32P-post-labelling of 7-(3-chloro-2-hydroxypropyl)guanine in white blood cells of workers occupationally exposed to epichlorohydrin.
(1/48)Epichlorohydrin (ECH) is a simple 3-carbon epoxide of industrial importance. It has been shown to be genotoxic in several systems and carcinogenic in experimental animals. The aim of the present investigation was to study DNA adducts of ECH as a biomarker of occupational exposure to this chemical. 7-(3-Chloro-2-hydroxypropyl)guanine (7-CHP-guanine) was analysed in DNA from white blood cells using an anion exchange-based adduct enrichment protocol of the (32)P-post-labelling/HPLC-based assay. Blood samples were collected from seven workers handling ECH (exposed), nine workers not handling ECH but normally present in the premises where this chemical is used (potentially exposed) and 13 office and factory workers from locations in the plant where ECH is not handled (controls). 7-CHP-guanine was detected in five of the seven workers exposed to ECH (1.6-7.1 mol/10(9) mol nucleotides) and in two of the nine workers potentially exposed to ECH (0.8-1.5 mol/10(9) mol nucleotides). This adduct was not detected in any of the 13 controls. The difference in adduct levels between exposed workers and controls was statistically significant (Mann-Whitney test, P < 0.001), as was the difference between exposed workers and potentially exposed workers (P = 0.017). The recovery of 7-CHP-guanine in the (32)P-post-labelling assay was on average 48 +/- 7%, which is considerably higher than previously reported for other 7-alkylguanines. The method used had a limit of detection of approximately 0.4 mol adduct/10(9) mol nucleotides using 20 microg DNA. This study shows for the first time ECH-induced DNA adducts in humans and suggests that 7-CHP-guanine may be used as a biomarker of occupational exposure to ECH. (+info)
Rapid improvement of icterus and pruritus by the oral administration of colestimide in two cases of drug-induced hepatitis.
(2/48)We report two cases of drug-induced hepatitis refractory to therapy of ursodeoxycholic acid and prednisolone, who were relieved of icterus and pruritus immediately by the oral administration of colestimide. Their liver dysfunction was not improved, by withdrawal of causative drugs or by treatment with prednisolone and ursodeoxycholic acid. Colestimide (3.0 g/day), a strong basic anion-exchange resin, was orally taken before breakfast and evening meal, leading to rapid and complete relief of icterus and pruritus. These cases suggested that colestimide would be useful for patients with cholestasis in drug-induced hepatitis, because this agent has few side effects and it is easy to take. (+info)
Release behaviour of drugs from tamarind seed polysaccharide tablets.
(3/48)PURPOSE: This study examines the sustained release behaviour of both water-soluble (acetaminophen, caffeine, theophylline and salicylic acid) and water insoluble (indomethacin) drugs from tamarind seed polysaccharide isolated from tamarind kernel powder. It further investigates the effect of incorporation of diluents like microcrystalline cellulose and lactose on release of caffeine and partial cross-linking of the polysaccharide on release of acetaminophen. Applying exponential equation, the mechanism of release of soluble drugs was found to be anomalous. The insoluble drug showed near case II or zero order release mechanism. The rate of release was in the decreasing order of caffeine, acetaminophen, theophylline, salicylic acid and indomethacin. An increase in release kinetics of drug was observed on blending with diluents. However, the rate of release varied with type and amount of blend in the matrix. The mechanism of release due to effect of diluents was found to be anomalous. The rate of release of drug decreased on partial cross-linking and the mechanism of release was found to be super case II. (+info)
Colestimide can be used as a phosphate binder to treat uraemia in end-stage renal disease patients.
