tablets, and the bioavailability of chloramphenicol from the palmitate ester was especially poor in starved cats. Chloramphenicol palmitate may thus be undesirable for antimicrobial therapy in inappetent cats. Food and fluid did not appear to influence the availability of chloramphenicol from the tablet preparation, although effects on plasma drug concentrations within 1.5 h of dosing would have been missed in this study. A relatively large proportion of an oral dose of chloramphenicol is excreted unchanged in feline urine. Because of the potential toxicity of the drug, chloramphenicol dose rates should be restricted in cats with renal insufficiency or another antibiotic used.
Some physiological and biochemical effects of the intravenous administration of five different electrolyte solutions in the dog
Authors: ROSE R. J.
Published: April 2008

Some physiological effects of the intravenous administration of five different commercial electrolyte solutions were studied in healthy conscious dogs. Measurements were taken before, during and up to 3 h after fluid administration. The measurements included temperature, heart rate, respiratory rate, systolic and diastolic arterial pressure, central venous pressure, pO2, pCO2, pH, packed cell volume, haemoglobin, total plasma protein, sodium, potassium, chloride, bicarbonate, base excess and creatinine. There were no significant changes in temperature, respiratory rate, systolic pressure, pO2 or pCO2. All dogs showed a similar rise in central venous pressure and a fall in packed cell volume, haemoglobin and total plasma protein in response to the fluid administration. Two saline solutions produced a metabolic acidosis, a fall in plasma potassium values and a rise in chloride. Administration of multi‐electrolyte solutions resulted in the least disturbance in acid‐base and electrolyte balance.
Plasma levels of sulphamethazine in the horse after spontaneous oral uptake
Authors: MEIER H. P. , TSCHUDI P. , GERBER H.
Published: April 2008

Ten adult horses were fed 6.5 mg/kg sodium‐sulphamethazine with the grain ration at 12 h intervals for 8 days. The mean minimal plasma concentration approached 75% of that which can be expected from published figures for the half time and the plasma binding constants, had the drug been given intravenously. Compared to an intravenous regime the plasma concentration oscillations were very much attenuated and peak concentrations shifted relative to the time of administration as predicted by theoretical considerations for repository drug administration.
Cerebral dopamine, apomorphine and oral activity in the neonatal pig
Authors: FRY J. P. , SHARMAN D. F. , STEPHENS D. B.
Published: April 2008

Neonatal piglets in which oral stimulation associated with feeding was reduced by intragastric tube feeding displayed an increase in stereotyped snout rubbing, licking and chewing behaviour. An investigation of a possible neurochemical basis for this behaviour was made by using sensitive radioenzymatic and micro‐fluorimetric assays to estimate the concentrations of the catecholamines and of the dopamine metabolites homovanillic acid (HVA) and 3,4‐dihydroxyphenyl‐acetic acid (DOPAC) in different brain regions. These observations revealed that the increased non‐nutritive oral activity of such piglets did not appear to be caused by an increased release of dopamine in the brain, since it was not associated with increases in the concentrations of the acidic metabolites of dopamine in either the caudate nucleus, the putamen, the nucleus accumbens, the olfactory tubercle, the hypothalamus, or the substantia nigra. The only neurochemical changes observed were small decreases in the concentration of HVA in the putamen and the nucleus accumbens. A lack of effect on catecholamine concentrations in any of the six brain regions examined suggested that the environmental manipulation caused no changes in the development of catecholamine‐containing nerve endings.

Subcutaneous injection of apomorphine was found to increase the non‐nutritive oral activity of piglets. Apparent conditioning effects of the environment on apomorphine‐induced stereotyped behaviour however, prevented any satisfactory testing of possible changes in cerebral dopamine receptor sensitivity following reduced oral stimulation.
Effects of chloramphenicol on the development of immune responses to canine distemper virus in Beagle pups
Authors: NARA P. L. , DAVIS L. E. , LAUERMAN L. H. , COYLE‐DENNIS JANICE E. , PAUL J.
Published: April 2008

