Effects of co-formulants on the absorption and secretion of active substances in plant protection products in vitro.

Currently, the authorisation process for plant protection products (PPPs) relies on the testing of acute and topological toxicity only. Contrastingly, the evaluation of active substances includes a more comprehensive set of toxicity studies. Nevertheless, mixture effects of active ingredients and co-formulants may result in increased toxicity. Therefore, we investigated effects of surface active co-formulants on the toxicity of two PPPs focussing on qualitative and quantitative toxicokinetic effects on absorption and secretion. The respective products are based on the active substances abamectin and fluroxypyr-meptyl and were tested for cytotoxicity in the presence or absence of the corresponding surfactants and co-formulants using Caco-2 cells. In addition, the effect of co-formulants on increased cellular permeation was quantified using LC-MS/MS, while potential kinetic mixture effects were addressed by fluorescence anisotropy measurements and ATPase assays. The results show that surface active co-formulants significantly increase the cytotoxicity of the investigated PPPs, leading to more than additive mixture effects. Moreover, analytical investigations show higher efflux ratios of both active substances and the metabolite fluroxypyr upon combination with certain concentrations of the surfactants. The results further point to a significant and concentration-dependent inhibition of Pgp transporters by most of the surfactants as well as to increased membrane fluidity. Altogether, these findings strongly support the hypothesis that surfactants contribute to increased cytotoxicity of PPPs and do so by increasing the bioavailability of the respective active substances.

Chitosan coated nanoparticles for efficient delivery of bevacizumab in the posterior ocular tissues via subconjunctival administration.

In several ocular diseases, vascular endothelial growth factor (VEGF) level has been found to be unregulated. Bevacizumab, an anti-VEGF drug, is the most commonly used off level drug for diabetic retinopathy (DR). The present study was to evaluate the chitosan-coated poly (lactide-co-glycolic acid) nanoparticles (CS-PLGA NPs) for sustained and effective delivery of bevacizumab to posterior ocular tissues. The penetration of NP through sclera was studied by confocal laser scanning microscopy (CLSM). For pharmacokinetic study, bevacizumab loaded NPs were administered into the rat eye through subconjunctival injection (SCJ) and pharmacokinetic parameters were compared to drug solution. CLSM and pharmacokinetic study showed better penetration of formulation and higher concentration of bevacizumab in posterior ocular tissues. In retinopathy model, CS-PLGA NPs by SCJ route showed more reduction of VEGF level in retina than the topical and intravitreal administration of formulation. Thus, CS-coated PLGA NPs can be potentially useful as carriers to target retina.

Review of the pharmacokinetics and metabolism of triclopyr herbicide in mammals: Impact on safety assessments.

A review of pharmacokinetic and metabolism studies show that triclopyr is well absorbed from the oral route in numerous species (≥80%), primarily as parent compound. Absorption is quite rapid in rats, dogs and human volunteers. Plasma or blood clearance is also rapid (t1/2 3-9 h), except for dog (12-96 h). Systemic exposure is not dose-proportional: in the rat above 20 mg/kg (dietary) or between 3 and 60 mg/kg (gavage), or in dogs above 5 mg/kg, with systemic exposure in human more comparable to rat than dog. Triclopyr is highly bound to protein in rat, dog and human plasma (≥97% at or below 7 µg/mL), indicating that species differences in systemic exposure are not due to differences in the free fraction of this test material in plasma. An in vitro flux study in renal proximal tubule cells showed that net renal transport of triclopyr is in the direction of secretion in rat and human donors, while reabsorption predominated in the dog, possibly via organic anion transporters such as OAT1/3. These results fit well into the framework of utilizing metabolism and toxicokinetics across species and exposure levels to allow for toxicity testing in the most relevant species as well as at proper dose levels.

In-vivo evidence of nephrotoxicity and altered hepatic function in rats following administration of diglycolic acid, a metabolite of diethylene glycol.

CONTEXT: Diglycolic acid (DGA) is one of the two primary metabolites of diethylene glycol (DEG). DEG is an industrial solvent that has been implicated in mass poisonings resulting from product misuse in the United States and worldwide, with the hallmark toxicity being acute kidney injury, hepatotoxicity, encephalopathy and peripheral neuropathy. Our laboratory has generated in-vitro evidence suggesting that DGA is the metabolite responsible for the proximal tubule necrosis and decreased kidney function observed following DEG ingestion. Furthermore, we have shown that DGA specifically accumulates in kidney tissues (100× higher than peak blood concentrations) following DEG administration. OBJECTIVE: To examine renal and hepatic accumulation and dysfunction following direct administration of DGA in-vivo. We hypothesize that administration of DGA will result in renal and hepatic DGA accumulation, as well as proximal tubular necrosis and liver injury. MATERIALS AND METHODS: Adult male Wistar rats were divided into three groups dosed with 0, 100 or 300 mg/kg DGA via single oral gavage. Urine was collected every 6-12 h and blood, kidneys and liver were removed upon sacrifice at 48 h post-dosing for analysis. RESULTS: DGA accumulated significantly in both kidney and liver tissue only at 300 mg DGA/kg. DGA concentrations in the kidneys and liver correlated with renal and hepatic injury, respectively. Histopathological and clinical chemistry analysis revealed that DGA-treated animals exhibited moderate liver fatty accumulation and marked renal injury, again only at 300 mg/kg. DISCUSSION: DGA-induced kidney injury demonstrated a steep dose response threshold, where severe damage occurred only in animals given 300 mg/kg DGA, while no toxicity was observed at 100 mg/kg. CONCLUSION: These results provide evidence for in-vivo toxicity following direct administration of DGA, a metabolite of DEG. The steep dose-response threshold for toxicity suggests mechanistically that there is likely a saturable step that results in DGA accumulation in target organs.

