Biomedical subjects

R Vijayaraghavan

Publications and source records attributed to R Vijayaraghavan.

At least 19 recordsLinked to original sources

PubMed2001

Design of peptides with alpha,beta-dehydro residues: a dipeptide with a branched beta-carbon dehydro residue at the (i+1) position, methyl N-(benzyloxycarbonyl)-alpha,beta-didehydrovalyl-L-tryptophanate.

The structure of the title peptide, C(25)H(27)N(3)O(5), has been determined and its conformation analysed. Values of the standard peptide torsion angles are phi(1) = -44.2 (3) degrees, psi(1) = 135.9 (2) degrees, phi(2) = -141.6 (2) degrees and psi(2)(T) = 168.0 (2) degrees. The crystal structure is stabilized by an intermolecular hydrogen bond, with an N...O distance of 2.919 (3) A, which is formed between screw-axis-related NH and CO groups of dehydrovaline residues.

Crystallography, X-Ray↗

PubMed2001

Protective effects of amifostine and its analogues on sulfur mustard toxicity in vitro and in vivo.

Sulfur mustard (bis(2-chloroethyl)sulfide, SM) is a highly reactive bifunctional alkylating agent that forms sulfonium ions in the body. SM alkylates DNA, leading to DNA strand breaks and cell death in a variety of cell types and tissues. Although several approaches have been proposed to challenge the toxic action(s) of SM, no satisfactory treatment regimen has evolved. The synthetic aminothiol amifostine, earlier known as WR-2721 (S-2-(3-aminopropylamino)ethyl phosphorothioate), has been extensively used as a chemical radioprotector for the normal tissues in cancer radiotherapy and chemotherapy. SM is known as a radiomimetic agent and this prompted us to evaluate the protective efficacy of amifostine (2.5 mM) and three of its analogues, DRDE-06 (S-2 (3-aminopropylamino) ethyl phenyl sulfide), DRDE-07 (S-2 (2-aminoethylamino) ethyl phenyl sulfide), and DRDE-08 (S-2 (4-aminobutylamino) ethyl phenyl sulfide), against SM toxicity in rat liver slices. Of the four agents tested, a 30-min pretreatment of amifostine and DRDE-07 enhanced the LC50 (a concentration producing 50% leakage of lactate dehydrogenase (LDH) or alanine aminotransferase (ALT)) of SM by 5.9- and 3.3-fold for LDH and 10.2- and 5.5-fold for ALT, respectively. Except DNA fragmentation, both these agents significantly attenuated the loss of intracellular K(+) and mitochondrial integrity (MTT assay), depletion of GSH levels, and histopathology produced by a toxic concentration (80 microM) of SM. However, when amifostine and DRDE-07 were introduced 2 h after SM, no significant protection was observed. SM (77.5 or 155 mg/kg) was also applied dermally on female albino mice and challenged by 0.20 LD50 (po) of amifostine, DRDE-06, DRDE-07, or DRDE-08 at -30 min, 0 min, or +6 h. Protection was observed only when the agents were administered at -30 min or 0 min; posttreatment (+6 h) did not offer any protection. The magnitude of in vivo protection was in the following order: DRDE-07 >or= amifostine > DRDE-08 > DRDE-06. Gas chromatographic analysis showed that there was no direct chemical interaction between SM and the antidotes. The po LD50s of amifostine, DRDE-06, DRDE-07, and DRDE-08 were 1049, 1345, 1248, and 951 mg/kg, respectively. Both in vitro and in vivo data indicate promising roles of amifostine and DRDE-07 as prophylactic agents against SM poisoning.

Amifostine↗

PubMed2001

Prophylactic efficacy of amifostine and its analogues against sulphur mustard toxicity.