The effect of oral chloramphenicol (CHPC) on the development of immune responses to canine distemper virus (CDV) in Beagle pups was studied. Dogs were treated with CHPC for 14 days at a dose of 50 mg/kg, three times a day. Hematologic changes in CHPC‐treated dogs included: polychromasia, anisocytosis, and target cell formation of red blood cells concurrent with vacuolation of lymphocytes and basophilic granule formation in neutrophils. Dogs given this therapy showed normal in vivo and in vitro immune responses after CDV vaccination and survived a virulent CDV challenge, whereas untreated, unvaccinated dogs became ill or died after challenge exposure. The results of this study indicate that CHPC therapy does not interfere with either the prechallenge immune response to attenuated viral antigen or the efficient immune mechanisms invoked during virulent virus challenge.
Anti‐convulsant activity of diazepam and clonidine on metaldehyde‐induced seizures in mice: effects on brain γ‐amino butyric acid concentrations and monoamine oxidase activity
Authors: HOMEIDA A. M. , COOKE R. G.
Published: April 2008

Metaldehyde when administered orally to mice at a dose of 1 g kg‐1 produced convulsions and death within 2 h. Brain concentrations of γ‐aminobutyric acid (GABA) were significantly reduced and monoamine oxidase (MAO) activity significantly increased in these animals relative to controls. Treatment with either intraperitoneal diazepam or clonidine 20 min after administration of metaldehyde delayed the onset of toxic symptoms and reduced the mortality rate. In those mice which survived longer than 5 h, brain concentrations of GABA, though still not restored to control values, were significantly higher than those in the mice which died. Clonidine, unlike diazepam, also inhibited the increase in brain MAO activity.
Disposition of ampicillin administered intravenously and intratracheally to young calves
Authors: LONG PATRICIA E. , GUARNIERI JOSEPH A. , HERBST DORIS V. , TESKE RICHARD H.
Published: April 2008

Long, P.E., Guarnieri, J.A., Herbst, D.V. & Teske, R.H. Disposition of ampicillin administered intravenously and intratracheally to young calves. J. vet. Pharmacol. Therap. 6, 273 279.

The profile of the blood concentration of ampicillin vs time was compared in 24 calves after ampicillin administration (10 mg/kg body weight) by the intratracheal (i.t.) and the intravenous (i.v.) routes in a crossover study. In a subsequent study, 12 of the calves were given ampicillin i.v. and 12 were given ampicillin i.t.; at 15 min and 2 h after drug administration, the calves were killed and lungs, kidneys, liver, urine and plasma were collected for ampicillin assay. The mean ampicillin concentration in blood after i.v. treatment was significantly (P<0.01) higher than after i.t. treatment. The mean ampicillin level in lungs after i.t. treatment was significantly higher than the level after i.v. treatment, but concentrations in kidneys, liver, urine and plasma after i.v. treatment were higher (but not significantly) than those after i.t. treatment.
The absorption of anabolic agents from pellets implanted at the base of the ear in sheep
Authors: HARRISON LYNNE P. , HEITZMAN R.J. , SANSOM B. F.
Published: April 2008

Twenty wether sheep were allocated to seven groups and received implants near the base of one ear with pellets containing: for group 1, (OE) 20 mg oestradiol‐17β alone; for group 2, (TBA/OE) 20 mg oestradiol‐17β intimately mixed with 140 mg trenbolone acetate; for group 3, (T/OE) 20 mg oestradiol‐17β mixed with 200 mg testosterone; for group 4, (P/OE) 20 mg oestradiol‐17β mixed with 200 mg progesterone; for group 5, (TBA/OE2) 20 mg oestradiol‐17β in one ear and 140 mg trenbolone in the other ear; for group 6, (TBA/OE1) 20 mg oestra‐diol‐17β and 140 mg trenbolone as separate pellets in one ear; group 7 sheep received implants of carrier material and served as controls. The concentrations of steroids were measured in plasma samples collected from both jugular veins during the 16‐week period after implantation. The absorption of oestradiol‐1 7β was slower and more sustained from the pellets in which it was mixed with other steroids (groups 2, 3 and 4) than from the pellets containing oestradiol‐17β alone (groups 1, 5 and 6).

