Effects of dichlorvos (DDVP) inhalation on the activity of acetylcholinesterase in the bronchial tissue of rats

The experiments presented here deal with the effects of the inhalation of dichlorvos [dimethyl-(2,2 dichlorvinyl)-phosphate, DDVP] vapor on acetyl-cholinesterase (ACHE) activity in rat bronchial tissue. Exposure to DDVP concentrations of 0.8 and 1.8 g/l for 3 days reduced ACHE activity in the bronchial tissue (62.8±0.8 and 51.6±1.6% of the control), but did not elicit any changes in blood ACHE activity (101±4.5% of the control each). Higher concentrations (4.3 g/l) induced a decline in ACHE activity also in the blood (38.2±1.1% of the control). In the histochemical preparations used to demonstrate CHE activity in bronchial tissue (thiolacetic acid method), a staining of the bronchial glands and smooth muscles characteristic of the enzyme activity was strongly reduced after exposure of the animals to even the lowest dose applied (0.2 g/l). The question of whether localized inhibition of ACHE in the bronchial tissue might cause increases in airway resistance due to activation of a broncho-bronchial reflex is discussed. This efferent cholinergic mechanism has been found to be at least partly responsible for maintenance of bronchospasm and hypersecretion in chronic obstructive deseases of the respiratory system.     

Effects of dichlorvos (DDVP) inhalation on the activity of acetylcholinesterase in the bronchial tissue of rats.

The experiments presented here deal with the effects of the inhalation of dichlorvos [dimethyl-(2,2 dichlorvinyl)-phosphate, DDVP] vapor on acetylcholinesterase (ACHE) activity in rat bronchial tissue. Exposure to DDVP concentrations of 0.8 and 1.8 micrograms/l for 3 days reduced ACHE activity in the bronchial tissue (62.8 +/- 0.8 and 51.6 +/- 1.6% of the control), but did not elicit any changes in blood ACHE activity (101 +/- 4.5% of the control each). Higher concentrations (4.3 micrograms/l) induced a decline in ACHE activity also in the blood (38.2 +/- 1.1% of the control). In the histochemical preparations used to demonstrate ACHE activity in bronchial tissue (thiolacetic acid method), a staining of the bronchial glands and smooth muscles characteristic of the enzyme activity was strongly reduced after exposure of the animals to even the lowest dose applied (0.2 microgram/l). The question of whether localized inhibition of ACHE in the bronchial tissue might cause increases in airway resistance due to activation of a broncho-bronchial reflex is discussed. This efferent cholinergic mechanism has been found to be at least partly responsible for maintenance of bronchospasm and hypersecretion in chronic obstructive diseases of the respiratory system.     

Toxicological effects of dichlorvos (DDVP) on brain and liver acetylcholinesterase (AChE) activity of Tilapia mossambica, peters

Acetylcholinesterace (AChE) activity of T. mossambica in relation to the interacting effects of aging and sub-lethal concentrations of Dichlorvos was studied. The enzyme activity of brain and liver decreased with increasing size (and age) and DDVP-exposed fish showed considerable inhibition of brain and liver AChe. The degree of enzyme inhibition followed a positive correlation with the insecticide concentration and the time of exposure. Brain exhibited a higher degree of enzyme inhibition in all age groups of fish as compared to liver. Small fish were more susceptible to the insecticide with respect to AChE activity. When transferred to clean water most of the exposed fish recovered their AChE activity and the recovery was greater in liver than in brain. Small fish exhibited comparatively a high level of recovery in the AChE activity. The degree of recovery followed an inverse relationship with the time of exposure.     

Exposure of professional pest control operator to dichlorvos (DDVP) and residue on house structures

Each of the 13 human volunteers carried out a 1-day urban pest control work in 4 homes using 10-14 aerosol cans (230-330 g dichlorvos (DDVP] and 18-22 pints of 0.5% emulsion spray (40-50 g DDVP). Average residue levels of 75.85 micrograms/ft2, 40.9 micrograms/ft2 were found on the applicator's back, chest and respirator filter, respectively. Residue on the house structure was 219.7 micrograms/ft2 on the first day, which fell to 50.9 micrograms/ft2 by the end of 5 days. Blood and urine analyses revealed no changes in various clinical parameters, including serum cholinesterase levels.     