The successful implication of the chemical weapons convention stimulated research with a new vigour on the destruction of the stockpiled sulphur mustard (SM). A prophylactic agent for SM will be very useful for personnel engaged in the destruction of SM and during inspections by the Organisation for the Prohibition of Chemical Weapons. Due to simple method of preparation, SM can be used clandestinely during war or by terrorist groups. Inspite of research over several decades no satisfactory prophylactic or treatment regimen has evolved for SM. Amifostine an organophosphorothioate, originally developed as a radioprotector, and its analogues were evaluated as a prophylactic agent for SM. Three analogues by varying the chain length and substitution at the sulphur atom were synthesised and coded as DRDE-06, DRDE-07 and DRDE-08. LD(50) of amifostine and its analogues were estimated through intraperitoneal (i.p.) route. For the protection studies, amifostine and its analogues were administered i.p. in mice, 30 min before dermal (percutaneous) application of SM. The dose of the prophylactic agent was 0.2 LD(50) (i.p.) and that of SM was 152 mg/kg (undiluted) equal to 19-fold LD(50) of SM. Amifostine and one of its analogues, DRDE-07 gave significant protection. Further studies were carried out using amifostine and DRDE-07, and both of them significantly protected mice against SM (155 mg/kg, in PEG 300, equal to 19 LD(50)) when they were administered i.p. either 30 min before or simultaneously. LD(50) of amifostine and DRDE-07 were also estimated through the oral route (1049 or 1248 mg/kg, respectively). Prophylactically administered amifostine and DRDE-07 (0.2 LD(50), p.o.) significantly protected the mice against dermally applied SM (155 mg/kg, in PEG 300, equal to 19 LD(50)). The protection offered by DRDE-07 was better than that of amifostine by the oral route. DRDE-07 (0.2 LD(50), p.o.) also protected significantly with respect to the decrease in body weight and the depletion of GSH induced by SM. DNA damage induced by SM was also significantly reduced by amifostine and DRDE-07 (0.2 LD(50), p.o.). Further studies are in progress on the various pharmacological and toxicological properties of DRDE-07.

Administration, Oral↗

PubMed2001

Protective effect of various antioxidants on the toxicity of sulphur mustard administered to mice by inhalation or percutaneous routes.

Protective effect of various antioxidants, trolox (water soluble analogue of vitamin E), quercetin (bioflavonoid) and glutathione reduced (GSH), was studied following sulphur mustard (SM) intoxication. SM, a blistering agent was administered to Swiss albino female mice through inhalation (1 LC50=42.3 mg/m3 for 1 h duration; 14 days observation for mortality) and percutaneous (1 LD50=154.7 mg/kg; 7 days observation for mortality) routes. The antioxidants were administered three times at the dose of trolox, 500 microg/kg; quercetin, 5 mg/kg and GSH, 400 mg/kg body weight by intraperitoneal injection, one immediately following SM exposure, then once each day for 2 days after SM treatment. The effect of antioxidants on survival, markers of oxidative damage and purine metabolites was investigated. Survival study animals were observed for 14 days. Oxidative markers (in blood, liver and lung) and purine metabolites (in blood and urine) were investigated 72 h after SM treatment. Survival time increased significantly following trolox and quercetin treatments through the inhalation route. Significant decrease in GSH and increase in the level of malondialdehyde (MDA) indicated oxidative damage to liver and lung tissues following SM inhalation and percutaneous exposure. Blood and urinary uric acid, end product of purine metabolism showed an increased following both routes of exposures. The antioxidants, trolox and quercetin protected the liver and lung tissues from oxidative damage caused by SM exposure through inhalation and percutaneous routes. This study showed that antioxidants could enhance survival time, protect liver and lung from oxidative damage and reduce accumulation of purine metabolites in blood following SM intoxication.

Administration, Cutaneous↗

PubMed2000

Acute inhalation toxicity study of 2-fluoroacetamide in rats.

One of the most potent rodenticides is 2-fluoroacetamide (2-FA). Toxicity of this chemical is well documented. However, its inhalation toxicity data is not available in the literature. Hence, acute inhalation toxicity study was carried out by exposing male and female rats to aerosols of 2-FA at different concentrations for 4 h in a dynamically operated whole body inhalation exposure chamber. During and after the inhalation exposure the rats were less active, and showed mild tremors and convulsions. At higher concentrations the rats died after 2-3 days. The estimated 4-h LC50 for male and female rats was 136.6 and 144.5 mg.m-3 respectively. Exposure to 0.7 LC50 for 4 h duration showed an increase in the liver weight of male and female rats 7 days after exposure. Various haematological and biochemical variables determined were within the normal limits. However, histological findings showed injured lung as indicated by desquamation and necrosis of the epithelium of the respiratory tract. Marked hypertrophy of hepatocytes displaying strong acidophilic granulated cytoplasm was observed. Focal dilatation of renal proximal tubules in kidney with cytoplasmic vacuolation, and irregularly placed pyknotic nuclei were seen. The present study shows that 2-FA is a highly toxic chemical through the inhalation route based on the LC50 value. Consequently necessary precautions should be taken during its handling.

