The present study was undertaken to examine the acute toxicity (LD50) and neurobehavioral manifestations in the open-field activity and tonic immobility tests in 7-14 day-old chicks treated with the H1-receptor antagonist diphenhydramine. Plasma and whole brain cholinesterase activities were also determined in the chicks. The LD50 of diphenhydramine in chicks was 49.3 mg/kg, intramuscularly (i.m.). The signs of diphenhydramine toxicosis in the chicks which appeared within one hour after injection included excitation, jumping, whole body tremor, ataxia, gasping, frequent defecation, paralysis and recumbency. Fifteen minutes after i.m. injection, diphenhydramine at 2.5 and 5 mg/kg decreased the general locomotor activity of the chicks in the 5-min open-field activity test, as seen by a significant increase in the latency to move from the center of the open-field arena and decreases in the numbers of lines crossed and escape jumps in comparison with control values. Diphenhydramine significantly decreased the frequencies of pecking and defecation only at 5 mg/kg when compared with respective control values. Diphenhydramine treatments at 2.5 and 5 mg/kg also significantly increased the durations of tonic immobility of the chicks and decreased their whole brain cholinesterase activity by 33 and 30%, respectively, in comparison with the control values. In conclusion, the data suggest that diphenhydramine induces central nervous system depression in chicks at doses below the LD50 value of the drug which is reported here for the first time.

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Oxidative stress may cause various neuronal dysfunctions and modulate responses to many centrally acting drugs. This study examines the effects of oxidative stress produced by hydrogen peroxide (H2O2) on sedation induced by diazepam or xylazine as assessed in 7–14 day-old chicks. Day-old chicks were provided with either plane tap water (control group) or H2O2 in tap water as 0.5% v/v drinking solution for two weeks in order to produce oxidative stress. Spectrophotometric methods were used to determine glutathione and malondialdehyde concentrations in plasma and whole brain. Drug-induced sedation in the chicks was assessed by monitoring the occurrence of signs of sedation manifested as drooping of the head, closed eyelids, reduced motility or immotility, decreased distress calls, and recumbency. The latency to onset of sedation and its duration were also recorded. H2O2 treatment for two weeks significantly decreased glutathione and increased malondialdehyde concentrations in plasma and whole brain of the chicks on days 7, 10 and 14 as compared with respective age-matched control groups. H2O2 decreased the median effective doses of diazepam and xylazine for the induction of sedation in chicks by 46% and 63%, respectively. Injection of diazepam at 2.5, 5 and 10 mg/kg, i.m. or xylazine at 2, 4 and 8 mg/kg, i.m. induced sedation in both control and H2O2-treated chicks in a dose dependent manner, manifested by the above given signs of sedation. H2O2 significantly decreased the latency to onset of sedation in chicks treated with diazepam at 5 and 10 mg/kg, increased the duration of sedation and prolonged the total recovery time in comparison with respective non-stressed control chicks. A similar trend occurred with xylazine in the H2O2-treated chicks, though the differences from control counterparts did not attain the statistical significance, except for the recovery time of the lowest dose of the drug. The data suggest that H2O2-induced oxidative stress sensitizes the chicks to the depressant action of the sedatives diazepam and xylazine. Further studies are needed to examine the potential role of oxidative stress in modulating the actions of therapeutic agents on the brain.

ABSTRACT:The goal of this study was to examine the effect of oxidative stress (OS) induced with hydrogen peroxide (H 2 O 2 ) on the anaesthetic properties of ketamine in seven and 14 day-old broiler chicks. Spectrophotometric analysis revealed that H 2 O 2 (0.5%) induced OS through significant inhibition of glutathione (GSH) and elevation of malondialdehyde (MDA) concentrations in the brain of chicks in comparison to control (tap water) group. The hypnotic and analgesic median effective doses (ED 50s ) decreased by 44% and 19%, respectively, in the stressed group compared to control group of chicks. On the other hand, the acute toxicity of ketamine increased through decreasing the acute median lethal dose (LD 50 ) (22%) in stressed chicks as determined by the up-anddown method. Injection of multiple ketamine doses at 10, 20 and 40 mg/kg, i.m. produced hypnotic effects for both groups of chicks depending on the dose, whereas H 2 O 2 caused an increase in ketamine hypnotic efficacy in comparison to the control group. In the same manner, the antinociceptive effect of ketamine increased in the stressed chicks that underwent electrostimulation for pain induction. Both AST and ALT concentrations in the plasma were significantly elevated in the stressed group when compared to the control group. The results of this study suggest that H 2 O 2 -induced OS modifies the anaesthetic properties of ketamine in chicks by increasing its efficacy and acute toxicity probably through its pharmacodynamic and pharmacokinetic interactions; thus, care must be taken when stressed animals are undergoing anaesthesia with ketamine.Keywords: ketamine; anaesthesia; hypnosis; oxidative stress; H 2 O 2 Ketamine is a short acting non-barbiturate anaesthetic agent used widely in human and veterinary medicine to produce anaesthesia that is characterized by good hypnosis and analgesia with weak muscle relaxation (Finkel et al. 2009;White and Trevor 2009). Ketamine produces its hypnotic and analgesic effects through its antagonistic effect on N-methyl-D-aspartate (NMDA) receptors causing a decrease in the calcium conductance in the neurons resulting in central nervous system (CNS) depression (Finkel et al. 2009;White and Trevor 2009). Several previous studies have used the powerful oxidant agent H 2 O 2 for induction of OS in laboratory animals such as rabbits, rats and chicks (Wohaieb et al. 1994;Mohammad et al. 1999; Mousa and Mohammad 2012a); further, it is known that OS modulates the pharmacological response to centrally acting sedatives and analgesics in chicks (Mousa and Mohammad 2012a). H 2 O 2 induces OS through its ability to elevate the reactive oxygen species and free radical formation in the body tissue especially in the CNS (Pastore et al. 2003;Watt et al. 2004;Sayre et al. 2008) as well as facilitating oxidative damage that affects the blood-brain barrier (Lochhead et al. 2010) which increase the permeability of materials and drugs. The goal of this study was to induce OS in chicks with H 2 O 2 and to examine its impact on the anaesth...