(4/48)Colestimide is a potent therapeutic compound used widely for treatment of hypercholesterolaemia, and it was discovered coincidentally that it can be used to lower the serum phosphate concentration in cases of secondary hyperparathyroidism with refractory hyperphosphataemia. Colestimide is useful for treating hyperphosphataemia in end-stage renal disease (ESRD) patients undergoing haemodialysis. Twenty-eight patients who were being treated for hyperphosphataemia with 3.5+/-1.1 g/day calcium carbonate were enrolled in the study. Colestimide was added to their prescription for 4 weeks at a mean dosage of 2.3 g/day. The serum phosphate concentration decreased significantly from 6.1+/-1.1 mg/dl before treatment to 5.3+/-1.1 mg/dl at 4 weeks (P<0.0001). The calcium-phosphate product also decreased significantly from 59.6+/-11.3 mg/dl(2) before treatment to 50.5+/-12.0 mg/dl(2) (P<0.0001). The serum total cholesterol significantly (P<0.001) decreased at 1 week and remained constant until the end of treatment. Colestimide is a cationic polymer with chloride as the counterion. Its chemical structure resembles that of sevelamer hydrochloride, which is already being used clinically as a phosphate binder. This suggests that colestimide uses the same mechanism as sevelamer hydrochloride to treat hyperphosphataemia. The present results demonstrate that colestimide can function as a Ca-free, aluminium-free, non-absorbable, phosphate binder in ESRD patients. In addition, colestimide can reduce the serum phosphate concentration in combination with calcium carbonate. (+info)
Active site engineering of the epoxide hydrolase from Agrobacterium radiobacter AD1 to enhance aerobic mineralization of cis-1,2-dichloroethylene in cells expressing an evolved toluene ortho-monooxygenase.
(5/48)Chlorinated ethenes are the most prevalent ground-water pollutants, and the toxic epoxides generated during their aerobic biodegradation limit the extent of transformation. Hydrolysis of the toxic epoxide by epoxide hydrolases represents the major biological detoxification strategy; however, chlorinated epoxyethanes are not accepted by known bacterial epoxide hydrolases. Here, the epoxide hydrolase from Agrobacterium radiobacter AD1 (EchA), which enables growth on epichlorohydrin, was tuned to accept cis-1,2-dichloroepoxyethane as a substrate by accumulating beneficial mutations from three rounds of saturation mutagenesis at three selected active site residues, Phe-108, Ile-219, and Cys-248 (no beneficial mutations were found at position Ile-111). The EchA F108L/I219L/C248I variant coexpressed with a DNA-shuffled toluene ortho-monooxygenase, which initiates attack on the chlorinated ethene, enhanced the degradation of cis-dichloroethylene (cis-DCE) an infinite extent compared with wild-type EchA at low concentrations (6.8 microm) and up to 10-fold at high concentrations (540 microm). EchA variants with single mutations (F108L, I219F, or C248I) enhanced cis-DCE mineralization 2.5-fold (540 microm), and EchA variants with double mutations, I219L/C248I and F108L/C248I, increased cis-DCE mineralization 4- and 7-fold, respectively (540 microm). For complete degradation of cis-DCE to chloride ions, the apparent Vmax/Km for the Escherichia coli strain expressing recombinant the EchA F108L/I219L/C248I variant was increased over 5-fold as a result of the evolution of EchA. The EchA F108L/I219L/C248I variant also had enhanced activity for 1,2-epoxyhexane (2-fold) and the natural substrate epichlorohydrin (6-fold). (+info)
Pilot study to reduce dioxins in the human body.
