Cholinesterase inhibition by aluminium phosphide poisoning in rats and effects of atropine and pralidoxime chloride.
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AIM: To investigate the cholinesterase inhibition and effect of atropine and pralidoxime (PAM) treatment on the survival time in the rat model of aluminium phosphide (AlP) poisoning. METHODS: The rats were treated with AlP (10 mg/kg; 5.55 x LD50; ig) and the survival time was noted. The effect of atropine (1 mg/kg, ip) and PAM (5 mg/kg, ip) was noted on the above. Atropine and PAM were administered 5 min after AlP. Plasma cholinesterase levels were measured spectrophotometrically in the control and AlP treated rats 30 min after administration. RESULTS: Treatment with atropine and PAM increased the survival time by 2.5 fold (1.4 h+/-0.3 h vs 3.4 h+/-2.5 h, P < 0.01) in 9 out of 15 animals and resulted in total survival of the 6 remaining animals. Plasma cholinesterase levels were inhibited by 47 %, (438+/-74) U/L in AlP treated rats as compared to control (840+/-90) U/L (P < 0.01). CONCLUSION: This preliminary study concludes that AlP poisoning causes cholinesterase inhibition and responds to treatment with atropine and PAM. (+info)
Effect of N-acetylcysteine and L-NAME on aluminium phosphide induced cardiovascular toxicity in rats.
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AIM: To investigate the protective effects of N-acetylcysteine (NAC) and Nomega-Nitro-L-arginine methyl ester (L-NAME) on aluminium phosphide (AlP) poisoning induced hemodynamic changes, myocardial oxygen free radical injury and on survival time in rats. METHODS: AlP (12.5 mg/kg) was administered intragastrically under urethane anaesthesia. The effect of pre- and post-treatment with NAC and L-NAME alone and in combination was studied on haemodynamic parameters [blood pressure (BP), heart rate (HR), and electrocardiogram (ECG)] and biochemical parameters (malonyldialdehyde, catalase, and glutathione peroxidase). RESULTS: AlP caused significant hypotension, tachycardia, ECG abnormalities, and finally marked bradycardia. The mean survival time was (90 +/- 10) min. There was significant increase in myocardial malonyldialdehyde (MDA), and decrease in catalase and glutathione peroxidase (GSH Px) levels. NAC infusion (6.25 mg . kg-1 . min-1, iv for 30 min) caused insignificant hemodynamic and biochemical changes. Pre- and post-treatment of NAC with AlP significantly increased the survival time, stabilized BP, HR, and ECG, decreased MDA and increased GSH Px levels compared to AlP group. L-NAME infusion (1 mg . kg-1 . min-1, iv for 60 min) as such caused significant rise in BP but precipitated ECG abnormalities. Pre- and post-treatment of L-NAME with AlP neither improved the survival time nor the biochemical parameters despite significant rise in BP. Co-administration of both the drugs with AlP worsened the hemodynamic and biochemical parameters with reduction in the survival time as compared to AlP. CONCLUSION: NAC increased the survival time by reducing myocardial oxidative injury whereas L-NAME showed no such protective effects in rats exposed to AlP. (+info)
Configurationally homogeneous diastereomers of a linear hexa(tertiary phosphine): enantioselective self-assembly of a double-stranded parallel helicate of the type (P)-[Cu(3)(hexaphos)(2)](PF(6))(3).
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Three configurationally homogeneous diastereomers of the linear hexa(tertiary phosphine) Ph(2)PCH(2)CH(2)P(Ph)CH(2)CH(2)P(Ph)CH(2)CH(2)P(Ph)CH(2)CH(2)P(Ph)CH(2)CH(2)PPh(2 ) (hexaphos) have been isolated in enantiomerically pure form, namely (R,S,S,R)-, (R,S,S,S)-, and (S,S,S,S)-hexaphos. The strongly helicating (R,S,S,R)-(-) form of the ligand combines with copper(I) ions to generate by stereoselective self-assembly the P enantiomer of a parallel helicate of the type [Cu(3)(hexaphos)(2)](PF(6))(3), which has been characterized by x-ray crystallography. Theoretical modeling of the cation indicates that it is the relationship between the helicities of the two 10-membered rings containing the three copper ions, each of which has the twist-boat-chair-boat conformation, and the configurations of the three chiral, tetrahedral copper stereocenters of P configuration that determines the stereochemistry of the parallel and double alpha-helix conformers of the double-stranded trinuclear metal helicate. (+info)
Aryl-aryl coupling reaction using a novel and highly active palladium reagent prepared from Pd(OAc)2, 1,3-bis[diphenylphosphino]propane (DPPP), and Bu3P.
