Nowadays, there is a need for good and efficacious NSAIDs with minimal side effects to be applied in veterinary medicine. The aim was to compare the pharmacodynamics (analgesia and inhibition of ...COX-2) and pharmacokinetics between selective (nimesulide) and non-selective (aspirin) COX-2 inhibitors in mice. Assessing the median effective doses by using the up-and-down method, COX-2 activity and plasma concentrations for both nimesulide and aspirin with their pharmacokinetic profiles in mice. The median effective doses (ED50s) of nimesulide and aspirin were found to be 7.9 and 212.23 mg/kg, respectively, using the hot-plate. Both nimesulide (15.8 mg/kg, i.m.) and aspirin (424.5 mg/kg, i.m.) inhibited COX-2 activity through a decrease in COX-2 concentrations in the plasma, liver, and kidney of mice, with superior inhibition when administering nimesulide in comparison to the control (negative and positive) and aspirin-treated groups. Plasma concentrations of nimesulide (15.8 mg/kg, i.m.) measured for different comparable periods of 0.5, 1, 2, 4, and 24 hours were higher than those of aspirin, which were 14.62, 9.22, 9.88, 7.38 and 2.27 µg/ml, respectively, while aspirin (424.5 mg/kg, i.m.) was 4.35, 3.17, 2.54, 2.25 and 1.21 µg/ml, at the same measured times. Nimesulide pharmacokinetic variables were estimated to be AUC0-∞ 169.18, AUMC0-∞ 2358,72, Kel 0.06, Cmax 14.62, Tmax 0.5, t1/2β 11.07, MRT 13.94, Vss 1.49, and Cl 0.09, while aspirin pharmacokinetic parameters differed to be 82.31, 2428.32, 0.03, 4.35, 0.5, 21.25, 158.12, and 5.16, respectively. The study concluded that nimesulide has superior pharmacological properties (analgesic, antipyretic, and anti-inflammatory) than aspirin due to its ability to inhibit COX-2 more selectively and its unique pharmacokinetics in mice, which may be useful in veterinary medicine.
Amitraz is used worldwide as a pesticide, it produces toxic effects when misused. The peresent study examined the histopathological changes of amitraz in the hepatocyte and kidney tissues of the ...laboratory albino rats. Thirty-six albino rats were used and they were randomly divided into six groups. Amitraz was given through oral gavage at different doses as follows: The control group (group one) received 5ml/kg of normal saline, group two received 100mg/kg, group three had 250mg/kg, group four received 500mg/kg , organs extraction from the rats (livers and kidneys) were performed after three hours from giving amitraz administration in groups one, two, three, and four. Group five received 500mg/kg and had organ collection after 5 hours of administration, group six received the same as last dose and had organ collection after 24 hours of administration. The results revealed that amitraz produced severe histopathological effects on the liver and kidney tissues compared to the control group. The changes were obvious in rats treated with high dose groups. Severe and significant histopathological changes were evident in the hepatocyte and kidney tissues in the group six of the treated rats compare to the group 5 and 4 of rats. While the lowest given dose group showed normal tissues, indicating that amitraz requires a larger quantity to produce the histopathological action. The study concluded that amitraz has hepatotoxic and nephrotoxic effects when overdose is used.
Ciprofloxacin (CFX) and ketoprofen (KPN) are used widely in combination in veterinary interventions for bacterial infections, so in this study the effect of KPN was studied on the efficacy of CFX, by ...measuring its plasma concentration and pharmacokinetic parameters in 7-10 day-old chickens. The analgesic median effective dose (ED50) of KPN was determined to be 1.62 mg/kg, IM, in the chickens. The preferable analgesic dose of KPN to be used with CFX was 4 mg/kg, IM, which differs significantly from KPN 2 mg/kg, IM,. The CFX plasma concentrations alone (8 mg/kg, IM) measured at different times (0.5, 1, 2, 4 and 24 hours) were 3.31, 3.60, 3.21, 2.70 and 0.17 μg/mL while its concentration was elevated by 53, 54, 90, 107 and 418 % when coadministered with KPN (4 mg/kg, IM) to 5.05, 5.53, 6.10, 5.59 and 0.88 μg/mL in the chickens, respectively. CFX pharmacokinetic parameters, such as the area under the curve (AUC), the area under the moment curve (AUMC), mean residence time (MRT), half-life (t1/2β), Tmax, and Cmax increased when KPN was coadministered with CFX by 129, 289, 70, 49, 100 and 69 %, whereas the elimination rate constant (Kel), the volume of distribution at steady state (Vss) and clearance (Cl) decreased by 36, 34 and 58 %, respectively. It was concluded that coadministration of KPN alters the plasma concentration and the pharmacokinetic parameters of CFX, suggesting that the CFX dose can be reduced when used with KPN to achieve the desired concentration of CFX in the plasma, as an antibacterial for treatment of infected animals.