A rapid and efficient analytical method for the quantification of a novel anticholinergic compound, R-phencynonate, by stable isotope-dilution LC-MS/MS and its application to bioavailability and dose proportionality studies.

A rapid, specific and high-throughput stable isotope-dilution LC-MS/MS method was developed and validated with high sensitivity for the quantification of R-phencynonate (a eutomer of phencynonate racemate) in rat and dog plasma. Plasma samples were deproteinized using acetonitrile and then separated on a C8 column with an isocratic mobile phase containing acetonitrile-water-formic acid mixture (60:40:0.1, v/v/v) at a flow rate of 0.2 mL/min. Each sample had a total run time of 3 min. Quantification was performed using triple quadrupole mass spectrometry in selected reaction monitoring mode with positive electrospray ionization. The method was shown to be highly linear (r2 > 0.99) and to have a wide dynamic range (0.1-100 ng/mL) with favourable accuracy and precision. No matrix effects were observed. The detailed pharmacokinetic profiles of R-phencynonate at therapeutic doses in rats and dogs were characterized by rapid oral absorption, quick clearance, high volume of distribution and poor absolute bioavailability. R-Phencynonate lacked dose proportionality over the oral dose range, based on the power model. However, the area under concentration-time curve and the maximum plasma concentration increased linearly in a dose-dependent manner in both animal models. The absolute bioavailability of R-phencynonate was 16.6 ± 2.75 and 4.78 ± 1.26% in dogs and rats, respectively.

Mutagenesis Analysis Reveals Distinct Amino Acids of the Human Serotonin 5-HT2C Receptor Underlying the Pharmacology of Distinct Ligands.

While exploring the structure-activity relationship of 4-phenyl-2-dimethylaminotetralins (PATs) at serotonin 5-HT2C receptors, we discovered that relatively minor modification of PAT chemistry impacts function at 5-HT2C receptors. In HEK293 cells expressing human 5-HT2C-INI receptors, for example, (-)-trans-3'-Br-PAT and (-)-trans-3'-Cl-PAT are agonists regarding Gαq-inositol phosphate signaling, whereas (-)-trans-3'-CF3-PAT is an inverse agonist. To investigate the ligand-receptor interactions that govern this change in function, we performed site-directed mutagenesis of 14 amino acids of the 5-HT2C receptor based on molecular modeling and reported G protein-coupled receptor crystal structures, followed by molecular pharmacology studies. We found that S3.36, T3.37, and F5.47 in the orthosteric binding pocket are critical for affinity (Ki) of all PATs tested, we also found that F6.44, M6.47, C7.45, and S7.46 are primarily involved in regulating EC/IC50 functional potencies of PATs. We discovered that when residue S5.43, N6.55, or both are mutated to alanine, (-)-trans-3'-CF3-PAT switches from inverse agonist to agonist function, and when N6.55 is mutated to leucine, (-)-trans-3'-Br-PAT switches from agonist to inverse agonist function. Notably, most point-mutations that affected PAT pharmacology did not significantly alter affinity (KD) of the antagonist radioligand [3H]mesulergine, but every mutation tested negatively impacted serotonin binding. Also, amino acid mutations differentially affected the pharmacology of other commercially available 5-HT2C ligands tested. Collectively, the data show that functional outcomes shared by different ligands are mediated by different amino acids and that some 5-HT2C receptor residues important for pharmacology of one ligand are not necessarily important for another ligand.

Supramolecular Cocrystals of Gliclazide: Synthesis, Characterization and Evaluation.

PURPOSE: To prepare the supramolecular cocrystals of gliclazide (GL, a BCS class II drug molecule) via mechanochemical route, with the goal of improving physicochemical and biopharmaceutical properties. METHODS: Two cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB; 1:1) and α-hydroxyacetic acid (GL-HA; 1:1) were screened out using liquid assisted grinding. The prepared cocrystals were characterized using thermal and analytical techniques followed by evaluation of antidiabetic activity and pharmacokinetic parameters. RESULTS: The generation of new, single and pure crystal forms was characterized by DSC and PXRD. The crystal structure determination from PXRD revealed the existence of both cocrystals in triclinic (P-1) crystal system. The hydrogen bonded network, determined by material studio was well supported by shifts in FTIR and SSNMR. Both the new solid forms displayed improved solubility, IDR, antidiabetic activity and pharmacokinetic parameters as compared to GL. CONCLUSIONS: The improvement in these physicochemical and biopharmaceutical properties corroborated the fact that the supramolecular cocrystallization may be useful in the development of pharmaceutical crystalline materials with interesting network and properties.

