PHARMACODYNAMIC AND PHARMACOKINETIC EVALUATION OF VERBENONE IN NORMAL AND OVALBUMIN INDUCED ASTHMATIC RATS
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Date
2017-05
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SRI VENKATESWARA VETERINARY UNIVERSITY TIRUPATI - 517 502. (A.P.) INDIA
Abstract
ABSTRACT:
Verbenone is a naturally occurring anti-aggregation pheromone generated by bark
beetles from a host tree resin precursor, -pinene. Asthma is a common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyper-responsiveness, and an underlying inflammation. In the current study, the acute toxicity at the rate of 2000 mg/kg body weight single oral dosing, sub acute toxicity at the rate of 200 mg/kg oral dosing for 30days, pharmacokinetics of verbenone in normal healthy as well as ovalbumin-induced asthmatic animals and pharmacodynamic activity of verbenone in healthy and asthmatic animals were done. It was found that the verbenone did not produce any toxicity at the dose rate of 2000 mg/kg single oral dose making it a practically non toxic compound. Besides, repeated dose administration for 30 days at the dose rate of 200 mg/kg orally also did not produce any appreciable toxicity. It was
also found that the drug did not produce any central nervous system effects as evidenced by lack of variation in spontaneous locomotor activity. In single dose non-compartmental pharmacokinetics in rats, it was found that the mean terminal elimination rate constant was 0.133±0.030/ h, mean elimination t1/2 of
4.368±0.888 hours, observed mean AUC0-inf was 1.361 ± 0.0520 μg/ml*h, observed AUMC0- inf was 6.441± 0.6356 μg/ml*h2, mean residence time was 6.304± 0.385 hours, Cmax and Tmax were 0.497±0.049 μg/ml and h hour, respectively. Apparent volume of distribution during terminal phase was 1134.798± 161.65 (mg)/(μg/ml) and apparent total body clearance of the drug from plasma was 147.1769±5.645 (mg)/(μg/ml)/h. Comparing the pharmacokinetics in normal and asthmatic animals it was found that though the Tmax did not change in disease condition all other parameters were significantly altered. In asthmatic animals maximum
plasma concentration changed from 0.497 ± 0.049 to 0.322 ± 0.015 μg/ml. The AUC0-inf had reduced from 1.361 ± 0.052 to 0.828 ± 0.012 μg/ml*h. The observed AUMC 0-inf reduced from 6.441 ± 0.636 to 2.5 ± 0.104 μg/ml*h2. The mean residence time reduced from 6.3036± 0.385h to 3.101± 0.11h and t1/2 had reduced from 4.368 ± 0.888 to 2.149 ± 0.109 hours in asthmatic animals. This experiment indicated that the elimination of verbenone from plasma was faster in asthma and as a result more frequent administration will be required in asthmatic condition.
The major pharmacodynamic activities assessed were modulatory activity in
contractile response of spasmogens like acetylcholine, histamine and 5-HT in isolated rat tracheal chains from normal, verbenone alone given rats, ovalbumin treated asthmatic rats, dexamethasone treated asthmatic rats and verbenone- treated asthmatic rat. It was found that verbenone reduced the airway yperresponsiveness to the spasmogens in asthma as indicated by the respective EC50’s. The EC50 value of acetylcholine in control animals was 6.17 X 10- 7M whereas the EC50 of verbenone pre incubated group was 7.24 X 10-7 M. In case of
verbenone treated control animals, mean EC50 of 7.24 X 10-7 M while the ovalbumin treated asthmatic model showed a significant reduction in EC50 of acetylcholine with a mean of 1.10 X 10-7M. In dexamethasone (5mg/kg) and the test group with verbenone (200 mg/kg) concomitantly with ovalbumin, EC50 of 6.76 X 10-7M and 7.24 X 10-7M were observed. Histamine failed to produce a consistent bronchospasm in rat trachea. The EC50 values of 5- HT in control animals was 2.88 X10-7 M while that of verbenone pre-incubated group was 8.51X10-7 M which was significantly less than control animals. In case of verbenone treated control animals, mean EC50 of 8.51X10-7 M; the effect being significantly less than that of ovalbumin as well as control animals. The ovalbumin treated asthmatic model showed a
significant reduction in EC50 of 5-HT with a mean of 1.07 X10-7 M and a range from 8.61 X10-8M to 1.33 X10-7M. The two treatment groups of induced asthma with ovalbumin, namely the standard treatment group which were given dexamethasone (5mg/kg) and the test group with verbenone (200 mg/kg) concomitantly with ovalbumin, showed significant change from ovalbumin alone treated asthmatic animals. The efficacy was comparable with control group, indicating the efficacy of the drugs in alleviating asthma. This was indicated by the mean EC50 of 3.89 X10-7M in case of concomitant dexamethasone and ovalbumin treated animals while in case of verbenone-treated asthmatic animals a mean EC50 of 4.47 X10-7M was noted, which was significantly less than ovalbumin group and even the control
group. Though verbenone was able to relieve the airway hyperresponsiveness in asthmatic animals akin to dexamethasone, it failed to produce any direct relaxant effect on precontracted trachea, indicating its inability to act through any bronchodilatory receptors or ion channels. But a non quantifiable relaxation was noted with histamine receptor, indicating the probability of acting on histamine receptors. This finding was supported by histopathology of lung and trachea wherein the verbenone administration reduced the inflammatory status of these organs to near normal stage. Also it was noted that the drug improved the antioxidant
status of vital organs like liver, kidney, lung, heart and plasma in asthmatic animals, restoring it to the normal status. Even in disease condition, administration of verbenone did not alter the structural and functional status of the organs grossly as indicated by the normal relative organ weights of the vital organs. Besides, it was found that verbenone possesses significant anti inflammatory activity as assessed by carrageenan induced paw oedema and wound healing activity as evidenced by improved excisional wound healing. But it was found to lack any central analgesic activity. From this it can be concluded that the verbenone is practically non toxic compound which is having a better pharmacokinetic profile so as to enable its use
as a drug and exerts anti-asthmatic activity by virtue of its anti inflammatory and anti oxidant activity, though its effect on bronchodilatory mechanisms are not predominant.
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