Intracerebroventricular injection of L-aspartic acid and L-asparagine induces sedative effects under an acute stressful condition in neonatal chicks

The present study was conducted to clarify the central functions of L-aspartic acid (Asp) and L-asparagine (Asn) during an acute stressful condition in chicks. Intracerebroventricular (i.c.v.) injection of Asp and Asn (0.84 µmol) attenuated the vocalization that normally occurs during social separation stress. Asp decreased the time spent in active wakefulness and induced sedation. Asn had a similar effect to Asp, although somewhat weaker. However, i.c.v. injection of Asp and Asn further enhanced plasma corticosterone release under social separation stress. Taken together, the i.c.v. injection of Asp and Asn has sedative effects under an acute stressful condition, which does not involve the hypothalamic-pituitary-adrenal axis.     

Central L-cysteine induces sleep, and D-cysteine induces sleep and abnormal behavior during acute stress in neonatal chicks

L-Cysteine (L-Cys) is a non-essential and glycogenic amino acid. Previously, we reported that the intracerebroventricular (i.c.v.) injection of L-Cys induced sedative effects under isolation-induced stress in neonatal chicks. L-Cys has an optical isomer, D-Cys. The aim of this study was to clarify the effect of L-Cys and D-Cys during a stressful condition in chicks. The i.c.v. injection of L-Cys and D-Cys (0.84 µmol) decreased both distress vocalization and spontaneous activity induced by isolation. However, the two cysteine isomers induced different behaviors. L-Cys increased sleep-like behavior while D-Cys caused abnormal behavior including syncope as well as sleep-like behavior. In conclusion, while both L-Cys and D-Cys caused a sedative effect when injected i.c.v, D-Cys caused abnormal behavior and may be detrimental to neonatal chicks.     

Feline pyothorax - new insights into an old problem: part 1. Aetiopathogenesis and diagnostic investigation

Relationships between onset latency and peak-to-peak amplitude of magnetic motor evoked potentials (MMEP) after transcranial magnetic stimulation (TMS), together with the electroencephalographic parameters bispectral analysis index (BIS) and the autoregressive model with exogenous input (ARX)-derived auditory evoked potential index (AAI) were explored during different sedative and hypnotic drug combinations in six dogs. TMS was performed under sedation with acepromazine/methadone or medetomidine and after a single bolus injection of propofol or etomidate. Data for BIS and AAI were continuously collected during the periods of treatment with the hypnotic drugs. Changes in BIS and AAI during both periods were not statistically correlated with changes in onset latencies and peak-to-peak amplitudes of MMEP after TMS. Therefore, both electroencephalographic techniques are of limited use in titrating sedation and anaesthesia during TMS in the dog.     

Evaluation of the sedative,analgesic, clinicophysiological and haematological effects of intravenous detomidine,detomidine‐butorphanol,romifidine and romifidine‐butorphanol in standing donkeys

The aim of this investigation was to determine and evaluate the sedative, analgesic, clinicophysiological and haematological effects of intravenous (i.v.) injection of detomidine, detomidine‐butorphanol, romifidine and romifidine‐butorphanol. Six standing donkeys were used. Each donkey received 4 i.v. treatments and the order of treatment was randomised with a one‐week interval between each treatment. We found that i.v. injection of a combination of detomidine‐butorphanol or romifidine‐butorphanol produced potent neuroleptanalgesic effects thus providing better, safe and effective sedation with complete analgesia in standing donkeys compared with injection of detomidine or romifidine alone. The changes and reduction in pulse rate were within acceptable limits. The changes in clinicophysiological, haematological and biochemical values were mild and transient in these clinically healthy donkeys.     

Disposition, bioavailability and clinical efficacy of orally administered acepromazine in the horse

The pharmacokinetics and pharmacological efficacy of orally (p.o.) administered acepromazine were studied and compared with the intravenous (i.v.) route of administration in a cross-over study using six horses. The oral kinetics of acepromazine can be described by a two-compartment open model with first-order absorption. The drug was rapidly absorbed after p.o. administration with a half-life of 0.84 h, t _max of 0.4 h and C _max of 59 ng/ml. The elimination was slower after p.o. administration (half-life 6.04 h) than after i.v. injection (half-life 2.6 h). The bioavailability of the orally administered drug formulation was 55.1%. After p.o. administration of 0.5 mg/kg acepromazine, the parameters of the sedative effect were similar to those obtained after i.v. injection of 0.1 mg/kg. The effect of the drug on blood cell count and haemoglobin content was similar after both p.o. administration and injection, while the effects on the parameters of penile prolapse and on the mean arterial blood pressure were less pronounced after p.o. administration than after injection. After p.o. administration, no significant effects on haematoerit-level as well as on the heart and respiratory rates were observed, while these parameters were significantly affected after injection. It is concluded that the high initial plasma level of the drug after i.v. injection may play a role in producing adverse effects of acepromazine.     