Animals↗

PubMed2000

Sulphur mustard induced oxidative stress and its prevention by sodium 2,3-dimercapto propane sulphonic acid (DMPS) in mice.

Sulphur mustard [bis(2-chloro ethyl) sulfide] (SM), a bifunctional alkylating agent has been frequently used as a chemical warfare agent. In the present study, the effects of sodium 2-3-dimercaptopropane sulphonic acid (DMPS) on some biochemical and histological parameters in mice, exposed to 1/4LC50 concentration of SM vapor (10.5 mg/m3) were examined over a period of seven days. Exposure of SM resulted in a significant loss of blood, hepatic and pulmonary glutathione (GSH) and an elevation of hepatic and pulmonary oxidized glutathione (GSSG). These biochemical changes were accompanied by a number of histopathological alterations. The most prominent was congestion and degeneration in viscera and obliteration of chromatin material. These biochemical and histopathological changes were less marked in animals pre-administered with DMPS followed by DMPS exposure indicating some protective value of the thiol (DMPS) against SM induced oxidative injury in mice.

Animals↗

PubMed2000

Subacute (90 days) oral toxicity studies of Kombucha tea.

Kombucha tea (KT) is a popular health beverage and is used as an alternative therapy. KT is prepared by placing the kombucha culture in solution of tea and sugar and allowing to ferment. The inoculum is a fungus consisting of symbiotic colony of yeast and bacteria. KT is consumed in several countries and is believed to have prophylactic and therapeutic benefits in a wide variety of ailments, viz., intestinal disorders, arthritis, ageing and stimulation of immunological system. Though KT is used in several parts of the world its beneficial effects and adverse effects have not been scientifically evaluated. Since there are no animal toxicological data on KT, subacute oral toxicity study was carried out. Five groups of rats were maintained: (a) control group given tap water orally, (b) KT given 2 ml/kg orally, (c) plain tea (PT) given 2 ml/kg orally, (d) KT given in drinking water, 1% (v/v) and (e) PT given in drinking water, 1% (v/v). The rats were given this treatment daily for a period of 90 days. Weekly records of weight, feed intake, water intake and general behaviour were monitored. There was no significant difference in the growth of the animals as evidenced by the progressive body weight change. The organ to body weight ratio and histological evaluation did not show any toxic signs. The haematological and biochemical variables were within the clinical limits. The study indicates that rats fed KT for 90 days showed no toxic effects.

Administration, Oral↗

PubMed1999

Sulphur mustard induced DNA damage in mice after dermal and inhalation exposure.

Sulphur mustard (SM) is a chemical warfare agent of the blistering agent category for which there is still no effective therapy. SM, being a strong electrophile, readily reacts with a wide range of cellular macromolecules including DNA, RNA and protein. Since the main intoxication routes for SM are inhalation and dermal penetration, in the present study we have exposed female mice to different concentrations of SM by dermal and inhalation exposures and estimated the DNA damage in different organs viz., liver, lung, spleen and thymus. SM was applied at 38.7, 77.4, 154.7 mg/kg body weight, on the hair-clipped skin (dermal exposure) equivalent to 0.25, 0.5 and 1.0 of the LD50. Inhalation exposure was carried out at 10.6, 21.2 and 42.3 mg/m3 for 1 h duration equivalent to 0.25, 0.5 and 1.0 LC50. SM induced a dose-dependent DNA damage in all the organs except the lung in dermal exposure. Similarly the inhalation exposure resulted in dose- and time-dependent effect in all the organs including lung. By both routes of exposure liver was the most affected organ followed by spleen, thymus and lung in decreasing order. The quantitative data were corroborated by qualitative analysis of DNA on agarose gel electrophoresis. The genomic DNA analysis of the organs had revealed random nuclear DNA fragmentation resulting in a 'smear' typical of necrotic form of cell death. Since DNA damage is not reversible especially in liver, this can be used as a marker for SM exposure through either the dermal or inhalation route.

Administration, Inhalation↗

PubMed1999

Histomorphological and histochemical alterations following short-term inhalation exposure to sulfur mustard on visceral organs of mice.

