Reduction of arsenic trioxide toxicity in mice by repeated treatment with glucose.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
B Fichtl
Publications and source records attributed to B Fichtl.
Effect of oral treatment with Bal, DMPS or DMSA arsenic in organs of mice injected with arsenic trioxide.
Explore the source record for details and available documents.
Administration, Oral↗
Influence of subchronic exposure to low dietary deoxynivalenol, a trichothecene mycotoxin, on intestinal absorption of nutrients in mice.
During a 6-wk feeding trial, effects of low dietary deoxynivalenol (DON; 0, 0.1, 1 and 10 ppm) on food consumption and weight gain were investigated in male mice. Food intake was similar in all four dietary groups. Weight gain in the group receiving 10 ppm DON was significantly (P less than 0.01) reduced. At the end of the feeding period, test animals were sacrificed and absorption of water, D-glucose, L-leucine, L-tryptophan, 5-methyltetrahydrofolic acid and iron was measured in isolated perfused jejunal segments in vitro. No effects were observed on absorption of water, leucine, tryptophan and iron. However, at a dietary DON concentration of 10 ppm, a slightly but significantly (P less than 0.05) reduced transfer of glucose was measured. Furthermore, transfer as well as tissue accumulation of 5-methyltetrahydrofolic acid in the jejunal segment were both significantly decreased up to 50%. Heavy metal and trace element content was determined in liver, kidney and small intestine. Manganese and molybdenum content in liver tissue was reduced with a DON concentration of 10 ppm in the diet. The findings indicate that subchronic ingestion of DON, in concentrations occurring in contaminated food and feed, results in an impairment of intestinal transfer and uptake of nutrients such as glucose and 5-methyltetrahydrofolic acid.
Animals↗
Pharmacokinetics, effect on clotting tests and assessment of the immunogenic potential of hirudin after a single subcutaneous or intravenous bolus administration in man.
The pharmacokinetics and the anticoagulant effects of hirudin were investigated in 12 healthy volunteers after single subcutaneous or intravenous bolus administrations. Hirudin concentrations in citrated plasma and urine were determined with a radioimmunobioassay, which detects the inhibitor by its thrombin-binding capacity. Plasma profiles could be adequately described by the equation for an open two-compartment model (intravenous route) and by the Bateman equation (subcutaneous route), respectively. Within 24 h half of the administered hirudin dose was recovered in the urine in biologically active form. The prolongation of clotting times (activated partial thromboplastin and thrombin time) was dependent on the hirudin plasma concentration. All test subjects tolerated the hirudin injection without visible or measurable side effects. No hirudin-specific antibodies were found after single parenteral administrations.
Biological Assay↗
Effect of glucose treatment on carbohydrate content in various organs in mice after acute As2O3 poisoning.
Glucose treatment improved survival and symptoms in mice poisoned with As2O3. In order to get more insight into the mechanisms involved, postmortum changes in glucose and glycogen content of various organs and pathology were investigated in mice acutely poisoned with As2O3 and treated with glucose. Forty mice each received 12.9 mg As2O3/kg sc as a single injection. The first group of 10 mice had no further treatment. Fifteen minutes after the As2O3 injection and every 2 h thereafter, the second group (10 mice) received saline and the third group (10 mice) received 5% glucose ip. Groups 4 and 5 (5 mice each) received either saline or glucose only. The injection volume in all groups was 10 microliters/g mouse. Group 6 (5 mice) had no treatment whatsoever. Immediately after death brain, muscle and kidneys were prepared for the enzymatic determination of glucose and glycogen. Samples of the brain, muscle, kidneys, liver, small intestine, colon and spleen were taken for microscopic examination. Independent of the therapeutic procedure, decreases in the glycogen in livers and increases in fat in livers and muscles were observed in mice which died. All mice which died showed heavy leucocytes disruptions, increased fat, and decreased glycogen in the spleen. Intrafolliculary disruptions of leucocytes in the small intestine and colon, as well as patchy hyperemias and hemorrhagic spots in the papilla of the kidneys, were observed in non-survivor mice. Decreased glucose and glycogen was in the brains of non-survivor mice; no differences in glucose and glycogen were found in brains of the mice which survived.(ABSTRACT TRUNCATED AT 250 WORDS)
Administration, Cutaneous↗
Effect of glucose in mice after acute experimental poisoning with arsenic trioxide (As2O3).