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A palladium-assisted coupling reaction of aryl triflate with arene was investigated, and a novel Pd reagent prepared from equimolar Pd(OAc)2, 1,3-Bis[diphenylphosphino]propane (DPPP), and Bu3P was developed. This method is useful for intramolecular biaryl coupling reactions, not only between aryl triflate and arene (triflate-amide), but also between aryl halide and arene (halo-amide). (+info)
Genetic linkage analysis of the lesser grain borer Rhyzopertha dominica identifies two loci that confer high-level resistance to the fumigant phosphine.
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High levels of inheritable resistance to phosphine in Rhyzopertha dominica have recently been detected in Australia and in an effort to isolate the genes responsible for resistance we have used random amplified DNA fingerprinting (RAF) to produce a genetic linkage map of R. dominica. The map consists of 94 dominant DNA markers with an average distance between markers of 4.6 cM and defines nine linkage groups with a total recombination distance of 390.1 cM. We have identified two loci that are responsible for high-level resistance. One provides approximately 50x resistance to phosphine while the other provides 12.5x resistance and in combination, the two genes act synergistically to provide a resistance level 250x greater than that of fully susceptible beetles. The haploid genome size has been determined to be 4.76 x 10(8) bp, resulting in an average physical distance of 1.2 Mbp per map unit. No recombination has been observed between either of the two resistance loci and their adjacent DNA markers in a population of 44 fully resistant F5 individuals, which indicates that the genes are likely to reside within 0.91 cM (1.1 Mbp) of the DNA markers. (+info)
Toxicology and carcinogenesis studies of indium phosphide (CAS No. 22398-90-7) in F344/N rats and B6C3F1 mice (inhalation studies).
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Indium phosphide is used to make semiconductors,injection lasers, solar cells, photodiodes, and light-emittingdiodes. Indium phosphide was nominated for study because of its widespread use in the microelectronics industry, the potential for worker exposure,and the absence of chronic toxicity data. Male and female F344/N rats and B6C3F1 mice were exposed to indium phosphide (greater than 99% pure) by inhalation for 14 weeks or 2 years. The frequency of micronuclei was determined in the peripheral blood of mice exposed to indium phosphide for 14 weeks. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were exposed to particulate aerosols of indium phosphide with amass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14) or 7 days per week (weeks 5 through 9) to accommodate a concurrent teratology study. One male in the 100 mg/m3 group died before the end of the study. Body weight gains of all males and females exposed to 100 mg/m3 were less than those of the chamber controls. As a result of indium phosphide exposure, the lungs of all exposed rats had a gray to black discoloration and were significantly enlarged, weighing 2.7- to 4.4-fold more than those of the chamber controls. Indium phosphide particles were observed throughout the respiratory tract and in the lung-associated lymph nodes. A spectrum of inflammatory and proliferative lesions generally occurred in the lungs of all exposed groups of rats and consisted of alveolar proteinosis, chronic inflammation, interstitial fibrosis, and alveolar epithelial hyperplasia. Pulmonary inflammation was attended by increased leukocyte and neutrophil counts in the blood. The alveolar proteinosis was the principal apparent reason for the increase in lung weights. Indium phosphide caused inflammation at the base of the epiglottis of the larynx and hyperplasia of the bronchial and mediastinal lymph nodes. Exposure to indium phosphide affected the circulating erythroid mass. It induced a microcytic erythrocytosis consistent with bone marrow hyperplasia and hematopoietic cell proliferation of the spleen. Hepatocellular necrosis was suggested by increased serum activities of alanine aminotransferase and sorbitol dehydrogenase in all exposed groups of males and in 10 mg/m3 or greater females and was confirmed microscopically in 100 mg/m3 males and females. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were exposed to particulate aerosols of indium phosphide with a mass median aerodynamic diameter of approximately 1.2 microm at concentrations of 0, 1, 3, 10, 30, or 100 mg/m3 by inhalation, 6 hours per day, 5 days per week (weeks 1 through 4 and weeks 10 through 14)or 7 days per week (weeks 5 through 9). Although the effects of indium phosphide exposure were similar in rats and mice, mice were more severely affected in that all males and females in the 100 mg/m3 groups either died or were removed moribund during the study. One male and three females in the 30 mg/m3 group were also removed before the end of the study. In general, body weight gains were significantly less in males and females exposed to 3 mg/m3 or greater compared to those of the chamber controls. Mice exposed to 30 or 100 mg/m3 were lethargic and experienced rapid, shallow breathing. As in rats, lungs were discolored and enlarged 2.6- to 4.1-fold greater than those of chamber controls due to the exposure-induced alveolar proteinosis. Indium phosphide particles were observed in the nose, trachea,larynx, and lymph nodes of some exposed males and females. Alveolar proteinosis, chronic active inflammation,interstitial fibrosis, and alveolar epithelial hyperplasia were observed; these effects were more severe than in rats. Hyperplasia in the bronchial lymph nodes and squamous metaplasia, necrosis, and suppurative inflammation of the larynx were observed in some exposed males and females. Exposure to indium phosphide induced a microcytic erythrocytosis which was consistent with the observed hematopoietic cell proliferation of the spleen.2-YEAR STUDY IN RATS Groups of 60 male and 60 female rats were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 22 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 group were maintained on filtered air from exposure termination at week 22 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation: Exposure to indium phosphide for 3 months caused a microcytic erythrocytosis and also caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. Although qualitatively similar to those observed in the 14-week studies, these effects were considerably less severe. However, the lesions in the lungs of rats exposed to 0.1 or 0.3 mg/m3 were considered sufficiently severe that exposure was discontinued in these groups, and the groups were allowed to continue unexposed for the remainder of the study. Survival, Body Weights, and Clinical Findings: Exposure to indium phosphide had no effect on survival or body weight gain. During the last 6 months of the study, rats in the 0.03 and 0.3 mg/m3 groups became lethargic and males breathed abnormally. Pathology Findings: At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar adenomas and carcinomas in rats. Squamous cell carcinoma of the lung occurred in four male rats exposed to 0.3 mg/m3. As observed in the 14-week study and at the 3-month interim evaluation, a spectrum of inflammatory and proliferative lesions of the lung were observed in all exposed groups of males and females;however, the extent and severity of the lesions were generally greater and included atypical hyperplasia,chronic inflammation, alveolar epithelial hyperplasia and metaplasia, alveolar proteinosis, and interstitial fibrosis. Exposure to indium phosphide also caused increased incidences of benign and malignant pheochromocytomas of the adrenal gland in males and females. Marginal increases in the incidences of mononuclear cell leukemia in males and females, fibroma of the skin in males, and carcinoma of the mammary gland in females may have been related to exposure to indium phosphide. 2-YEAR STUDY IN MICE: Groups of 60 male and 60 female mice were exposed to particulate aerosols of indium phosphide at concentrations of 0, 0.03, 0.1, or 0.3 mg/m3, 6 hours per day,5 days per week, for 21 weeks (0.1 and 0.3 mg/m3 groups) or 105 weeks (0 and 0.03 mg/m3 groups). Animals in the 0.1 and 0.3 mg/m3 groups were maintained on filtered air from exposure termination at week 21 until the end of the studies. Ten males and 10 females per group were evaluated at 3 months. 3-Month Interim Evaluation:Exposure to indium phosphide for 3 months affected the circulating erythroid mass and caused enlarged lungs and lesions in the respiratory tract and lung associated lymph nodes. These effects, although qualitatively similar to those observed in the 14-week studies, were considerably less severe. However, the lesions in the lungs of mice exposed to 0.1 mg/m3 and greater were considered sufficiently severe that exposure was discontinued in these groups and the groups were allowed to continue unexposed for the remainder of the study. Survival and Body Weights: In general, exposure to indium phosphide for 2 years reduced survival and body weight gain in exposed males and females. Pathology Findings:At 2 years, exposure to indium phosphide caused increased incidences of alveolar/bronchiolar carcinomas in males and alveolar/bronchiolar adenomas and carcinomas in females. In addition to the alveolar proteinosis and chronic active inflammation seen at earlier time points, serosa fibrosis and pleural mesothelial hyperplasia were also present. The incidences of hepatocellular neoplasms were also significantly increased in exposed males and females. Exposed groups of males and females had increased incidences of eosinophilic foci of the liver at 2 years. Marginal increases in the