The concentration of each steroid in plasma was higher in the jugular vein ipsilateral to the implant than in the vein on the opposite side. The difference between the concentrations in the two veins was used to calculate the biological half‐lives of the steroids; for oestradiol‐17β and trenbolone the mean values ranged from 1.8 to 6.8 min and from 3 to 4 min, respectively, and for testosterone and progesterone the mean values were 4.7 and 3.5 min, respectively.
Placental transfer and renal clearance of sulphamethoxazole and its metabolite N4‐acetylsulphamethoxazole in a pregnant ewe
Authors: VREE TOM B. , REEKERS‐KETTING JOKE J. , NOUWS JAC F. M. , ARTS THEO H. M.
Published: April 2008

Sulphamethoxazole and its metabolite, N4‐acetylsulphamethoxazole, were shown to cross the placenta of a pregnant ewe. The plasma concentration of N4‐acetylsulphamethoxazole increased in the foetus due to the limited elimination properties of the immature kidney. The amniotic fluid concentration of sulphamethoxazole and N4‐acetylsulphamethoxazole were low, amounting to 2.0 and 0.46μg/ml respectively. Protein binding of the sulphonamides was slightly higher in the foetus than in the ewe.
Effects of erythromycin‐inactivating Lactobacillus crop flora on blood levels of erythromycin given orally to chicks
Authors: DEVRIESE L. A. , DUTTA G. N.
Published: April 2008

Germ‐free, day‐old chickens were colonized with a Lactobacillus fermentum strain isolated from poultry which was able to inactivate in vitro erythromycin and other macrolide and lincosamide antibiotics. Similar control chickens were colonized with a non‐degrading L. fermentum strain. Only in chickens colonized with the non‐degrading strain were blood levels considered to be therapeutically active achieved with erythromycin in the drinking water.

Five groups of broiler chickens of different age originating from three farms all possessed an erythromycin‐degrading crop flora. In none of these were therapeutic blood levels attained when erythromycin was given in the drinking water.
Interaction of Fasciola hepatica with albendazole and its metabolites
Authors: FETTERER R. H. , REW R. S.
Published: April 2008

Adult Fasciola hepatica recovered from sheep 12 and 24 h after a single oral dose of albendazole (20 mg/kg) contained significant amounts of two oxidized metabolites of albendazole (ABZ), a sulphoxide (SX) and a sulphone (SO), but not ABZ. Flukes incubated in vitro with 10 μM SX or SO contained these metabolites at a level two to three times the level observed in flukes recovered from sheep 24 h after a curative oral dose of ABZ. The concentration of ABZ in flukes was 10‐fold greater than either SX or SO after a 24 h in vitro incubation in 10 μM of the respective drug. Flukes exposed to ABZ in vitro contained twofold higher SX levels than SX‐treated flukes due to a combination of spontaneous oxidation in media and fluke‐mediated oxidation of ABZ. Measurement of end‐products of glucose metabolism following 24 h incubation in 10 μM of either ABZ, SX or SO did not show a significant difference between treated and untreated flukes.
Preliminary pharmacological characterization of ovine mesenteric vasculature
Authors: MIRBAHAR K. B. , EYRE P.
Published: April 2008

Spirally cut strips of ovine mesenteric vein and artery were studied in isolated organ baths. No qualitative differences were observed in the autonomic and auta‐coid reactivity of these blood vessels. Both arterial and venous preparations responded in a dose‐related manner to 5HT < adrenaline < phenylephrine < histamine. The responses of venous and arterial strips to 5HT were antagonized by methysergide while mepyramine inhibited histamine‐induced contractions. Phentolamine competitively inhibited adrenaline on arteries. Vascular preparations, incubated with mepyramine (2 × 10‐7 M) and contracted half‐maximally with 5HT, responded with relaxations to the higher doses of histamine. Specific H2‐agonists, impromidine and dimaprit also caused relaxations of half‐maximally contracted venous and arterial strips. Impromidine was approximately 500‐5000 times more potent than histamine and dimaprit. Trimetaquinol effectively relaxed both venous and arterial preparations while isoproterenol had either no effect or produced weak contractions/relaxations. This investigation suggested the presence of (i) both excitatory and inhibitory receptors for histamine, (ii) D‐tryptaminergic receptors mediating contractile effects of 5HT, and (iii) a predominance of α‐adren‐ergic receptors, in the mesenteric vasculature of sheep.
Gastro‐intestinal motor disturbances induced by lysine‐acetylsalicylate treatment in sheep
Authors: HONDE C. , BUÉNO L.
Published: April 2008