Carbohydrate depletion (glucose and glycogen) was reported to be a major problem in acute arsenic poisoning. In the present paper the effectiveness of glucose substitution was investigated in mice after acute experimental poisoning with As2O3. Four groups of ten mice each received As2O3, 12.9 mg/kg, s.c. After the injection the first group remained without further treatment, the second received saline every 2 h, the third 5% glucose, and the fourth 5% glucose +0.12 IE insulin/kg i.p. Groups 5 and 6, five mice each, received either saline or glucose only. Group 7, five mice, remained without any treatment. Immediately after death the livers were removed for the enzymatic determination of glucose and glycogen. Mice receiving As2O3 only died within 22 h. The mean survival time was 12.4 h. In mice receiving As2O3 and after that saline, glucose, or glucose + insulin, an increase in the survival time to 30.8, 40.7, and 43.6 h, respectively, was observed. All mice which died showed a significant decrease in the liver glucose and glycogen content, compared to control animals. In livers of survivors, the glucose and glycogen content was not different to the control groups. The data support the assumption that carbohydrate depletion is an important factor in arsenic toxicity, and its substitution should be considered in the treatment of arsenic poisoning.
Animals↗
Efficacy of various dithiol compounds in acute As2O3 poisoning in mice.
The efficacy of DL-dimercaptopropanol (British Anti-Lewisite, BAL), DL-dimercaptopropanesulfonate (DMPS), and meso-dimercaptosuccinic acid (DMSA) was compared in reducing the acute As2O3 toxicity in mice. Mice were treated with a single equimolar dose of a dithiol compound (0.7 mmol/kg i.p.) 0.5 or 30 min after the s.c. injection of various doses of As2O3. Both DMPS and DMSA were significantly (p less than or equal to 0.05) more effective in mice treated 0.5 min after the poisoning if compared to BAL on an equimolar level. The highest potency ratio (PR) (LD50 with treatment/LD50 without treatment) was found in animals injected with DMSA (PR = 8.6). The corresponding value for DMPS was 4.2, and for BAL 2.1, respectively. In animals treated 30 min after poisoning the efficacy of DMPS (PR = 2.6) was similar to the efficacy of DMSA 2.4, both being only slightly superior to BAL 2.0. DMPS and DMSA were found to be much less toxic than BAL. The LD50 of arsenic was 0.057 mmol/kg. The efficacy of BAL, DMPS, and DMSA in reducing the tissue content of arsenic following acute As2O3 poisoning was investigated in mice (n = 6/group) and guinea pigs (n = 3-4/group). The animals were injected s.c. with 0.043 mmol/kg As2O3 (containing a tracer dose of 74As(III)). Thirty minutes later the antidotes were administered i.p. (0.7 mmol/kg). From 2 to 4 h after As2O3 poisoning bile was collected from guinea pigs. Four h after As2O3 injection the content of 74As in blood, liver, kidneys, spleen, heart, lungs, brain, testes, skeletal muscle, and skin in mice and guinea pigs was measured.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effect of chelating agents on biliary excretion of arsenic in perfused livers of guinea pigs pretreated with As2O3.
The effect of the dithiols British Anti-Lewisite (Bal), dimercapto-propanesulfonic acid (DMPS), dimercaptosuccinic acid (DMSA) and a new metal binding agent 2,3-bis-(acetylthio)-propanesulfonamide (BAPSA) on the biliary excretion of arsenic in perfused livers of guinea pigs pretreated with As2O3 was investigated. Guinea pigs received As2O3, 2.5 mg/kg sc twice daily for 5 consecutive days. Sixteen hours after the last dose the livers were perfused (35 ml/min) with Krebs-Henseleit buffer with glucose for 80 min. After 50 min of perfusion 0.1 mmol/L or 0.7 mmol/L BAL, DMSA, DMPS, or BAPSA were added to the perfusate and arsenic elimination in the bile and effusate was measured. The total arsenic excretion in control livers between the 50th and 80th min was 6.1% of the total arsenic liver content. After antidote addition (0.1 mmol/L) the excretion increased to 7.9% (DMSA), 9.2% (BAL), 23.9% (BAPSA), and 27.1% (DMPS), respectively. After 0.7 mmol/L of antidote the excretion of arsenic was found to be 19.3% (DMSA), 19.9% (DMSA), 24.0% (BAL), and 43.3% (BAPSA), respectively. The increase resulted mainly from increased biliary excretion. In these experiments BAPSA was significantly more effective in the overall elimination of arsenic than DMSA, DMPS, and BAL. The treatment with chelating agents may cause a substantial shift to fecal elimination by the increase in biliary excretion (BAL less than DMSA less than DMPS less than BAPSA). From the therapeutic view the shift to fecal elimination may have the advantage that the amount of the toxicant which passes the kidney is reduced and thereby also the portion which might be harmful for the organ.