Pharmacological evidence for the involvement of alpha-2 adrenoceptors in the sedative effect of detomidine, a novel sedative-analgesic

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 time 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 [3H]clonidine 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.     

Characterization of the antinociceptive and sedative effect of amitraz in horses

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

Leptin attenuates the acute effects of centrally administered neuropeptide Y on somatotropin but not gonadotropin secretion in ovariectomized cows

We tested the hypothesis that recombinant ovine leptin would attenuate the acute effects of neuropeptide Y (NPY) on secretion of GH and gonadotropins (LH and FSH) in cows. Ovariectomized cows (n=6) fitted with third ventricle guide cannulas were assigned randomly to each of three groups in a Latin square arrangement: (1) control; saline treatment only, (2) NPY; saline followed by NPY, and (3) L-NPY; leptin pretreatment followed by NPY. Treatments were: s.c. injection of saline or leptin (30 microg/kg BW) at time 0, i.v. injection of saline or leptin (30 microg/kg BW) at 70 min, and intracerebroventricular (i.c.v.) injection of saline or NPY (500 microg) at 90 min. Plasma leptin was elevated (P<0.01) at least four-fold throughout the experiment in the L-NPY group. Mean plasma concentrations of LH declined within 1 h and were lower (P<0.03) than controls in both the NPY and L-NPY groups beginning 2 h after NPY injection. An acute increase in plasma concentrations of GH was observed within 1 h after NPY in the NPY group and mean values were greater (P<0.01) than controls. However, in the L-NPY group, leptin pretreatment attenuated the NPY effect on GH. Treatments had no effect on FSH secretion. Results confirm suppressive and stimulatory effects of NPY on LH and GH secretion, respectively, and indicate that leptin can attenuate the acute effects of NPY on GH secretion in cattle.     

Fever and acute phase response induced in dwarf goats by endotoxin and bovine and human recombinant tumour necrosis factor alpha

Tumour necrosis factor (TNF), a polypeptide produced by mononuclear phagocytes, has been implicated as an important mediator of inflammatory processes and of clinical manifestations in acute infectious diseases. To study further the potential role of TNF in infectious diseases, recombinant Escherichia coli (E. coli) derived human (r.HuTNF-alpha) and bovine TNF (r.BoTNF-alpha) were intravenously (i.v.) administered in dwarf goats. Rectal temperature, heart rate, rumen motility, plasma zinc and iron concentrations, and certain other blood biochemical and haematological values were studied and compared with the changes seen after E. coli endotoxin (LPS) was administered (dose: 0.1 microgram/kg i.v.). Following a single injection of 4 micrograms/kg of r.BoTNF-alpha, shivering and biphasic febrile response were observed, accompanied by tachycardia, inhibition of rumen contractions, drop in plasma zinc and iron concentrations, lymphopenia, and neutropenia followed by neutrophilia. The i.v. administration of a single injection of 4 micrograms/kg r.HuTNF-alpha induced shivering and biphasic febrile responses, accompanied by anorexia and a similar drop in plasma trace metal concentrations when compared with r.BoTNF-alpha-treated goats. The TNF-alpha-induced symptoms were essentially the same as those that occurred after LPS administration. However, the time of onset of these changes after the injection of TNF-alpha was significantly shorter than after LPS. Moreover, the r.BoTNF-alpha induced a longer lasting neutrophilic leucopenia, less neutrophilia, and a more persistent lymphopenia than after LPS injection. Neither r.BoTNF-alpha nor LPS caused severe haemo-concentration. Furthermore, no cross-tolerance between r.BoTNF-alpha and LPS could be demonstrated. We conclude that both r.BoTNF-alpha and r.HuTNF-alpha induce many of the physiologic, haematologic and metabolic changes that characterize the acute phase response to LPS. The overlapping biological activities of r.BoTNF-alpha, r.HuTNF-alpha and LPS in dwarf goats may indicate that both recombinant tumour necrosis factors have some homology with caprine TNF-alpha.     