The effects of intravenous (i.v.), intramuscular (i.m.) and oral administration of lysine‐acetylsalicylate (Lys‐ASA) on gastro‐intestinal motility were investigated in sheep using electromyography. A dose of 20 mg/kg Lys‐ASA intravenously reduced the frequency of reticular contractions for 86 ± 18 min, produced abomasal hypomotility and caused a disruption of the cyclical pattern of intestinal motility for at least 120 min. The frequency of reticular contractions measured from 20 to 30 min after Lys‐ASA administration was negatively correlated (ß= 0.97; PΔ0.01) to the log of the dose used for doses varying from 10 to 40 mg/kg. Similar effects were observed with intramuscular and oral dose rates of 40 and 80 mg/kg, respectively. Previous i.v. administration of phentolamine (0.1 mg/kg) or tolazoline (2 mg/kg) abolished the effects of Lys‐ASA (20 mg/kg) administered intravenously on both reticular contractions and abomaso‐intestinal motility.

It was concluded that Lys‐ASA administered at therapeutic doses in sheep produced gastro‐intestinal motor disturbances and that α‐and α2‐adrenergic antagonists are able to block them.
Pharmacokinetics of sulfamethazine in male, female and castrated male swine
Authors: DUFFEE NICOLE E. , BEVILL RICHARD F. , THURMON JOHN C. , LUTHER HERBERT G. , NELSON DALE E. , HACKER FRANCES E.
Published: April 2008

The concentration of sulfamethazine in plasma and sulfamethazine and its metabolites in urine were compared in male, female and castrated male swine. A surgical technique for placement of catheters in the urinary bladder was used to facilitate the collection of urine in males and castrated males. The elimination rate of sulfamethazine from plasma and the excretion of parent drug and metabolites into urine did not differ significantly among females, males and castrated male swine.
A health index to evaluate clinically a ß‐hemolytic streptococcal infectious disease model in the horse
Authors: POWERS J. D. , POWERS T. E. , VARMA K. J. , GABEL A. A. , SPURLOCK S. L.
Published: April 2008

Quantification of the clinical manifestations of a disease has been a serious problem particularly as related to clinical trials or drug efficacy studies. Historically, this quantification has been limited to categorizing each patient into one of three or four groups, e.g. worse, no improvement, improved. This problem becomes serious when an investigation utilizes an experimentally induced animal disease model.

A health index, which quantifies the clinical state of horses which have an experimentally induced ß‐hemolytic streptococcal infection, is described. Aspects of experimental design and statistical analysis are also discussed in relationship to the use of the index for drug efficacy studies.
Milk fever and calcium metabolism
Authors: ALLEN W.M. , SANSOM B.F.
Published: April 2008

Allen, W.M. & Sansoni, B.F. Milk lever and calcium metabolism. J. vet. Pharmacol. Therap. 8, 19–29.

W.M. Allen, Department of Functional Pathology, AFRC Institute for Research on Animal Diseases, Campion, Newbury, Berkshire RC16 ONN, England.
Pharmacological evidence for the involvement of alpha‐2 adrenoceptors in the sedative effect of detomidine, a novel sedative‐analgesic
Authors: VIRTANEN R. , RUSKOAHO H. , NYMAN L.
Published: April 2008

Virtanen, R., Ruskoaho, H. & Nyman, L. Pharmacological evidence for the involvement of alpha‐2 adrenoceptors in the sedative effect of detomidine, a novel sedative‐analgesic. J. vet. Pharmacol. Therap. 8, 30–37.

The sedative effect and mechanism of action of a novel imidazole derivative, detomidine, were studied in laboratory animals. Three methods were used to quantify drug‐induced sedation: (i) decrease in spontaneous activity of mice; (ii) increase in barbiturate induced anaesthesia lime in mice; (iii) loss of righting reflex in chicks. Clonidine and xylazine were included in the studies for comparison. The sedative potency of detomidine was shown to be approximately equal to that of clonidine and much higher than that of xylazine. In all tests, the sedative effect of detomidine was inhibited by antagonists of alpha‐2 adrenoceptors (yohimbine, rauwolscine and idazoxan) but not by alpha‐1 antagonists (prazosin, corynanthine). Furthermore, an ex vivo receptor binding study in the rat showed that detomidine‐induced decrease in spontaneous activity was significantly correlated to [3Hc]onidine but not to [3H]prazosin displacement in brain membranes. These results show that detomidine has potent sedative effects in mice, rats and chicks, and suggest that this action is mediated through stimulation of alpha‐2 adrenoceptors.

