Anshoo Gautam

Comparative evaluation of some flavonoids and tocopherol acetate against the systemic toxicity induced by sulphur mustard

Objective: To evaluate the protective value of quercetin, gossypin, Hippophae rhamnoides (HR) flavone and tocopherol acetate against the systemic toxicity of percutaneously administered sulphur mustard (SM) in mice. Materials and Methods: Quercetin, gossypin, HR flavone or tocopherol acetate (200 mg/kg, i.p.) were administered just before percutaneous administration of SM and protection against the SM lethality was evaluated. In another experiment quercetin, gossypin, HR flavone or tocopherol acetate were administered against 2 LD50 SM. The animals were sacrificed seven days post SM administration and various biochemical parameters were estimated. Results: The protection against the lethality of SM was very good with the flavonoids (quercetin = 4.7 folds; gossypin = 6.7 folds and HR flavone = 5.6 folds), compared to no protection with tocopherol acetate (0.7 fold). SM (2 LD50) showed decrease in reduced and oxidised glutathione (GSH and GSSG) levels, and an increase in malondialdehyde level (MDA). Oxidative stress enzymes like glutathione peroxidase, glutathione reductase and superoxide dismutase were significantly decreased. The total antioxidant status was also significantly decreased. Additionally, there was a significant increase in red blood corpuscles and hemoglobin content. All the flavonoids significantly protected the GSH, GSSG and MDA, and also the hematological variables. Tocopherol acetate failed to offer any protection in those parameters. Gossypin protected glutathione peroxidase, while HR flavone protected both glutathione reductase and glutathione peroxidase significantly. The decrease in body weight induced by SM and the histological lesions in liver and spleen were also significantly protected by the flavonoids but not by tocopherol acetate. Conclusion: The present study supports that SM induces oxidative stress and flavonoids are promising cytoprotectants against this toxic effect.

DRDE-07 and its analogues as promising cytoprotectants to nitrogen mustard (HN-2)--an alkylating anticancer and chemical warfare agent.

Nitrogen mustard (HN-2), also known as mechlorethamine, is an alkylating anticancer agent as well as blister inducing chemical warfare agent. We evaluated the cytoprotective efficacy of amifostine, DRDE-07 and their analogues, and other antidotes of mustard agents against HN-2. Administration of 1 LD(50) of HN-2 (20mg/kg) percutaneously, decreased WBC count from 24h onwards. Liver glutathione (GSH) level decreased prominently and the maximum depletion was observed on 7th day post-HN-2 administration. Oxidised glutathione (GSSG) level increased significantly at 24h post-administration and subsequently showed a progressive decrease. Hepatic malondialdehyde (MDA) level and percent DNA damage increased progressively following HN-2 administration. The spleen weight decreased progressively and reached a minimum on 3-4 days with subsequent increase. The antidotes were administered repeatedly for 4 and 8 days after percutaneous administration of single sublethal dose (0.5 and 0.25 LD(50)) of HN-2. Treatment with DRDE-07, DRDE-30 and DRDE-35 significantly protected the changes in spleen weight, WBC count, GSH, GSSG, MDA and DNA damage following HN-2 administration (0.5 and 0.25 LD(50)). There was no alteration in the transaminases (AST and ALT), and alkaline phosphatase (ALP) activities, neither with HN-2 nor with antidotes. The present study shows that HN-2 is highly toxic by percutaneous route and DRDE-07, DRDE-30 and DRDE-35 can partially protect it.

Medical Countermeasures and Other Therapeutic Strategies for Sulfur Mustard Toxicity

Publisher Summary Chemically, sulfur mustard (SM) is bis (2-chloroethyl) sulfide and is well known as mustard gas. There are various mustard agents. However, SM is one of the most important blistering or vesicating agents. SM forms sulfonium ion in the body and alkylates DNA leading to DNA strand breaks and cell death. Due to the high electrophilic property of the sulfonium ion, SM binds to a variety of cellular macromolecules. The most common complications of SM occur in lung, skin, and eye, which are the principal target organs due to its direct effect. The systemic toxicity leads to several manifestations. The first clinical manifestations of SM poisoning in victims occur in the eyes with a sensation of grittiness, lacrimation, photophobia, blepharospasm, and corneal ulceration. If exposure to vapor is prolonged, rhinorhea, laryngitis, bronchitis, necrosis of mucous membranes of the respiratory tract, and bronchopneumonia will occur. Skin lesions include erythema, blisters, and necrosis. The current treatment strategy consists of symptomatic management that prevents infections and promotes healing. There are no standardized or optimized methods of casualty management to reduce the suffering and provide speedy wound healing. At present, no antidote exists for SM poisoning. The best method of minimizing the injury is by immediate decontamination of the exposed individuals, followed by palliative treatment of symptoms.