The pharmacokinetics and bioavailability of acepromazine in the plasma of dogs]

Acepromazine is extensively used in veterinary practice. In dogs, it is used mainly as a preanaesthetic and sedative agent, without the knowledge of pharmacokinetic data in this species. We studied the disposition both after oral and intravenous administration. It was shown, that the sedative effect after an oral dose of 1.3-1.5 mg/kg lasted for about 4 hours. The elimination was slower after oral administration (half-life 15.9 h) than after i. v. injection (half-life 7.1 h). The bioavailability of the orally administered drug formulation averaged 20%. The calculation of the pharmacokinetic parameters was performed computer-aided, using conventional compartmental analysis and non-compartmental statistical moment analysis and the results were compared.     

Side effects of etomidate in dogs

Intravenous administration of etomidate, a nonbarbiturate sedative hypnotic, induced excitement, myoclonus, pain on injection, vomiting, and apnea during induction of anesthesia in 20 experimental dogs and 70 hospitalized dogs. The dogs had excitement and purposeless muscle movements during recovery from anesthesia. The frequency and severity of the side effects were markedly attenuated or eliminated by the administration of diazepam, acepromazine, or morphine prior to etomidate administration.     

Pharmacokinetics of probenecid in sheep

Six Merino ewes were given 1 g (27 g/kg) probenecid by the intravenous (i.v.), intramuscular (i.m.) and subcutaneous (s.c.) routes. After i.v. injection, the biological half-life was 1.55 h and apparent volume of distribution at the steady state (Vdss) 0.18 l/kg. Body clearance (ClB) and renal clearance (ClR) were 0.12 l/h/kg and 0.03 l/h/kg, respectively. Approximately 28% of unchanged probenecid was excreted in urine. Plasma probenecid concentrations after i.v., i.m. and s.c. injections were 133, 37, and 31 micrograms/ml, respectively, at 15 min; 76, 36, and 34 micrograms/ml at 1 h; and 43, 23 and 34 micrograms/ml at 2 h. The average bioavailability of probenecid given by i.m. and s.c. injection was 46% and 34%, respectively. However, after 2 h, probenecid plasma concentrations remained higher when it was given subcutaneously than when it was given intramuscularly. Urine output was correlated positively (P less than 0.05) with kel and ClB. Urine pH increased significantly (P less than 0.01) for the first 2 h, and then steadily declined over the subsequent 6 h. The results suggested that probenecid in sheep was rapidly eliminated because it was rapidly excreted in the normal but alkaline urine. Subcutaneous administration of probenecid in animals may be a useful alternative to oral or i.v. administration.     

Sedative-hypnotic effects of midazolam in goats after intravenous and intramuscular administration

Objective To examine the effect of dose and route of administration on the sedative‐hypnotic effects of midazolam. Design Prospective randomized controlled study Animals Six indigenous, African bred goats. Methods Pilot studies indicated that the optimum dose of midazolam for producing sedation was 0.6 mg kg^?1 for intramuscular (IM) injection, while the optimum intravenous (IV) doses causing hypnosis without, and with loss of palpebral reflexes were 0.6 mg kg^?1 and 1.2 mg kg^?1, respectively. These doses and routes of administration were compared with a saline placebo in a randomized block design in the main experiment, and the sedative‐hypnotic effects evaluated according to pre‐determined scales. Results Intramuscular midazolam produced sedation with or without sternal recumbency in all animals with the peak effect occurring 20 minutes after administration. The scores for IM sedation with midazolam were significantly different (p < 0.05) from placebo. Intravenous midazolam at 0.6 mg kg^?1 resulted in hypnosis, and at 1.2 mg kg^?1 increased reflex suppression was observed. The maximum scores for hypnosis at both doses were obtained 5 minutes after IV injection. The mean (± SD) duration of lateral recumbency was 10.8 (± 3.8) minutes after IV midazolam (0.6 mg kg^?1) compared to 20 (± 5.2) minutes after midazolam at 1.2 mg kg^?1. Compared to baseline, the heart rate increased significantly (p < 0.05) after high dose IV midazolam. Conclusion Intramuscular midazolam (0.6 mg kg^?1) produced maximum sedation 20 minutes after injection. Intravenous injection produced maximum hypnosis within 5 minutes. Increasing the IV dose from 0.6 to 1.2 mg kg^?1 resulted in increased reflex suppression and duration of hypnosis. Clinical relevance For a profound effect with rapid onset midazolam should be given IV in doses between 0.6 and 1.2 mg kg^?1.     