Raima Virtanen, Fartnos Group Ltd, Research Centre, P.O. Box 425, SF‐20101 Turku 10, Finland.
An increase in metabolic acidosis induced by chloralose anaesthesia in dogs after sino‐vagal denervation
Authors: SHUKLA R. , SHUKLA S. B.
Published: April 2008

Shukla, R. & Shukla, S.B. An increase in metabolic acidosis induced by chloralose anaesthesia in dogs after sino‐vagal denervation. J. vet. Pharmacol, Therap. 8, 71–75.

Chloralose anaesthesia in dogs increased the H+ ion concentration significantly from its reference values. The findings favoured thai it was most probably engendered through anaesthetic depression of neural centre regulating H+ ion concentration of blood. Such increase was largely contributed by a significant increase in its metabolic fraction. A further increase of metabolic fraction after separate and joint section of carotid sinus nerves and vagi indicated their holding effect. The section of carotid sinus nerve induced greater increase in this fraction than that of vagi. It indicated differences between the two nerves in their metabolic fraction controlling influence. Hvperpnoea after vagi section decreased the carbonic acid fraction, whereas marginally reduced ventilation alter carotid sinus nerve section increased the carbonic acid fraction. Moreover, the overall changes in H+ ion concentration followed the changes in carbonic acid fraction. The present study suggested that the depressive effect of chloralose anaesthesia on H+ ion controlling neural mechanism could be largely determined by degree of increase in its metabolic fraction.

R. Shukla, Department of Physiology, Institute of Medical Sciences, B.H.U. Varanasi‐221005, India.
Pharmacokinetic studies of theophylline in horses
Authors: INGVAST‐LARSSON C. , PAALZOW G. , PAALZOW L. , OTTOSSON T. , LINDHOLM A. , APPELGREN L. E.
Published: April 2008

Ingvast‐Larsson, C, Paalzow, G., Paalzow, L., Ottosson, T., Lindholm, A. & Appelgren, L.E. Pharmacokinetic studies of theophylline in horses. J. vet. Pharmacol. Therap. 8, 76–81.

The pharmacokinetics of theophylline were determined in Standardised trotters after single intravenous and oral administration. A bi‐exponential equation was fitted to the intravenous data and a tri‐exponential equation to the oral data. The biological half‐life of theophylline was found to be 14.8 h, the volume of distribution 1.02 l/kg and the total plasma clearance 0.86 ml/kg/min. The oral absorption of the drug was complete (bioavailability 108%) and rapid (absorption half‐life 0.4 h).

Professor L. E. Appelgren, Department of Pharmacology and Toxicology, Biomedicum. Box 573, S‐75J 23 X'ppsala, Sweden.
The pharmacokinetic behaviour of chloramphenicol in liver‐damaged mini‐pigs
Authors: KROKER R.
Published: April 2008

Koker, R. The pharmacokinetic behaviour of chloramphenicol in liver‐damaged mini‐pigs. J. vet. Pharmacol. Therap. 8, 82–87.

Using mini‐pigs with an indwelling vascular catheter, the pharmacokinetics of chloramphenicol were investigated in healthy and liver‐damaged animals. The liver damage was induced by thioacetamide and its degree was estimated by measuring the level of bile acids in serum. Employing a two‐compartment open model for analysing the time‐dependent course of the chloramphenicol concentration in serum, it was shown that in liver‐damaged animals the elimination half‐time was almost doubled as a result of reduced total body clearance. The consequences of liver damage for withdrawal limes and dosage schedules are discussed.

R. Kroker, Federal Health Office. Institute for Veterinary Medicine, 1000 Berlin 33. Germany.
Pharmacokinetics of pentobarbital and thiamylal as combined anesthetics in sheep
Authors: SHORT CHARLES R. , KAPPEL LEONARD C. , RUHR LAWRENCE P. , BAGGOT J. DESMOND
Published: April 2008

Short, C.R., Kappel, L.C., Ruhr, L.P. & Baggot, J.D. Pharmacokinetics of phenobarbital and thiamylal as combined anesthetics in sheep. J. vet. Pharmacol. Therap. 8, 234–245.