DDVP (dichlorvos) detoxification by binding and interactions with DDT, dieldrin, and malaoxon

Binding to tissue carboxylesterases has been suggested as an important mechanism of detoxification for several organophosphates. In this study DDVP, malaoxon, and paraoxon were inactivated, in vitro, by mouse liver under assay conditions that were consistent with a binding mechanism of inactivation. Binding of the three organophosphates was inhibited in livers of mice pretreated, 18 hr before sacrifice, with TOTP (triorthotolyl phosphate, 125 mg/kg, ip). Previous studies have shown that similar TOTP treatment enhanced the toxicity of malaoxon and paraoxon but did not alter the toxicity of DDVP. Both DDT (50 mg/kg, ip, given 4, 3.5, and 2.5 days before sacrifice) and dieldrin (16 mg/kg, po, given 4 days before sacrifice) increased liver/body weight ratios and decreased the duration of pentobarbital-induced loss of righting ability. Dieldrin increased liver carboxylesterase activity and liver binding of malaoxon and paraoxon but not of DDVP. In contrast, DDT did not increase liver carboxylesterase activity nor did it increase binding of malaoxon or paraoxon. Yet DDT pretreatment increased mouse liver binding of DDVP. Neither DDT nor dieldrin pretreatments altered the toxicity of subsequently administered DDVP. These results support the hypothesis that carboxylesterase binding does not represent an important mechanism for DDVP detoxification in the mouse. In other experiments, in vitro inactivation of malaoxon by binding was inhibited in livers of mice given DDVP (30 mg/kg, ip) 30 min before sacrifice. Similar DDVP pretreatment potentiated the anticholinesterase action of malaoxon (10 mg/kg, ip). Thus, even though DDVP toxicity was not altered by DDT- or dieldrin-induced changes in organophosphate binding, DDVP inhibited malaoxon binding and increased malaoxon toxicity.     

Cardiotoxic effects of arsenic trioxide/imatinib mesilate combination in rats

Cardiotoxicity is an important consideration in the evaluation of cancer chemotherapy, because chemotherapy-induced myocardial damage might be irreversible and lethal. This in-vivo study investigated the cardiotoxicity of either arsenic trioxide or imatinib mesilate, or a combination of both drugs, following repeated administration in male Wistar rats. Both arsenic trioxide and imatinib mesilate were administered daily at a dose of 5 mg kg(-1) intraperitoneally and 30 mg kg(-1) orally for 10 days, respectively. Cardiotoxicity was evaluated by biochemical and histopathological examination 48 h after the last dose. Treatment with either arsenic or imatinib, or both, resulted in significant increases in serum creatine kinase isoenzyme (CK-MB), glutathione peroxidase (GPx), lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) activity levels. Cardiac tissue of rats treated with arsenic showed significant increases in levels of reduced glutathione (GSH) content, GPx activity, malondialdehyde (MDA) and total nitrate/nitrite (NOx), whereas imatinib treatment significantly increased cardiac GSH content and MDA production level and decreased GPx activity level and NOx content. A combination of arsenic and imatinib produced significant increases in cardiac GSH content, GPx activity and MDA production levels, in addition to a reduction in NOx content. Combination arsenic/imatinib treatment extensively increased GPx activity and MDA production levels compared with imatinib treatment alone. Moreover, rats treated with arsenic or imatinib, or both, showed a significant increase in serum bilirubin, creatinine and urea levels. Histopathological examination of cardiac tissue of the combination-treated group revealed fibroblastic proliferation, myocardial disorganization and myocardial necrosis. Liver peroxidative alterations revealed that treatment with either arsenic or imatinib, or the two combined, increased levels of reduced-GSH and MDA production levels. However, imatinib treatment depleted liver GPx activity level contrary to treatment with the combination. Rats treated with arsenic alone or arsenic/imatinib combination showed significant elevation in liver NOx. In conclusion, both arsenic trioxide and imatinib mesilate might have significant cardiotoxicity and cardiac function should be monitored during treatment with them alone or in combination, as well as in the presence of pre-existing cardiac dysfunction.     