Ameliorative effect of DRDE 07 and its analogues on the systemic toxicity of sulphur mustard and nitrogen mustard in rabbit

Despite extensive research efforts, there is no unanimous approval of any animal model to evaluate the toxicity of sulphur mustard [SM; bis (2-chloroethyl) sulphide] or nitrogen mustard [HN-3; tris-(2-chloroethyl) amine] and screening of various prophylactic and therapeutic agents against them. In this study, differential toxicity of mustard agents in higher animal model that is male rabbit was determined. Protective efficacy of DRDE 07 [S-2(2-aminoethylamino) ethyl phenyl sulphide] and its analogues were also evaluated against SM and HN-3 toxicity. Differential toxicity study of SM and HN-3 reveals that both the compounds were more toxic by percutaneous route as compared to subcutaneous route. Till date, there is no recommended drug to counteract SM induced toxicity or mortality in vivo. However, DRDE 07 (an amifostine analogue) and its analogues are found to be very effective protective agents against percutaneously exposed SM in rabbits. The present experiments also showed that SM does not cause skin injury alone but also can cause systemic toxicity as well. DRDE 07 and many of its analogues may prove as prototype compounds for the development of better prophylactic and therapeutic drugs to counter the toxicity of SM or HN-3. In conclusion, rodents and rabbits can be used for the screening of drugs against the blistering agents.

Comparative effects of pyrolytic products of fiber reinforced plastic and wood shavings on the respiratory variables in mice

Comparative inhalation toxicity studies of pyrolytic products (smoke) from synthetic polymer, fiberglass reinforced plastic (FRP) and teak wood shavings were carried out in male Swiss albino mice. The breathing pattern and the respiratory variables were monitored using a computer program that recognizes the modifications of the respiratory pattern. Exposure to the smoke from both the polymers caused a concentration dependent decrease in normal breathing and an increase in sensory irritation measure. The acute lethal concentration 50 values for a 15 min static inhalation exposure to the smoke from FRP and teak wood shavings were found to be > 200.00 and 62.99 g/m3, respectively. Hence the inhalation toxicity of smoke from FRP sample on a mass basis is approximately one-third that of the smoke from teak wood. The concentration of smoke causing 50% respiratory depression of the exposed animals were found to be 6.877 and 0.106 g/m3 for FRP and teak wood samples, respectively. Thus the sensory irritancy of the smoke from FRP sample is approximately 65 times lesser than the smoke from teak wood. The higher sensory irritancy potential of wood smoke as compared to FRP smoke may be caused by a greater number of submicron particles (size range of 2 micron and less) and greater percentage of gases present in wood smoke as compared to FRP smoke. Thus in case of accidental fires, synthetic polymers like FRP may be a safer choice for structural parts and interiors than the natural wood.

Acute Toxicity Studies of Safer and More Effective Analogues of N,N-Diethyl-2-Phenylacetamide

ABSTRACT The present work was designed to evaluate the toxicity of various synthesized aromatic amides that are analogs of N,N-diethyl-2-phenylacetamide, a well known insect repellent. The toxicity profile of these compounds was compared with N,N-diethyl-2-phenylacetamide as well as other registered insect repellents namely N,N-diethyl-3-methyl benzamide and N,N-diethylbenzamide. The primary skin irritation index values of the compounds, dermal toxicity of the chemicals and acute oral toxicity data to assess the safety of the synthesized aromatic amides are reported in this paper. Results of hematological and biochemical studies of these analogues are reported and discussed.

Quantitative estimation of DRDE-07 in mice urine using ion-paired reversed-phase high-performance liquid chromatography

DRDE-07 is a newly synthesized amifostine analog found to be very effective as a prophylactic agent against sulphur mustard toxicity. It has been proven that orally administered DRDE-07 is more efficacious than amifostine, against percutaneously administered SM. We validated an analytical protocol for DRDE-07 in mice urine using high performance liquid chromatographic method. Heptane sulphonic acid and tetramethyl ammonium chloride were used in the mobile phase as an ion pairing agent to perform the chromatographic separation. UV detection was carried out at 249 nm, a wavelength at which an absorption peak was detected. The calibration curve for DRDE-07 was linear in the range from 1 to 100 μg ml−1. The lower limit of quantification (LLOQ) was 1 μg ml−1. The results demonstrate that this method has high linearity (R2 = 0.9986), compound specificity, and acceptable precision/accuracy. The protocol is suitable for in vivo determination of DRDE-07 in mice urine.