This study was performed to investigate the possible mechanisms underlying prolongation of anesthesia times in sheep caused by the sequential administration of thiamylal and pentobarbital. Sodium thiamylal was injected as an intravenous bolus dose (13.2 mg/kg) followed in 7 min by sodium pentobarbital (14.3 mg/kg) by the same route to seven sheep. Separate studies were conducted for each of the two drugs administered separately to the same animals at the same doses. Mean anesthesia times (to the return of the palpebral reflex) were 7.89 min (thiamylal), 5.39 min (pentobarbital) and 34.1 min (the sequential combination). The kinetic parameters Vd(area), Vd(ss), t1/2ß, and ClB for either drug were not affected by the other when given in combination. The t1/2α was shorter, and the Vc was smaller, for pentobarbital when administered with thiamylal, while there were no changes in thiamylal disposition for the combination regimen. Computer‐generated curves, associated with the two‐compartment open model showing the fraction of dose in each compartment as a function of time, illustrated that pentobarbital rapidly achieved higher concentrations in the peripheral compartment after prior thiamylal administration. Protein‐binding studies showed that this could not be attributed to displacement of pentobarbital from plasma albumin by thiamylal. Calculation of total and free drug concentrations at the time of awakening showed that, when the drugs were combined, the concentration of each drug was less than half of that observed at awakening when they were studied separately. It can be concluded that the prolonged sleeping times associated with the sequential combination of the two agents were not due to an alteration in kinetic parameters of either drug caused by the other, but rather to an additive effect of the subanesthetic concentrations of the two drugs when combined. The fact that sleeping times were supra‐additive is attributed to a shift of awakening time from the distribution (α) phase, when given independently, to the elimination (ß) phase when administered in combination.

Charles R. Short, Department of Veterinary Physiology, Pharmacology and Toxicology, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana 70803, U.S.A.
Immediate and long‐term effects of halothane anesthesia on equine platelet function
Authors: KELLY A. B. , STEFFEY E. P. , McNEAL D. , WILLITS N.
Published: April 2008

Kelly, A.B., Steffey, E.P., McNeal, D. & Willits, N. Immediate and long‐term effects of halothane anesthesia on equine platelet function. J. vet. Pharmacol. Therap. 8, 284–289.

The acute and long‐term quantitative and qualitative effects of halothane anesthesia on equine platelet performance were studied in fourteen horses. Horses were anesthetized with only halothane in O2 for about 8.0 MAC* hours. Platelet numbers declined during the anesthetic period but returned to normal within 24 h. Platelet aggregation was significantly diminished during the anesthetic period and for up to 4 days after anesthesia. A period of hyperaggregability occurred at the 7th day.

Dr A. B. Kelly, Department of Surgery, School of Veterinary Medicine, University of California, Davis, CA 95616, U.S.A.
Central and peripheral serotonergic control of forestomach motility in sheep
Authors: SORRAING JEAN‐MARC , FIORAMONTI JEAN , BUÉNO LIONEL
Published: April 2008

Sorraing, J.‐M., Fioramonti, J. & Bueno, L. Central and peripheral serotonergic control of forestomach motility in sheep. J. vet. Pharmacol. Therap. 8, 312–319.

Participation of tryptaminergic receptors in the control of forestomach motility was investigated in conscious sheep using strain‐gauges and chronically implanted electrodes. Two hours after feeding the sheep, serotonin (5‐HT) was infused into the jugular vein (i.v.), or the carotid artery (i.e.), or into the lateral cerebral ventricles (i.e.v.), over a 10‐tnin period. An i.v. dose of 16 μg/kg/min abolished the cyclic propagated contractions throughout the forestomach, increased ruminoreticular tone, and induced simultaneous contractions of all the parts of the rumen. A dose of 1.6 μg/kg/min i.c. or i.v. 5‐HT inhibited phasic contractions.