Cardiotoxic effects of anthracycline-taxane combinations

The association of doxorubicin (DOX) and paclitaxel (PTX) is very active in breast cancer. Unfortunately, PTX may potentiate the cardiotoxic effects of anthracyclines: it causes nonlinear disposition of DOX and its metabolites, leading to persistant of elevated plasma concentrations of the anthracyclines. However, this pharmacokinetic interference is not sufficient to explain the enhanced cardiotoxicity of the combination. Recent data suggest that PTX stimulates the conversion of DOX to cardiotoxic metabolites (namely doxorubicinol) inside cardiomyocytes. Docetaxel (DTX) does not have a major influence on DOX plasma concentration because it does not interfere with its elimination. Clinical data suggest that DTX may not enhance anthracycline cardiotoxicity, but patients seldom received a total anthracycline dose compatible with increased risk. Furthermore, there are experimental data indicating that DTX can also stimulate the metabolism of DOX to toxic species in human heart.     

Hematotoxic and hepatotoxic effects of dichlorvos at sublethal dosages in rats

The present study was designed to understand the effects of sublethal concentrations of dichlorvos (DIC) on hematological constituent [red blood corpuscles, white blood corpuscles (WBC), mean cell volume, mean corpuscular hemoglobin, mean corpuscular hemoglobin concentration, platelet counts, hemoglobin and hematocrite levels] and serum damage marker enzymes (aspartate aminotransferase, alanin aminotransferase, alkaline phosphatase, and lactate dehydrogenase) in rats at subacute period under laboratory conditions. DIC at dosages of 5 and 10 ppm was administered orally to six male rats ad libitum during the tests for 4 weeks consecutively. According to the results, DIC treatments increased significantly the levels of serum marker enzyme activities, whereas they did not change hematologic constituent except for WBC number treated with both dosages of DIC. The observations presented led us to conclude that the administrations of subacute DIC induced the levels of damage marker enzymes and leukocytosis.     

Neurotoxicologic investigations of the pesticide dichlorvos (DDVP). Effects on the central and peripheral nervous system

The neurotoxic effect on the central and peripheral nervous system of dichlorvos (DDVP) was investigated by a computer system in acute and subchronic experiments in CFY male rats. The administered peroral doses were given by gavage; the acute group was given a single 88 mg/kg dose and the 2 subchronic groups were given 1.6 mg/kg or 0.8 mg/kg daily for a period of 6 weeks. Significant changes of the function of CNS - increase of EEG mean frequency, decrease of EEG mean amplitude, that of activity of EEG bands (power density) - and peripheral nervous system - decrease of conduction velocity, increase of relative and absolute refractory periods - were found after treatment with both the single large and repeated small doses of dichlorvos. There were no correlations between the functional disturbances of the central and peripheral nervous systems and the inhibition of the cholinesterase activity in various organs and the blood.     

Toxicological effects of cypermethrin on female albino rats

A study was undertaken to evaluate the effects of cypermethrin on reproduction of female albino rats. The experimental rats were fed cypermethrin at 50 mg/kg b. wt. continuously for a period of 2 and 4 weeks. Feed and water intake was also noted daily for control, vehicle treated and cypermethrin-treated rats. It was observed that there was no effect on feed and water intake in treated rats as compared to the control group. Chronic exposure to cypermethrin for 4 weeks resulted in loose fecal pellets and hyperirritability in the treated rats. Treatment related mortality also occurred at the 4(th) wk of treatment. Significant changes in body weight and various organ weights due to cypermethrin were observed along with disruption of estrous cycle in rats. The body weight gain in treated rats was lower at both 2 and 4 weeks as compared to the control rats. The weight of liver and spleen decreased, while that of kidneys increased as compared to the control rats. Thyroid and adrenal showed increase in weight at both 2 and 4 weeks of treatments.     