incidences of neoplasms of the small intestines in male mice may have been related to exposure to indium phosphide. Exposure to indium phosphide also caused inflammation of the arteries of the heart, primarily the coronary arteries and the proximal aorta, and to a lesser extent the lung-associated lymph nodes in males and in females. TISSUE BURDEN ANALYSES: Deposition and clearance studies of indium following long term exposure of rats and mice to indium phosphide by inhalation were performed. Although there were quantitative differences in lung burden and kinetic parameters for rats and mice, qualitatively they were similar. Deposition of indium in the lungs appeared to follow a zero-order (constant rate) process. Retained lung burdens throughout the studies were proportional to exposure concentration and duration. No differences in elimination rates of indium from the lungs were observed as a function of exposure concentration in either rats or mice. These studies indicated that elimination of indium was quite slow. Mice exhibited clearance half-times of 144 and 163 days for the 0.1 and 0.3 mg/m3 groups, respectively, as compared to 262 and 291 days for rats exposed to the same concentrations. The lung deposition and clearance model was used to estimate the total amount of indium deposited in the lungs of rats and mice after exposure to 0.03 mg/m3 for 2 years or to 0.1 or 0.3 mg/m3 for 21 or 22 weeks, the lung burdens at the end of the 2-year study, and the area under lung burden curves (AUC). For both species, estimates at the end of 2 years indicated that the lung burdens in the continuously exposed 0.03 mg/m3 groups were greater than those in the 0.1 or 0.3 mg/m3 groups. (ABSTRACT TRUNCATED) (+info)
Systemic vascular disease in male B6C3F1 mice exposed to particulate matter by inhalation: studies conducted by the National Toxicology Program.
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Epidemiological studies suggest an association between ambient particulate matter and cardiopulmonary diseases in humans. The mechanisms underlying these health effects are poorly understood. To better understand the potential relationship between particulate-matter-induced inflammation and vascular disease, a 2-phase retrospective study was conducted. Phase one included the review of heart, lung, and kidney tissues from high-dose and control male B6C3F1 mice exposed by inhalation to 9 particulate compounds for a 2-year period. The results showed that high-dose males developed significantly increased incidences of coronary and renal arteritis over controls in 2 of the 9 studies (indium phosphide and cobalt sulfate heptahydrate), while marginal increases in arteritis incidence was detected in 2 additional studies (vanadium pentoxide and gallium arsenide). In contrast, arteritis of the muscular arteries of the lung was not observed. Morphological features of arteritis in these studies included an influx of mixed inflammatory cells including neutrophils, lymphocytes, and macrophages. Partial and complete effacement of the normal vascular wall architecture, often with extension of the inflammatory process into the periarterial connective tissue, was observed. Phase 2 evaluated the heart, lung, kidney, and mesentery of male and female B6C3F1 mice from the 90-day studies of the 4 compounds demonstrating arteritis after a 2-year period. The results showed arteritis did not develop in the 90-day studies, suggesting that long-term chronic exposure to lower-dose metallic particulate matter may be necessary to induce or exacerbate arteritis. (+info)
Common denominator of Cu/Zn superoxide dismutase mutants associated with amyotrophic lateral sclerosis: decreased stability of the apo state.
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More than 100 point mutations of the superoxide scavenger Cu/Zn superoxide dismutase (SOD; EC ) have been associated with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). However, these mutations are scattered throughout the protein and provide no clear functional or structural clues to the underlying disease mechanism. Therefore, we undertook to look for folding-related defects by comparing the unfolding behavior of five ALS-associated mutants with distinct structural characteristics: A4V at the interface between the N and C termini, C6F in the hydrophobic core, D90A at the protein surface, and G93A and G93C, which decrease backbone flexibility. With the exception of the disruptive replacements A4V and C6F, the mutations only marginally affect the stability of the native protein, yet all mutants share a pronounced destabilization of the metal-free apo state: the higher the stability loss, the lower the mean survival time for ALS patients carrying the mutation. Thus organism-level pathology may be directly related to the properties of the immature state of a protein rather than to those of the native species. (+info)