Toxic effects of inhaled sulfur mustard (SM) on the histology of visceral organs was investigated by exposing mice to 84.6 mg/m3 for 1 h duration, using controlled single exposure conditions. A progressive fall in body weight from third day onwards was noticed. Light microscopic examination of the pulmonary tissue of these animals at 6 h post exposure revealed that the tracheobronchial epithelium remained intact, but was infiltrated by inflammatory cells. By 24 h post exposure, the mucosecretory cells were destroyed. The inflammatory reaction was maximum at 48 h. By 7th day post exposure there was swelling and vacuolation of lung parenchymal cells and thrombi formation. In addition SM caused congestion and hemorrhage at alveolar level. SM also caused granulovacuolar degeneration with perinuclear clumping of the cytoplasm of hepatocytes and renal parenchymal cells. Renal lesions were characterized by congestion and hemorrhage. Among visceral tissues, maximum atrophy was observed in spleen. Distribution of lesions increased with post exposure period. The maximum lesions were observed at 7th day post-exposure.

Animals↗

PubMed1998

Design of peptides with alpha,beta-dehydro residues: synthesis, crystal structure and molecular conformation of N-Boc-L-Ile-deltaPhe-L-Trp-OCH3.

The dehydro-peptide Boc-L-Ile-deltaPhe-L-Trp-OCH3 was synthesized by the azlactone method in the solution phase. The peptide was crystallized from methanol in an orthorhombic space group P2(1)2(1)2(1)with a = 10.777(2), b = 11.224(2), c = 26.627(10) A. The structure was determined by direct methods and refined to an R value of 0.069 for 3093 observed reflections [I > or = 2delta(I)]. The peptide failed to adopt a folded conformation with backbone torsion angles: phi1 = 90.8(8)degrees, psi1 = -151.6(6)degrees, phi2 = 89.0(8)degrees, psi2 = 15.9(9)degrees, phi3 = 165.7(7)degrees, psi3T = -166.0(7)degrees . A general rule derived from earlier studies indicates that a three-peptide unit sequence with a deltaPhe at the (i + 2) position adopts a beta-turn II conformation. Because the branched beta-carbon residues such as valine and isoleucine have strong conformational preferences, they combine with the deltaPhe residue differently to generate a unique set of conformations in such peptides. The presence of beta-branched residues simultaneously at both (i + 1) and (i + 3) positions induces unfolded conformations in tetrapeptides, but a beta-branched residue substituted only at (i + 3) position can not prevent the formation of a folded beta-turn II conformation. On the other hand, the present structure shows that a beta-branched residue substituted at the (i + 1) position prevents the formation of a beta-turn II conformation. These observations indicate that a beta-branched residue at the (i + 1) position prevents a folded conformation whereas it cannot generate the same degree of effect from the (i + 3) position. This may be because of the trans disposition of the planar deltaPhe side-chain with respect to the C=O group in the residue. The molecules are packed in an anti-parallel manner to generate N2-H2...O2 (-x, y -1/2, -z + 3/2) and N3epsilon1-H3epsilon1 ...O1(-X, y -1/2, -z + 3/2) hydrogen bonds.

Crystallography↗

PubMed1998

Protective efficacy of calcium channel blockers in sulphur mustard poisoning.

The present study was designed to ascertain the in vivo protective efficacy of Ca(2+)-channel blockers against dermally applied sulphur mustard (SM). Male albino mice were exposed to 1.5 LD50 of SM (232 mg/kg) percutaneously and the control group received an equal volume of vehicle (polyethylene glycol 300). Prior to SM application, the animals were administered nifedipine and dextrose saline containing antibiotic by intraperitoneal route. The protection assessed by the mean survival time (MST) was determined by Dunnett's method. The MST was significantly increased in nifedipine treated group. The characteristic biochemical indices of SM intoxication, i.e. lipid peroxidation and reduced glutathione (GSH) were determined in liver from animals sacrificed at 24, 48 and 72 h after exposure. SM application (1 LD50) caused a reduction in GSH level which was restored in nifedipine treated group. SM-induced lipid peroxidation was also prevented by nifedipine administration. The protective effect of nifedipine may be related to its capacity of attenuating SM-induced lipid peroxidation and glutathione depletion.

Administration, Cutaneous↗

PubMed1998

Dose response of sulphur mustard: behavioral and toxic signs in rats.