Toxicological effects of cadmium during pregnancy in Wistar albino rats

Cadmium is a heavy metal and widespread environmental toxicant. This study investigated the effects of prenatal Cd exposure on fetal growth and limb development in rats. Pregnant rats were given 0, 4 or 8 mg/kg/day (equivalent to ≈ 0, 30 or 60 ppm) of cadmium as CdSO₄ in their drinking water from conception to gestation day 20. Cd significantly (p<0.001) and dose-dependently inhibited maternal weight gain and caused abortion of pregnancy. In addition, Cd significantly (p<0.001) decreased fetal body weight, forelimb and hindlimb bone lengths, compared to controls. These effects were sex-dependent, greater in the female offspring. Furthermore, there were reductions in the weights, and alterations in the histology of maternal placenta, ovary and liver of Cd-exposed rats. The results indicate that cadmium will cause abortion of pregnancy and sex-dependent impairment of fetal growth and limb development, which may be consequent upon alterations in ovarian and placental functions.     

Cardiotoxic effects and the influence on the beta-adrenoceptor function of doxorubicin (Adriamycin) in the rat

The possible relationship between the effect of the anthracycline-cytostatic doxorubicin (Dox) on the cardiac beta-adrenoceptor function in vitro and the development of delayed cardiotoxicity in vivo has been investigated in the rat. Dox (10(-5)-10(-4) M) blocked the chronotropic effect of isoprenaline on isolated atria in a competitive manner. Treatment with a single dose of Dox 5 mg/kg intravenously caused marked ECG changes manifested by progressive prologations of the Q alpha T and S alpha T-intervals, which amounted to 37% and 58% respectivity 5 weeks after the medication. At this time no beta-blocking action was detectable when tested on the isolated atria in the same rats. The results indicate that the delayed cardiotoxicity induced by Dox is not mediated by an interference with the cardiac beta-adrenoceptor function.     

Modulatory effects of sesamol in dinitrochlorobenzene-induced inflammatory bowel disorder in albino rats

BackgroundInflammatory bowel disease (IBD) is a chronic inflammatory condition of gastrointestinal tract of immune, genetic and environmental origin. In the present study, we examined the effect of sesamol (SES), the main anti-oxidative constituent of Sesamum indicum (sesame seed) Linn. in the dinitrochlorobenzene (DNCB)-induced model for IBD in rats.MethodsThe groups were divided into normal control, DNCB control, SES and sulfasalazine (SS). On day 24, the rats were killed, colon removed and the macroscopic, biochemical and histopathological evaluations were performed.ResultsThe levels of MPO, TBARS and nitrite increased significantly (p < 0.05) in the DNCB group, whereas reduced significantly in the SES, SS treated groups. Serum nitrite levels were found to be insignificant between the different groups. IL-6 and TNF-α levels were significantly high in the DNCB group.ConclusionsWe conclude the mucosal protective effect of SES on colon due to its potent antioxidant actions. Further investigation is required in a chronic model of different rodent strain for its role involved in the cytokine pathway.     

Protective effects of syringic acid against acetaminophen-induced hepatic damage in albino rats

The protective effect of the phenolic compound syringic acid, one of the major benzoic acid derivatives from edible plants and fruits, was evaluated against acetaminophen (APAP)-induced hepatotoxicity in rats. Toxicity was induced in adult male albino Wistar rats by the administration of APAP (750 mg/kg body weight) intraperitoneally. Rats were treated with syringic acid (25, 50, and 100 mg/kg body weight) by the oral route. We assessed the activity of hepatic markers aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, and bilirubin. Lipid peroxidative markers thiobarbituric acid reactive substances (TBARS), lipid hydroperoxides, and a decrease in enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, and non-enzymatic antioxidants vitamin C, vitamin E and reduced glutathione levels. Liver histology also showed convincing evidence regarding their protective nature against fatty changes induced during APAP intoxication. Syringic acid administered at a dose of 50 mg/kg body weight significantly decreased the activities of hepatic and renal function markers to near normal values when compared with the other two doses. The results suggest that syringic acid could afford a significant protective effect against APAP induced hepatic damage in rats.     