Animals↗
Lack of effectiveness of D-penicillamine in experimental arsenic poisoning.
Based on some anecdotal case reports D-penicillamine (DPA) has been advocated for the treatment of arsenic poisoning. Experimental evidence, however, supporting that recommendation is lacking. In the present experiments the effectiveness of DPA was compared with dimercaprol (British Antilewisite, BAL), dimercaptopropanesulfonate (DMPS), and dimercaptosuccinic acid (DMSA) using different controlled experimental settings. In one study mice received As2O3 (9-14 mg/kg sc). Treatment with DMSA after 30 min afforded almost complete protection against the lethal effects of arsenic whereas DPA was not effective. In a second study, mice and guinea pigs were injected sc with 8.4 mg/kg As2O3 (containing a tracer dose of 74As). Thirty min later 0.7 mmol/kg of DPA or one of the other antidotes was injected ip. As determined 4 and 12 h after the arsenic injection, DPA was unable to reduce the 74As content in any of the organs investigated (blood, liver, kidneys, lungs, heart, brain, testes, spleen, skeletal muscle, and skin). On the other hand, BAL, DMPS, and DMSA markedly reduced the tissue content of 74As with respect to controls. Finally, the ability of the antidotes to reverse biochemical effects of arsenic was investigated in vitro using suspensions of incubated renal tubulus cells. The marked inhibition of gluconeogenesis induced by 30 mumol/L As2O3 was almost completely reversed upon addition of 90 mumol of either BAL, DMPS, or DMSA. In this experimental model, too, DPA was ineffective. It was concluded that the use of DPA in arsenic poisoning needs to be reevaluated.
Animals↗
Metabolism of T-2 toxin in vascularly autoperfused jejunal loops of rats.
The intestinal metabolism of T-2 toxin, a major trichothecene mycotoxin, was investigated in rats using the method of the vascularly autoperfused jejunal loop in situ. Tritium-labeled T-2 toxin was injected into the tied-off intestinal segments at a dose of 5 or 500 nmol, respectively. T-2 toxin and its metabolites in the blood draining from the jejunal loops, in the intestinal lumen, and in the intestinal tissue were determined by HPLC and GLC-MS. There was an extensive metabolic degradation of T-2 toxin, the metabolite pattern being similar for the two dosage levels. During the experimental period of 50 min only some 2% of the total dose appeared in the effluent plasma as unchanged T-2 toxin. Likewise at the end of the experiments unchanged T-2 toxin in the intestinal lumen and tissue was present in minute amounts only (less than 1% of the dose). HT-2 toxin was the main metabolite. About 25% of the total radioactivity administered appeared in the effluent plasma as HT-2 toxin, 18% in the lumen and 10% in the tissue. 3'-OH-HT-2 toxin accounted for 4-7% (effluent plasma), 5% (lumen), and 2% (tissue) of the total dose. Furthermore small amounts (less than 2% of the dose) of 3'-OH-T-2 toxin, T-2 tetraol, and 4-deacetylneosolaniol were found. No glucuronide or sulfate conjugates could be detected. In the jejunal segments which had been exposed to the 5-nmol dose only minimal morphological alterations were observed. On the other hand, in jejunal segments exposed to the high dose marked tissue damage was present. Nevertheless the gut tissue retained its ability to metabolize T-2 toxin. From the present results it is concluded that T-2 toxin is subject to a marked presystemic first pass effect after oral ingestion in vivo.
Animals↗
Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration.