The objective designated to discover the analgesic effect of nefopam in the normal (non-stressed) chickens and its possible alteration due to hydrogen peroxide (H2O2)-induced oxidative stress (OS) in ...7-14 day old chickens. The analgesia of nefopam has been increased by 47% in the stressed chickens by measuring the analgesic Median Effective Dose (ED50) value. This value was 9.10 mg/kg, IM in the normal chickens where it became 4.80 mg/kg, IM in stressed chickens. There is a significant rise in the antinociceptive action of nefopam 18 mg/kg, IM by 88% in the stressed group of chickens in comparison with the normal one elicited by an electro-stimulation and formaldehyde 0.05 ml of 0.1% tests for induction of nociception. The observations showed several significant stimulatory modifications in the neurobehaviour when nefopam treated with a subtle dosage 1 mg/kg, IM in the stressed chickens concerning the latency to move, squares crossed and time of the tonic immobility response test. Significant damage was detected in the liver function when nefopam injected at 18 mg/kg, IM in stress chickens in comparison to normal one by 28, 33 and 65% as estimated through Alkaline phosphatase (ALP), Aspartate trans-aminase (AST) and Alanine trans-aminase (ALT) concentrations in the serum, respectively. The sum of data findings indicated that H2O2-inducedOS increased the analgesic activity of nefopam in the chickens; despite the changes occur on the neurobehaviour and liver function. The dose of nefopam should be reduced when preparing the therapeutic regimen in the stressed animals.
The H
-antihistamine diphenhydramine antagonizes cholinesterase inhibitor poisoning in various animal species. One aspect of acute antidotal actions of diphenhydramine is increasing the median lethal ...doses (LD50) of toxicants. The objective of this meta-analysis was to assess the antidotal action of diphenhydramine against short-term toxicity (LD50) of cholinesterase inhibitors in experimental animals. The experimental studies selected were according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. They were conducted in laboratory animals (mice, rats, and chicks) to determine acute LD50 values of cholinesterase inhibitors (organophosphates, carbamates, and imidocarb) under the influence of diphenhydramine vs. controls. Twenty-eight records were selected from 12 studies on mice (n= 242), rats (n= 27), and young chicks (n= 128). The forest plot of randomized two-group meta-analysis assessed effect size, subgroup analysis, drapery prediction, heterogeneity, publication bias-funnel plot as well as one-group proportions meta-analysis of percent protection. Diphenhydramine significantly increased the combined effect size (i.e. increased LD50) in intoxicated experimental animals in comparison to controls (-3.71, standard error (SE) 0.36, 95%CI -4.46, -2.97). The drapery plot proposed a wide range of confidence intervals. The I
index of heterogeneity of the combined effect size was high at 81.03% (
= 142.3, p < 0.0001). Galbraith regression also indicated data heterogeneity; however, the normal quantile plot indicated no outliers. Subgroup analysis indicated significantly high heterogeneity with organophosphates (I
= 63.72%) and carbamates (I
= 76.41%), but low with imidocarb (I
= 51.48%). The funnel plot and Egger regression test (t= -13.7, p < 0.0001) revealed publication bias. The median of the diphenhydramine protection ratio was 1.655, and the related forest plot of one group proportion meta-analysis revealed a statistically high level of protection (0.594, SE 0.083, 95%CI 0.432, 0.756), with high heterogeneity (I
= 99.86). The risk of bias assessment was unclear, while the total score (16 out of 20) of each study leaned towards the side of the low risk of bias. In conclusion, the meta-analysis of LD50 values indicated that diphenhydramine unequivocally protected experimental animals from the acute toxicity of cholinesterase inhibitors. The drug could be an additional antidote against acute poisoning induced by cholinesterase inhibitors, but a word of caution: it is not to be considered as a replacement for the standard antidote atropine sulfate. Further studies are needed to examine the action of diphenhydramine on adverse chronic effects of cholinesterase inhibitors.