The present study elucidates the behavioral and toxic signs in rats following dermal application of sulphur mustard (SM). Graded doses of SM (0.10, 0.25, 0.50, 0.75 and 1.0 LD50) were topically applied to male Wister rats. The body weight as well as behavioral/toxic signs and symptoms were recorded at 1, 2, 3, and 4th day after application of SM. Sulphur mustard consistently decreased body weights of rats in a dose and time dependent manner with maximum decrease on 3rd day post treatment. Sedation and diarrhea were significant in response to doses of SM intoxication in rats. It is concluded that the body weight, sedation and diarrhea may be used as a reliable parameter in evaluating SM intoxication. It is also suggested that hydration and hypertonic saline must be used as a rescue agent within 1-3 days after exposure to SM.

Animals↗

PubMed1997

Changes in certain hematological and physiological variables following single gallium arsenide exposure in rats.

Gallium arsenide (GaAs), a group III-VA intermetallic semiconductor, possesses superior electronic and optical properties and has a wide application in electronic industry. Exposure to GaAs in the semiconductor industries could be a possible occupational risk. The aim of the present study was to determine the dose-dependent effect of single oral exposure to GaAs (500, 1000, or 2000 mg/kg) on some biochemical variables in heme synthesis pathway and few selected physiological variables at d 1, 7, and 15 following administration. The results indicate that GaAs produced a significant effect on the activity of delta-aminolevulinic acid dehydratase (ALAD) in blood and heart (particularly at d 7) following exposure to 2000 mg/kg, whereas urinary delta-aminolevulinic acid (ALA) excretion was elevated only at d 7. No marked influence of GaAs on blood hemoglobin, zinc protoporphyrin, and packed cell volume was noticed. Blood glutathione (GSH) was significantly reduced at d 7, but remained unchanged at two other time intervals. On the other hand, heart GSH contents remained uninfluenced on GaAs exposure. Most of the physiological variables, viz. blood pressure, heart and respiration rate, and twitch response, remained unchanged, except for some minor alterations observed at d 7 and 15 following exposure to GaAs at a dose of 2000 mg/kg. Blood gallium concentration was not detectable in normal animals and rats exposed to 500 mg/kg GaAs. Blood arsenic concentration was, however, detectable even at the a lower dose level and increased in a dose-dependent manner. All these changes showed a recovery pattern at d 21, indicating that the alterations are reversible.

Aminolevulinic Acid↗

PubMed1997

Modifications of breathing pattern induced by inhaled sulphur mustard in mice.

A head-only exposure assembly was used for exposing mice to vapours of sulphur mustard (SM). The respiration was monitored using an on-line computer program, capable of recognizing the breathing pattern as sensory irritation, airflow limitation and pulmonary irritation. SM was dissolved in acetone and vapourized using a compressed air nebulizer. Mice were exposed to the vapours (8.5, 16.9, 21.3, 26.8, 42.3 and 84.7 mg/m3) for 1 h in a body plethysmograph fitted with a 20-gauge needle and a microphone for sensing the respiratory flow signals. The signals were amplified, digitized and integrated to give tidal volume, and stored in a computer for further analysis. The respiration of the mice was followed for modifications in the breathing pattern until 7 days post-exposure. SM induced sensory irritation during exposure, and there was a concentration dependent decrease in the respiratory frequency and an increase in tidal volume. Lower concentrations showed recovery after stopping the exposure. RD50, the concentration that depresses 50% of the respiration was estimated to be 27.4 mg/m3. Following exposure to higher concentrations the animals started dying after 6 days. The LC50 was estimated to be 42.5 mg/m3 (14 days observation period). The respiratory frequency decreased on subsequent days of exposure depending upon the exposure concentration, and the breathing pattern was characteristic of airflow limitation. The ratio of flow/tidal volume was decreased following exposure to concentrations of 26.8 and 42.3 mg/m3. The ratio of flow/tidal volume may be a better measurement than the measurements based on flow alone for the assessment of airflow limitation. Pulmonary irritation was not observed showing that the lungs were not affected. The body weight of the animals decreased progressively. The present methodology will be useful for identifying the effects of SM on the respiratory system, one of the endpoints considered when establishing occupational exposure limits.

Administration, Inhalation↗

PubMed1996