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PubMed | Defence Research and Development
Type: Journal Article | Journal: Acta pharmaceutica Sinica. B | Year: 2015

DRDE-07, a newly synthesized amifostine analog currently under clinical investigation in a phase I trial, is a potent antidote against sulfur mustard toxicity. The purpose of this research was to evaluate the pharmacokinetic profile of DRDE-07 in female Swiss Albino mice after a single oral dose of 400 or 600mg/kg. The physicochemical properties of DRDE-07, including solubility, pK a, LogP, plasma protein binding and plasma/blood partitioning, were determined to support the pharmacokinetic characterization. DRDE-07 concentration was determined by an HPLC-UV method. The profile of plasma concentration versus time was analyzed using a non-compartmental model. Plasma protein binding was assessed using ultrafiltration. DRDE-07 appeared rapidly in plasma after oral administration with peak plasma levels (C max) observed in less than 15min. There was a rapid decline in the plasma levels followed by a smaller second peak about 90min after dosing. The plasma protein binding of DRDE-07 was found to be less than 25% at all concentrations studied. Plasma clearance of DRDE-07 is expected to be ~1.5 fold higher than the blood clearance of DRDE-07. The probable metabolite of DRDE-07 was identified as phenyl-S-ethyl amine.


Chouhan S.,Defence Research and Development | Kushwaha P.,Defence Research and Development | Kaul R.,Defence Research and Development | Flora S.J.S.,Defence Research and Development
Biomedicine and Preventive Nutrition | Year: 2013

Fluoride toxicity is known to be associated with oxidative stress, altered antioxidant defense mechanism and DNA damage. The current study was undertaken to evaluate the efficacy of co-administration of selenium (6.3. μM) and iron (7.2. μM) with fluoride (50. ppm) in preventing fluoride-induced oxidative injury, DNA damage and in reducing body fluoride burden in rats. The data suggested that sodium fluoride administration, (50. ppm, in drinking water) in rats led a significant oxidative stress which is evident from elevated levels of reactive oxygen species (ROS), lipid peroxidation (TBARS) and reduced activities of antioxidants such as superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx) in rats. Co-administration of selenium with fluoride led to a significant recovery in blood and tissue ROS and TBARS levels accompanied by restored activities of antioxidant enzymes studied. Interestingly, selenium also exhibited a remarkable effect in preventing DNA damage in blood and fluoride accumulation in blood and soft tissues. In contrast, administration of iron with fluoride provided significant beneficial effects on blood oxidative stress and DNA damage but failed in reducing tissue oxidative stress conditions and fluoride concentration. Thus, present study provides some useful data concerning beneficial role of selenium against fluoride toxicity by virtue of its ability to eliminate fluoride from target organs and providing recovery in altered biochemical variables. © 2012 Elsevier Masson SAS.


Jain A.,Defence Research and Development | Flora S.J.S.,Defence Research and Development
Journal of Environmental Biology | Year: 2012

Nicotine affects a variety of cellular process ranging from induction of gene expression to secretion of hormones and modulation of enzymatic activities. The objective of the present study was to study the dose dependent toxicity of nicotine on the oxidative stress in young, adult and old rats which were administered 0.75, 3 and 6 mg kg-1 nicotine as nicotine hydrogen tartarate intraperitoneally for a period of seven days. No changes were observed in blood catalase (CAT) activity and level of blood reactive oxygen species (ROS) in any of the age group at the lowest dose of nicotine. However, at the highest dose (6 mg kg-1 nicotine) ROS level increased significantly from 1.17to 1.41>M ml-1 in young rats and from 1.13 to 1.40


PubMed | Defence Research and Development
Type: Journal Article | Journal: Current medicinal chemistry | Year: 2013