Cardiotoxic effects of adriamycin and mitochondrial oxidation in rat cardiac tissue

Rats were subjected to chronic treatment with adriamycin (ADR). Significant alterations of ECG tracings were induced, starting from the third week of treatment. These alterations were related to mitochondrial damage of the heart tissue. A decrease of respiration rate in phosphorylating conditions was observed in isolated organelles over a period of three weeks. Meanwhile, adriamycinol (ADRol) concentration in heart extracts increased during chronic treatment.     

Cardiotoxic effects of antihistamines: from basics to clinics (...and back)

Drug-induced arrhythmias, particularly those caused by a prolonged QT interval, have become a critical safety issue for compound selection during development by pharmaceutical companies and for health care regulators. The last two decades have witnessed enormous progress in the definition of the clinical conditions that facilitate the occurrence of such serious adverse effects, of its molecular basis, and in the preclinical strategies aimed at early identification of the cardiotoxic liability of compounds undergoing investigation or already used in the clinic. Moreover, despite the fact that acquired factors play an obvious role in drug-induced arrhythmias, it has become evident that the disease is often manifested upon the interaction of strong environmental stressors with specific genetic determinants of the affected individuals; in that sense, few examples can illustrate the existing interaction between acquired and genetic factors in disease manifestation better than drug-induced arrhythmogenesis. Progress in this field has been mainly driven by a strong interaction among various disciplines, including medicinal chemistry, pharmacology, electrophysiology, molecular genetics, and clinical cardiology; such an interdisciplinary approach has often generated unexpected discoveries of great clinical value, allowing clinicians to drive drug selection toward compounds of proven efficacy and safety. Historically, studies on antihistamines have paved the way for much of our current understanding of the mechanisms and problems associated with QT prolongation and drug-induced arrhythmogenesis; therefore, in this perspective, we will attempt to summarize how basic research studies have helped the interpretation of clinically relevant phenomena (from basics to clinics...) and how this information has prompted new emphasis in preclinical studies aimed at predicting the cardiotoxic potential of compounds (...and back). The current availability of several strategies provided with great predictive potential, together with an increased awareness of physicians, pharmaceutical industries, and health care regulators to this potentially serious cardiovascular side effect, has significantly decreased the risk associated with drug-induced arrhythmias caused by drugs newly introduced into the market; nevertheless, given the large number of cases of QT prolongation still occurring during treatment with a wide variety of congeners, it seems appropriate to review the issue of the cardiotoxic actions of antihistamines, as a better comprehension of the underlying mechanisms and risk factors is likely to contribute to the improvement of the risk/benefit ratio for pharmacological treatment in several therapeutic areas.     

In vivo antioxidant potential of rice bran oil (RBO) in albino rats

Rice Bran Oil (RBO) has got many health benefits. RBO has been analyzed for physico-chemical characteristics and compared with those of groundnut oil (GNO). The two oils were similar in various physicochemical characteristics. The major difference in the two oils lay in the amount of unsaponifiable matter, which was higher in the case of RBO. To find the in vivo antioxygenic potential of RBO, particularly its ability to protect against oxidative stress, rats were divided into two groups of 10 animals, each and were maintained on diets containing RBO or GNO for a period of 4 weeks. After which stress was induced to half the animals of each group by administering intraperitoneally N-nitrosodiethylamine (NDEA) (100 mg/kg) body weight and remaining half served as respective controls. Animals were sacrified 1 week after stress induction. Intraperitoneal administration of NDEA resulted in a significant reduction in body weight and feed intake, the effect being appreciably less in RBO fed group. NDEA toxicity was mainly reflected in liver as supported by increased activities of enzymes of liver function test (AST, ALT, ALP) on stress induction but the effect was appreciably of lesser degree in the group fed on RBO. The urea levels were also less in the group fed on RBO, The lipid peroxidation (LPO) increased on stress induction in erythrocytes and in all the tissues, the increase being less in RBO fed group except in kidneys. Stress induction resulted in decreased catalase (CAT) activity, the decrease being less in RBO fed group. The increase in peroxidase (Px) activity on stress induction was more in RBO fed group. Stress induction had no significant effect on superoxide-dismutase (SOD) activity except in liver and heart where it increased on stress induction. Thus, it appears that inclusion of RBO in the diet improves the antioxygenic potential and protect against oxidative stress.