(6/48)OBJECTIVE: The accumulation of dioxins, characterized by its lipophilicity and persistency in human tissue, is a great concern since many of these compounds elicit adverse health effects and developmental toxicity. Although the half-life of dioxins in the human body have been described to be as long as 3-25 years, there are very few drugs or methods that can exclude them from the human body. Thus, it is necessary to establish a new method to reduce them and prevent adverse health effects. Here, a pilot study to reduce the dioxins accumulated in the human body using the cholesterol-lowering drug, colestimide, is reported. PATIENTS AND METHODS: Eight male and two female subjects were investigated. All of them were treated with colestimide for six months, and the dioxin level of the blood samples was assessed before and after the treatment. The dioxins in the blood samples were measured by gas-chromatography/mass spectrometry. RESULTS: Nine out of the ten subjects completed the treatment, and their blood samples were analyzed. The mean dioxin level in the blood samples before the treatment was 44.0 +/- 8.22 pg-TEQ/g-fat. Six months later, the mean dioxin level was lowered about 20% on average to 34.7 +/- 5.49 pg-TEQ/g-fat. CONCLUSION: Previous studies have reported that the blood dioxin level increases with age. In this study, the results suggest that colestimide can decrease the blood dioxin level of humans. A randomized placebo-controlled clinical study including large numbers of subjects are needed to confirm the present result. (+info)
Polymorphonuclear leukocytes may impair endothelial function: results of crossover randomized study of lipid-lowering therapies.
(7/48)OBJECTIVES: To examine whether polymorphonuclear leukocytes (PMNs) in hypercholesterolemia (HC) are activated to generate large amount of superoxide in vivo and hence impair endothelial function and, if so, whether statins, which possess anti-inflammatory properties, may restore PMN-mediated endothelial dysfunction. METHODS AND RESULTS: At baseline, subjects with HC showed impaired endothelial function (P<0.001), estimated by flow-mediated vasodilation of the brachial artery, and increased susceptibility of low-density lipoprotein (LDL) to oxidation (P<0.0001) compared with control subjects. PMNs obtained from HC produced greater amount of superoxide (P<0.0001), showed higher adhesiveness to cultured endothelial cells (HUVECs) (P<0.0001), and impaired endothelial nitric oxide synthase (eNOS) Ser1177 phosphorylation of HUVECs compared with controls (P<0.001). Crossover administration of fluvastatin or colestimide for 3 months lowered LDL to the same levels (P<0.001 for both). Endothelial function was restored (P<0.0001). LDL oxidation (P<0.0001) and superoxide release from PMNs (P<0.0001) were diminished only in fluvastatin but not in colestimide arm. Fluvastatin attenuated PMN adhesion to HUVECs (P<0.0001) and restored eNOS Ser1177 phosphorylation of HUVECs (P<0.001). CONCLUSIONS: Statins may improve endothelial function at least in part by inactivating neutrophils independently of LDL reduction. Our results raise a novel concept that polymorphonuclear leukocytes may attack endothelia and play a pivotal role in the pathogenesis of atherosclerosis. (+info)
Efficacy of colestimide coadministered with atorvastatin in japanese patients with heterozygous familial hypercholesterolemia (FH).
(8/48)BACKGROUND: Colestimide, a 2-methylimidazole-epichlorohydrin polymer, is a new bile-acid-sequestering resin, that is 4-fold as powerful at lowering low-density lipoprotein cholesterol (LDL-C) as the conventional resin (cholestyramine). Moreover, colestimide has excellent patient compliance because it is available in tablet form. METHODS AND RESULTS: The clinical efficacy of colestimide coadministered with atorvastatin on lipid and apolipoprotein concentrations was examined in 15 patients (M/F=10/5, mean+/-SE age=54+/-9 years) with heterozygous familial hypercholesterolemia (FH). After a period of wash-out of any lipid-lowering drugs, atorvastatin (20-40 mg) was administered to patients for at least 8 weeks, and then 3 g of colestimide was administered for a further 8 weeks. Total and LDL-C significantly (<0.0001) decreased by 35% from 361 to 233 mg/dl and 41% from 274 to 161 mg/dl, respectively. Addition of colestimide caused a further significant 12% and 20% reduction, respectively, from the initial values to 205 and 129 mg/dl, respectively. Colestimide was also effective in reducing serum LDL-C concentrations in heterozygous FH patients with hypertriglyceridemia (triglycerides>or=150 mg/dl). CONCLUSIONS: When monotherapy with atorvastatin is insufficient to treat severely hypercholesterolemic patients, such as those with heterozygous FH, colestimide acts to reinforce the action of statins. (+info)