Early distribution of radioactive liposomes and scrapie infectivity in mouse tissues following administration by different routes

Mice were injected with ^99mtechnetium-labelled liposomes or with a standard homogenate of scrapie-affected brain. Four different routes of injection were used, intracerebral (i.c.), intravenous (i.v.), intraperitoneal (i.p.) and subcutaneous (s.c.). Blood and a range of other tissues were removed between 5 min and several hours after injection. The tissues included spleen and salivary gland in which appreciable agent replication (or at least accumulation) is known to occur and, liver where replication of scrapie agent does not occur.Within 30 min of injection by any of the four routes used, radioactivity, and infectivity were detected in tissues remote from the site of injection. The distribution of radioactivity in various tissues was similar to that of infectious scrapie agent, but in both cases it occurred much more rapidly after i.v. injection than after injection by the i.p. or s.c. route. It is suggested that the 1000-fold reduced efficiency of scrapie infection by the s.c. route, compared to the i.v. route, is related to the extensive localisation of inoculum at the site of injection. Despite the relatively high efficiency of infection of the i.v. route, much of the detectable agent is taken up by liver where the agent does not replicate. It is concluded that only a very small proportion of the agent injected i.v. (and presumably by other routes) is involved in establishing scrapie infection of mice.     

A pharmacokinetic study including some relevant clinical effect of medetomidine and atipamezole in lactating dairy cows

Medetomidine is the most potent and selective alpha2-agonist used in veterinary medicine and its effects can be antagonized by the alpha2-antagonist atipamezole. The pharmacokinetics of medetomidine and atipamezole were studied in a cross-over trial in eight lactating dairy cows. The animals were injected intravenously (i.v.) with medetomidine (40 microg/kg) followed by atipamezole i.v. (200 microg/kg) or saline i.v. after 60 min. Drug concentrations in plasma were measured by HPLC. After the injection of atipamezole, the concentration of medetomidine in plasma increased slightly, the mean increment being 2.7 ng/mL and the mean duration 12.1 min. However, atipamezole did not alter the pharmacokinetics of medetomidine. It is likely that the increase in medetomidine concentration is caused by displacement of medetomidine by atipamezole in highly perfused tissues. The volume of distribution at steady state (Vss) for medetomidine followed by saline and medetomidine followed by atipamezole was 1.21 and 1.32 L/kg, respectively, whereas the total clearance (Cl) values were 24.2 and 25.8 mL/min x kg. Vss and Cl values for atipamezole were 1.77 mL/kg and 48.1 mL/min x kg, respectively. Clinically, medetomidine significantly reduced heart rate and increased rectal temperature for 45 min. Atipamezole reversed the sedative effects of medetomidine. However, all the animals, except one, relapsed into sedation at an average of 80 min after injection of the antagonist.     

Dynamics of a protective avian inflammatory response: the role of an IL-8-like cytokine in the recruitment of heterophils to the site of organ invasion by Salmonella enteritidis

Increased resistance to Salmonella enteritidis (SE) organ infectivity in chickens can be conferred by the prophylactic administration of SE-immune lymphokines (ILK). Resistance is associated with an enhanced heterophilic accumulation within 4 h of ILK injection. In these studies, the role of IL-8 in ILK-mediated heterophil recruitment during SE infections in young chickens was investigated. Heterophil accumulation was enhanced 2-4 h after the i.p. injection of both ILK and SE (ILK/SE) when compared to the control chicks. An i.p. injection of a rabbit polyclonal anti-human IL-8 antibody significantly (P < 0.01) reduced the accumulation of heterophils in the peritoneum after the injection of ILK/SE. Injections of preimmune rabbit IgG had no effect on peritoneal heterophil numbers. Within 2 h of injection of ILK/SE, a ten-fold increase in heterophil chemotactic activity was found in the peritoneal lavage fluid from these chicks compared to the saline control chicks. Pretreatment, with the anti-IL-8 antibody, of the peritoneal lavage fluids collected from the ILK/SE-treated chicks dramatically reduced this heterophil chemotactic activity. Treatment of the lavage fluids from all groups with preimmune IgG had no effect on heterophil chemotaxis. Additionally, pretreatment of ILK with the anti-human IL-8 antibody had no effect on heterophil chemotaxis. The results from these experiments suggest that IL-8 is produced locally by the host in response to both the SE infection and the ILK. With these studies, it was established that IL-8 is a major chemotactic factor produced by the host, which aids in mediating the ILK/SE-induced recruitment of heterophils to the site of SE invasion.     