The effects of 5‐HT were blocked completely by i.c.v. administration of methysergide (20 μg/kg) and imipramine (200 μg/kg), and blocked partially by naloxone (25 μg/kg), but unaffected by atropine (50 μg/kg).

The inhibitory effects of i.v. 5‐HT were antagonized by methysergide (200 μg/kg, i.v.) but unaffected by imipramine (2 mg/kg, i.v.) and atropine (250 μg/kg, i.v.). Only the i.v. administration of methysergide blocked the inhibition induced by i.c. infusion (1.6 μg/kg/min) of 5‐HT.

It is suggested that 5‐HT exhibits an inhibitory control on forestomach phasic contractions through hypothalamic and bulbar 5‐HT receptors, and exerts peripheral excitatory effects on the tone of the rumen wall.

Dr L. Buéno, Station de Pharmacologie‐Toxicologie, INRA, 180 chemin de Tournefeuille, 31300 Toulouse, France.
Absorption and pharmacokinetics of phenylbutazone in Welsh Mountain ponies
Authors: MAITHO T. E. , LEES P. , TAYLOR J. B.
Published: April 2008

The disposition of phenylbutazone (4.4 mg/kg), administered intravenously to six Welsh Mountain ponies, was described by a two‐compartment open model. Pharmacokinetic parameters were not significantly different after morning dosing in comparison with afternoon dosing. When phenylbutazone (4.4 mg/kg) was administered orally to the same ponies, marked variations in time to peak concentrations were produced with different feeding schedules. When access to hay was permitted before and after dosing, the mean time to peak concentration was 13.2 ± 1.2 h and double peaks in the plasma concentration–time curve were common. Double peaks were also encountered when phenylbutazone was given to ponies deprived of food prior to, and allowed access to hay after, dosing. In this circumstance, mean times to peak concentration were much shorter (3.8 ± 1.3 h after morning dosing and 5.3 ± 1.5 h followed afternoon dosing). Absorption was more regular and double peaks were less apparent when food was withheld both before and after dosing. In order to explain these findings, it is tentatively postulated that, whereas some of the administered dose of phenylbutazone may be absorbed quickly, some may become adsorbed on to the feed and subsequently released by fermentative digestion in the large intestine and/or caecum. The consequences of delayed absorption in fed animals for toxicity and clinical efficacy, and for the use of phenylbutazone in equestrian sports, are considered. Delayed absorption in ponies given access to hay was not accompanied by a significant reduction in total absorption. Bioavailability was estimated to be approximately 69% in fed and 78%, in unfed ponies. Estimates of bioavailability gave similar values for morning (72%) and afternoon (71%) dosing.
The kinetics of triclabendazole disposition in sheep
Authors: HENNESSY D. R. , LACEY E. , STEEL J. W. , PRICHARD R. K.
Published: April 2008

Hennessy, D.R., Lacey, E., Steel, J.W. & Prichard, R.K. The kinetics of triclabendazole disposition in sheep. J. vet. Pharmacol. Therap. 10, 64–72.

To investigate whether the disposition of triclabendazole (TCBZ) and its metabolites in blood or bile influenced its flukicidal potency, TCBZ was administered intraruminally at 10 mg kg‐1 to sheep surgically fitted with a permanent re‐entrant bile duct cannula. The profiles of TCBZ metabolites in peripheral plasma and bile were determined using high performance liquid chromatography.

In plasma, only TCBZ sulphoxide (TCBZ‐SO) and TCBZ sulphone were present and reached their maximum concentrations (> 13 μg ml‐1) at 18 and 36 h, respectively, after administration. TCBZ metabolites were specifically bound to plasma albumin, which is believed to exert a major influence on the duration of plasma TCBZ metabolite concentrations and consequent exposure of liver fluke.

In bile, the major TCBZ metabolites were hydroxylated in the 4'position and secreted predominantly as sulphate esters with lesser proportions as glucuronide conjugates. The major biliary metabolite was conjugated hydroxy TCBZ‐SO which reached a maximum concentration in excess of 40 μg ml‐′ and contributed almost half the total conjugated metabolites. The major free biliary metabolite was TCBZ‐SO. Of the administered TCBZ dose, 9.7% was secreted as free metabolites in bile whereas 35.8% was secreted as conjugated metabolites. Approximately 6.5% of the dose was excreted in urine.