The pharmacokinetics (half-life time of absorption and elimination, total clearance, distribution volume etc.), effects on hemostasis (clotting times, blood cell counts) and renal excretion of hirudin were investigated on healthy volunteers after single subcutaneous (600, 800 or 1000 antithrombin units (AT-U)/kg; n = 3 per each dose) or intravenous (1000 AT-U/kg; n = 3) injections. Hirudin concentrations in citrated plasma and urine were determined by means of a radioimmunobioassay, whereby the inhibitor is detected by its thrombin binding capacity. Plasma profiles were adequately described by the Bateman equation (subcutaneous injection) and by an open two-compartment model (intravenous injection), respectively. Within 24 h about half of the applied hirudin dose was renally excreted in active form. The prolongation of clotting times (thrombin time, partial thromboplastin time (PTT), Quick) was dependent on the hirudin plasma level. The PTT proved to be the most reliable test for representation of the actual inhibitor plasma concentrations. Generally, the blood cell counts were unchanged by the hirudin administration. All test subjects tolerated the hirudin injection without visible or measurable side effects.
Adult↗
Role of lipid peroxidation in the toxicity of T-2 toxin.
Recent reports suggest that lipid peroxidation may be involved in the toxicity of T-2 toxin. In the present study the influence of T-2 toxin on two parameters of lipid peroxidation was examined: the formation of thiobarbituric acid reactive material in isolated hepatocytes and liver homogenates from rats and ethane exhalation in vivo. In isolated hepatocytes there was no significant increase in thiobarbituric acid reactive material, neither after addition of T-2 toxin in vitro nor when the toxin had been applied to the rats 15 hr before preparation of hepatocytes. In liver homogenates the amount of thiobarbituric acid reactive material was increased up to 50% over the controls, depending on the dose of T-2 toxin. The increased values are difficult to interpret, because the extent of the increase depends on the method used for determination of thiobarbituric acid reactive material. Measuring another parameter of lipid peroxidation, i.e. ethane exhalation, there was no difference between the T-2 toxin treated rats and the controls whereas carbon tetrachloride treated rats exhaled high amounts of ethane. These results suggest that lipid peroxidation does not play a major role in T-2 toxin toxicity.
Animals↗
Dexamethasone decreases lethality of rats in acute poisoning with T-2 toxin.
T-2 toxin, a major trichothecene mycotoxin, was administered intravenously to rats. At a dose of 0.75 mg/kg two thirds of the animals died. In animals that received dexamethasone (1.6 mg/kg IV) either 30 min before or 1 h after the toxin, there was a more than fourfold reduction in lethality rate. Dexamethasone injected 3 h after the toxin was less effective. At a lethal dose of T-2 toxin (1 mg/kg IV) pretreatment with dexamethasone only delayed death, whereas lethality rate was barely affected (9/10 vs 10/10 in controls). Dexamethasone markedly reduced the incidence of lung edema and diarrhea. The incidence of hemorrhages, however, was not reduced by dexamethasone. Gastrointestinal bleeding was even more frequent in treated rats than in controls.
Acute Disease↗
Influence of quinidine on the intestinal secretion of digoxin and digitoxin in guinea pigs.
The secretion of digoxin and digitoxin into in situ perfused jejunal and colonic segments of normal or quinidine treated guinea pigs was studied. Quinidine was administered intravenously by constant rate infusion resulting in a quinidine plasma concentration of about 6 micrograms/ml. After 2 h digoxin or digitoxin was injected i.v. (10 micrograms/kg). The quinidine treatment enhanced the plasma concentration of [3H]digoxin to about 140% as compared to controls, whereas the [3H]digitoxin concentration was not influenced by the quinidine infusion. Both, digoxin and digitoxin were secreted against a concentration gradient into the intestinal lumen. During the experimental period of 180 min controls secreted 0.24% of the administered digoxin dose per cm of jejunal and 0.13% per cm of colonic segment. Quinidine treatment resulted in a decrease of the jejunal digoxin secretion to about 80% of the control values. In both, jejunum and colon the concentration ratio between lumen and plasma (L/P) was diminished by quinidine to 50% as compared with the controls. The amount of [3H]digitoxin secreted into the intestinal segments was decreased by quinidine from 0.19% of the dose/cm to 0.13% in the jejunal and from 0.17% to 0.12% in the colonic segments, respectively. The decrease of the L/P ratio for [3H]digitoxin was more pronounced in the colon (58%) than in the jejunum (77% of the control values). As compared with controls the content of [3H]digoxin in the jejunal as well as colonic tissue was decreased by quinidine to 60% or 73%, respectively. On the other hand quinidine increased the tissue content of [3H]digitoxin in jejunum (+56%) and colon (+88%). In conclusion quinidine inhibits the intestinal secretion of both, digoxin and digitoxin, possibly by different mechanisms.