Hypnoanalgesia with R 8110/fentanyl in the dog: pharmacodynamic and pharmacokinetic interactions

The pharmacokinetics and clinical effects of the short-acting hypnotic R 8110 and of the narcotic analgesic fentanyl were studied in the dog. The effects of separate intravenous (i.v.) injections of R 8110 (4 mg/kg) and fentanyl (0.015 mg/kg) and of concurrent i.v. injection of the two were studied. After administration of R 8110, induction of hypnosis occurred within 1 min, maximal depth of anaesthesia and satisfactory analgesia and muscle relaxation were obtained after 5 min. The effects had decreased within 15 min and full recovery occurred within 30 min. Fentanyl alone produced neither hypnosis nor muscle relaxation. When fentanyl and R 8110 were given simultaneously, the duration of hypnosis was doubled in comparison with R 8110 alone. Moreover, markedly improved and longer lasting analgesia and muscle relaxation were observed with the combination. When the drugs were injected together, the plasma concentrations of R 8110 were initially much higher than after separate injection of R 8110, but they became similar after 30 min. Although statistically non-significant, fentanyl reduced the total plasma clearance of R 8110 (31.1 +/- 6.9 vs. 21.9 +/- 2.3 ml/kg/min) and decreased the volume of distribution (3.78 +/- 1.83 vs. 2.23 +/- 0.90 l/kg, P less than 0.05). Fentanyl did not alter the elimination half-life of R 8110. R 8110 had no apparent influence on the pharmacokinetics of fentanyl.     

Effects of hypothalamic dopamine on growth hormone‐releasing hormone‐induced growth hormone secretion and thyrotropin‐releasing hormone‐induced prolactin secretion in goats

The aim of the present study was to clarify the effects of hypothalamic dopamine (DA) on the secretion of growth hormone (GH) in goats. The GH‐releasing response to an intravenous (i.v.) injection of GH‐releasing hormone (GHRH, 0.25 μg/kg body weight (BW)) was examined after treatments to augment central DA using carbidopa (carbi, 1 mg/kg BW) and L‐dopa (1 mg/kg BW) in male and female goats under a 16‐h photoperiod (16 h light, 8 h dark) condition. GHRH significantly and rapidly stimulated the release of GH after its i.v. administration to goats (P < 0.05). The carbi and L‐dopa treatments completely suppressed GH‐releasing responses to GHRH in both male and female goats (P < 0.05). The prolactin (PRL)‐releasing response to an i.v. injection of thyrotropin‐releasing hormone (TRH, 1 μg/kg BW) was additionally examined in male goats in this study to confirm modifications to central DA concentrations. The treatments with carbi and L‐dopa significantly reduced TRH‐induced PRL release in goats (P < 0.05). These results demonstrated that hypothalamic DA was involved in the regulatory mechanisms of GH, as well as PRL secretion in goats.     

Insulin resistance induced in dairy steers by tumor necrosis factor alpha is partially reversed by 2,4-thiazolidinedione

The aim of this study was to determine whether 2,4-thiazolidinedione (2,4-TZD) influences the effects of peripheral insulin action in steers given recombinant bovine tumor necrosis factor (TNF) alpha (rbTNF). Steers were treated once daily for 9 d (d0 - d8) with either s.c. injection of rbTNF (2.5 microg/kg), rbTNF + i.v. injection of 2,4-TZD (2.0 mg/kg), or s.c. injection of saline (control). The plasma glucose, NEFA, and insulin concentrations in the rbTNF-treated group increased compared to those in the control and rbTNF + 2,4-TZD groups, whereas glucagon concentration decreased. A single i.v. injection of insulin (0.2 U/kg), glucose (112.5 mg/kg), or growth hormone (GH)-releasing hormone (GHRH) (0.25 microg/kg) was performed on d4, d6, and d8, respectively. In the insulin challenge, the net area under the glucose curve (AUC) was smaller in the rbTNF group than in the control and rbTNF + 2,4-TZD groups. In the glucose challenge, the net insulin AUC was smaller in rbTNF + 2,4-TZD group than in rbTNF group. In the GHRH challenge, there was no difference in GH responses to GHRH between the rbTNF and rbTNF + 2,4-TZD groups, respectively. We conclude that 2,4-TZD treatment partially reverses the impairment of peripheral insulin action caused by rbTNF injection in steers.