The current study aimed to evaluate the etomidate anesthetic action, its toxicity profile and safety alone and to determine the benefit of xylazine coadministration to enhance its anesthetic duration, efficacy and to reach a state of balanced anesthesia in chicks. By using the up-and-down technique, it was found that the hypnotic Median Effective Dose (ED50) of the etomidate was 4.30 mg/kg, IM, whereas the acute Median Toxic Dose (TD50) was 17.90 mg/kg, IM in the chicks. In response, the calculated Therapeutic Index (TI) and Standard Safety Margin (SSM) indicate that the etomidate has a wide safety margin. Etomidate injection at 4, 8 and 16 mg/kg, IM yields a significant dose-response and dependent hypnosis in the chicks by evaluating the onset of the righting reflex loss, its period and regaining from it. The combination composed of etomidate and xylazine at 5 mg/kg, IM for each, reduced the onset of hypnosis and significantly distended its period besides a significant rise of the recovery time when compared with the group receiving etomidate alone. At the same time, this coadministered drugs elicited a significant raise in analgesic efficacy. Concerning plasma glucose, Alanine Transaminase (ALT) and Aspartate Transaminase (AST) concentrations, neither etomidate nor etomidate plus xylazine differ significantly from the control group. The results of this study propose the likelihood of using etomidate as an anesthetic agent for short surgical trials in the chickens that can be more effective by using xylazine to yield balanced anesthesia without causing significant side effects.

Plasma and brain cholinesterase activities were determined in three wild bird species to assess their exposure to organophosphate and carbamate insecticides which are used in agriculture and public health. In the present study, we used an electrometric method for measurement of cholinesterase activities in the plasma and whole brain of three indigenous wild birds commonly found in northern Iraq. The birds used were apparently healthy adults of both sexes (8 birds/species, comprising 3–5 from each sex) of quail (Coturnix coturnix), collard dove (Streptopelia decaocto) and rock dove (Columba livia gaddi), which were captured in Mosul, Iraq. The mean respective cholinesterase activities (Δ pH/30 minutes) in the plasma and whole brain of the birds were as follows: quail (0.96 and 0.29), collard dove (0.97and 0.82) and rock dove (1.44 and 1.42). We examined the potential susceptibility of the plasma or whole brain cholinesterases to inhibition by selected insecticides. The technique of in vitro cholinesterase inhibition for 10 minutes by the organophosphate insecticides dichlorvos, malathion and monocrotophos (0.5 and 1.0 µM) and the carbamate insecticide carbaryl (5 and10 µM) in the enzyme reaction mixtures showed significant inhibition of plasma and whole brain cholinesterase activities to various extents. The data further support and add to the reported cholinesterase activities determined electrometrically in wild birds in northern Iraq. The plasma and whole brain cholinesterases of the birds are highly susceptible to inhibition by organophosphate and carbamate insecticides as determined by the described electrometric method, and the results further suggest the usefulness of the method in biomonitoring wild bird cholinesterases.

Formulation components of organophosphate insecticidal preparations might affect their toxic action in animals. The objective of this study was to examine and compare the acute toxicity and cholinesterase inhibition in seven to 14-day-old chicks dosed orally with dichlorvos and diazinon in standard veterinary and agricultural formulations. The acute (24 h) oral median lethal doses (LD 50 ) of the formulations were determined using the up-and-down method. Respective LD 50 of dichlorvos of the veterinary and agricultural formulations in chicks were 11.1 mg kg -1 and 6.51 mg kg -1 and those of diazinon 6.4 mg kg -1 and 6.7 mg kg -1 . Plasma and brain cholinesterase activities were measured by electrometry after in vivo and in vitro exposure to organophosphates. The chicks showed signs of cholinergic toxicosis within one hour of dosing. Dichlorvos (8 mg kg -1 ) and diazinon (4 mg kg -1 ) in the veterinary and agricultural formulation signifi cantly reduced both plasma and brain cholinesterase activities in the chicks. The veterinary formulation of dichlorvos reduced plasma ChE by 60 % and agricultural by 40 % and brain ChE by 93 % and 87 %, respectively. In contrast, ChE inhibition by diazinon in the agricultural formulation of diazinon was stronger than by the veterinary formulation; 72 % vs. 64 % in plasma and 97 % vs. 80 % in the brain, respectively. The highest in vitro inhibitions were observed with dichlorvos in the agricultural formulation (50 %) in the brain samples and with diazinon in the agricultural formulation (52 %) in the plasma samples. While they exist, differences between formulations cannot be taken as a rule and further investigations should inventory the toxicity of standard veterinary and agricultural organophosphate formulations in addition to the known data for pure forms.

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