Heavy metals are known to cause oxidative deterioration of bio-molecules by initiating free radical mediated chain reaction resulting in lipid per-oxidation, protein oxidation and oxidation of nucleic acid like DNA and RNA. The development of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging properties should bring into play. Administration of natural and synthetic antioxidants like, quercetin, catechin, taurine, captopril, gallic acid, melatonin, N-acetyl cysteine, - lipoic acid and others have been recognized in the disease prevention and clinical recovery against heavy metal intoxication. These antioxidants affect biological systems not only through direct quenching of free radicals but also via chelation of toxic metal(s). These antioxidants also, have the capacity to enhance cellular antioxidant defense mechanism by regenerating endogenous antioxidants, such as glutathione and vitamin C and E. They also influence cellular signaling and trigger redox sensitive regulatory pathways. The reactivity of antioxidants in protecting against heavy metal induced oxidative stress depends upon their structural properties, their partitioning abilities between hydrophilic and lipophilic environment and their hydrogen donation antioxidant properties. Herein, we review the structural, biochemical and pharmacological properties of selected antioxidants with particular reference to their ability to (i) chelate heavy metals from its complex (ii) ameliorate free radical (iii) terminate heavy metal induced free radical chain reaction (iv) regenerate endogenous antioxidants and, (v) excretion of metal without its redistribution.


PubMed | Defence Research and Development
Type: Journal Article | Journal: Journal of environmental biology | Year: 2012

Nicotine affects a variety of cellular process ranging from induction of gene expression to secretion of hormones and modulation of enzymatic activities. The objective of the present study was to study the dose dependent toxicity of nicotine on the oxidative stress in young, adult and old rats which were administered 0.75, 3 and 6 mg kg(-1) nicotine as nicotine hydrogen tartarate intraperitoneally for a period of seven days. No changes were observed in blood catalase (CAT) activity and level of blood reactive oxygen species (ROS) in any of the age group at the lowest dose of nicotine. However, at the highest dose (6 mg kg(-1) nicotine) ROS level increased significantly from 1.17 to 1.41 microM ml(-1) in young rats and from 1.13 to 1.40 microM ml(-1) in old rats. However, no change was observed in blood ROS levels of adult rats. Administration of 3 mg kg(-1) nicotine resulted in an increase in level of reduced glutathione (GSH) in rats of all the age groups. The young animals were the most sensitive as a dose of 6 mg kg(-1) resulted in decline in the levels of reduced GSH to 0.89 mg ml(-1) as compared to normal control (1.03 mg ml(-1)). The antioxidant enzymes SOD and CAT were sensitive to a dose of 6 mg kg(-1) as it resulted in decline of the enzymatic activity in all age group animals. Also, administration of nicotine at a lower dose of 3 mg kg(-1) inhibited SOD activity from 1.48 to 1.20 units min(-1) mg(-1) protein in old rats. Catalase activity showed a similar trend at a dose of 3 mg kg(-1). Administration of nicotine also increased the blood lipid peroxidation levels at all three doses in young and old rats dose dependently. Nicotine exposure also increased ROS in brain at the doses of 3 and 6 mg kg(-1) in all the three age groups. Brain GSH decreased significantly at high dose of nicotine (6 mg kg(-1) b.wt.) in adult rats (4.27 mg g(-1)) and old rats (3.68 mg g(-1)) but in young rats level increased to 4.40 mg g(-1) at the lower dose (0.75 mg kg nicotine). Brain lipid peroxidation increased at all three doses of nicotine in young as well as old rats as compared to their respective normal control. The SOD activity increased significantly in young (2.88 units min(-1) mg(-1) protein) and old rats (1.81 units min(-1) mg(-1) protein) as compared to their respective normal at a dose of 6 mg kg(-1). Interestingly, the SOD activity decreased in adult rats (2.18 units min(-1) mg(-1) protein) as compared to its normal control. Catalase activity decreased at the dose of 3 mg kg(-1) and 6 mg kg(-1) nicotine in young and old rats but no effect was observed in adult rats at any of the doses. Acetylcholine esterase (AchE) activity decreased in a dose dependent manner in adult and old rats. Overall, the results of the study indicate that young and old rats are more sensitive to nicotine induced oxidative stress as compared to the adult ones.

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