Animals↗
Stimulation of the faecal excretion of 2,4,5,2',4',5'-hexachlorobiphenyl in rats by squalane.
Faecal excretion of 2,4,5,2',4',5'-hexachlorobiphenyl (6-CB) was followed for 19 weeks in rats fed a control diet, or a squalane-supplemented diet, for up to 17 weeks. In 3 d after a single oral dose of 8 mg/kg of 6-CB, 20% dose was excreted in faeces as unchanged 6-CB, which probably represents that not-absorbed. From day 4 to 133 only an additional 2-4% dose was excreted in faeces by control animals. Addition of 8% squalane to the diet 2, 6 and 15 weeks after dosing resulted in a five-fold increase of daily 6-CB excretion in faeces independent of the time of beginning the treatment. Total excretion of 6-CB in faeces from day 4 to 133 was 3.6, 6-7 and 9.3% dose after 4, 13 and 17 weeks of squalane treatment, respectively. No adverse effects of long-term squalane treatment on body-weight gain, feed efficiency and organ weights were observed. Plasma cholesterol and triglycerides were significantly lowered. Independent of the duration of treatment, the livers of rats fed the squalane-supplemented diet contained 40-50 micrograms/g squalane. Within the limits of detection no squalane could be found in lungs, kidneys, abdominal fat, spleen and blood. It is concluded that 6-CB elimination can be enhanced by oral treatment with squalane even a long time after uptake of the poison. As there was no alteration in the tissue distribution of 6-CB, the 6-CB excreted after squalane treatment probably originates from all tissues.
Animals↗
The quinidine-digoxin interaction in patients with impaired renal function.
Quinidine has been reported to reduce clearance and the distribution volume of digoxin. Data are presented indicating that serum digoxin concentration (SDC) is increased throughout the coadministration of quinidine. This strongly suggests that the quinidine-induced reduction of digoxin clearance is the main mechanism underlying this drug interaction. It has been suggested that beside renal clearance quinidine also reduces non-renal clearance of digoxin. Direct evidence is provided by a study in patients with impaired renal function. Irrespective of the degree of renal impairment, quinidine increases SDC to about the same amount as found in patients with normal renal function. Since quinidine does not interfere with plasma protein binding of digoxin, this implies a decrease in non-renal clearance. In all patient groups the incidence of this drug interaction is rather high; however, pronounced interindividual differences occur as regards the extent of the increase in SDC. Regardless of the state of renal function careful monitoring of digitalized patients is mandatory once quinidine therapy is initiated. Since it may take a week or more until a new steady state is established in patients with impaired renal function, this period of close monitoring should be extended correspondingly.
Blood Proteins↗
Serum protein binding of drugs is not altered in patients with severe chronic cardiac failure.
The aim of this study was to investigate whether serum protein binding of drugs is altered in patients with severe chronic cardiac failure. A total of 27 patients of the cardiac unit participated in the study. One group comprised 15 subjects with chronic cardiac failure (grade III-IV according to the New York Heart Association); 12 patients served as controls (grade I-II). The extent of binding was determined in the therapeutic concentration range by means of equilibrium dialysis at pH 7.4 and 37 degrees C. The binding of six marker drugs shows no difference between controls and patients with chronic cardiac failure. Furthermore, measured free fractions were in the range reported in the literature for healthy, untreated individuals. Our selection of drugs comprised substances that are representative of the three major drug-binding sites on human albumin (diazepam-digitoxin-warfarin/phenytoin). Furthermore, propranolol and imipramine represent examples of drugs binding mainly to lipo- and glycoproteins. The results suggest that the binding of most drugs encountered in clinical practice will be unchanged in patients with chronic cardiac failure.
Adult↗