No former studies are dealing with the pharmacological (pharmacodynamics and pharmacokinetics) interaction between nefopam and tramadol in the chicks' model. The median effective doses (ED50s) for ...nefopam and tramadol produces analgesia has been estimated each alone as 9.24 and 0.83 mg/kg, IP, respectively. The interaction concerning nefopam and tramadol combination was estimated by isobolographic analysis to be 2.91 and 0.25 mg/kg, IP. The kind of interaction between nefopam and tramadol was synergistic as indicated by the interaction index 0.61. The analgesic efficacy of the combination was significantly different from nefopam and tramadol administered alone. Nefopam plasma concentration 18.48 mg/kg, IP for different measured times 0.5, 1, 2, 4, and 24 hours 33.25, 27.10, 15.05, 13.61, and 2.45 µg/ml while the concentration was increased once coadministered with tramadol 1.66 mg/kg, IP by 22, 26, 43, 45, and 81% been 40.72, 34.27, 21.53, 19.76, and 4.43 µg/ml, respectively. Nefopam pharmacokinetic profile comprised of area-under-curve (AUC), area-under-moment-curve (AUMC), mean-residence-time (MRT), half-life (t1/2β), maximal concentration (Cmax) amplified after tramadol is coadministered with nefopam by 52, 260, 23, 15, and 22%. The elimination constant (Kel), distribution volume (VD), clearance (Cl) were diminished 13, 25, and 29%, similarly. The sum results suggested a synergistic interaction between nefopam and tramadol along with a modification in nefopam pharmacokinetic parameters which improve the therapeutic efficacy of nefopam in the chickens besides, advocate using these two drugs as preanesthetics in veterinary medicine.
The objective of this study was to examine the effect of ketoprofen with or without combination with xylazine on the level of cyclooxygenase-2 in mice. The intraperitoneal (i.p.) dose of ketoprofen ...and xylazine that caused an analgesic response in half of the mouse population was 1.26 mg/kg and 6.63 mg/kg, respectively. Serum cyclooxygenase-2 concentration (activity) in the control mice was 16.94 ng/ml. The ketoprofen-treated group (2.52 mg/kg, i.p.) decreased the cyclooxygenase-2 concentration by 58% (7.16 ng/ml). The combined ketoprofen and xylazine treatment (13.26 mg/kg, i.p.) decreased the cyclooxygenase-2 by 94% (0.98 ng/ml). The ketoprofen plasma concentration in the combined treatment group was significantly higher compared to the ketoprofen treatment group. Ketoprofen plasma concentrations measured at 0.25, 0.5, 1, 2, 4, and 24 hours were 19.07, 18.94, 14.66, 6.53, 5.44, and 5.54 µg/ml, respectively. Plasma concentrations of ketoprofen and xylazine were raised to 28.74, 29.74, 15.32, 13.04, 14.64, and 11.95 µg/ml or by 51%, 56%, 5%, 100%, 169%, and 116%, respectively. Ketoprofen pharmacokinetic variables were increased (AUC
(515%), AUMC
(2389%), MRT (305%), t
(375%), T
(100%), and C
(55%)), while other values were decreased (K
(79%), V
(25%), and Cl (88%)). Our findings suggested a synergistic interaction between ketoprofen and xylazine on the level of cyclooxygenase-2 (pharmacodynamic interaction) which was exerted by modification of the ketoprofen pharmacokinetic properties in mice.
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