Uptake of triclopyr (3,5,6-trichloro-2-pyridinyloxyacetic acid) and dicamba (3,6-dichloro-2-methoxybenzoic acid) from the apical membranes of the human intestinal Caco-2 cells.

We investigated whether the uptake of triclopyr (3, 5, 6-trichloro-2-pyridinyloxyacetic acid) and dicamba (3,6-dichloro-2-methoxybenzoic acid) across the apical membrane of Caco-2 cells was mediated via proton-linked monocarboxylic acid transporters (MCTs). The uptake of triclopyr from the apical membranes was fast, pH-, temperature-, and concentration dependent, required metabolic energy to proceed, and was competitively inhibited by monocarboxylic acids such as benzoic acid and ferulic acid (substrates of L-lactic acid-insensitive MCTs), but not by L-lactic acid. Thus, the uptake of triclopyr in Caco-2 cells appears to be mediated mainly via L-lactic acid-insensitive MCTs. In contrast, the uptake of dicamba (a benzoic acid derivative) was slow, and it was both pH- and temperature dependent. Coincubation with ferulic acid did not decrease the uptake of dicamba, although coincubation with benzoic acid moderately decreased it. The uptake of dicamba appears to be mediated mainly via passive diffusion, which is in contrast to the uptake of benzoic acid via MCTs. We speculate that the substituted groups in dicamba may inhibit uptake via MCTs.

Stereoselective metabolism of the herbicide fluroxypyr methylheptyl ester in rabbits.

We investigated the stereoselective degradation kinetics of fluroxypyr methylheptyl ester (FPMH) in rabbits using a chiral high-performance liquid chromatographic method. In 20% rabbit plasma, the half lives of (+)-FPMH and (-)-FPMH were 2.5 and 10.9 min, respectively. Thus, the enantioselective degradation was faster for (+)-FPMH than for (-)-FPMH in rabbit plasma in vitro, and there was no chiral conversion or transformation during incubation of the plasma. The degradation of (+)-FPMH was also much faster than that of the (-)-FPMH in the kidney, lung, and muscle after the intravenous administration of 50 mg/kg racemic FPMH (rac-FPMH), whereas the concentrations of FPMH were below the limit of quantification in other tissues. Furthermore, 98% rac-FPMH was quickly (within 10 min) hydrolyzed to fluroxypyr (FP) in rabbit liver microsomes. Therefore, we examined FP in rabbit plasma and tissues in vivo. We detected FP in all tissues; its concentration was higher in the urine than in the other tissues. FP was rapidly excreted unchanged, principally in the urine. The data presented here are important for a more thorough understanding of this pesticide and should be useful for its full environmental assessment.

Concurrent 2,4-D and triclopyr biomonitoring of backpack applicators, mixer/loader and field supervisor in forestry.

Two herbicides, 2,4-D and triclopyr esters (application ratio 1.6:1 acid equivalents) were applied as a tank mix by a crew of 8 backpack sprayer applicators, a mixer/loader, and a field supervisor. The crew was employed in a conifer release program in northern California during the summer of 2002. Biomonitoring (urine, 24 h) utilized 2,4-D and triclopyr (a.e.) as rapidly excreted exposure biomarkers. The absorbed dosages of 2,4-D and triclopyr were calculated based upon cotton whole body suits and biomonitoring. Dosages based upon accumulation of the herbicides on body suits averaged 42.6 µg (a.e.) 2,4-D/kg-d and 8.0 µg (a.e.) triclopyr/kg-d. Six consecutive days of concurrent urine collections showed that backpack applicators excreted an average of 11.0 µg (a.e.) 2,4-D/kg-d and 18.9 µg (a.e.) triclopyr/kg-d. Estimates based upon curve fitting were 17.1 and 29.3 µg (a.e.)/kg-d, respectively. Results suggest that passive dosimetry for 2,4-D consistently overestimated the dosage measured using biomonitoring by a factor of 2-3 fold, while for triclopyr, passive dosimetry underestimated the absorbed dose based on biomonitoring by a factor of 2-4 fold.

Extension of a PBPK model for ethylene glycol and glycolic acid to include the competitive formation and clearance of metabolites associated with kidney toxicity in rats and humans.

A previously developed PBPK model for ethylene glycol and glycolic acid was extended to include glyoxylic acid, oxalic acid, and the precipitation of calcium oxalate that is associated with kidney toxicity in rats and humans. The development and evaluation of the PBPK model was based upon previously published pharmacokinetic studies coupled with measured blood and tissue partition coefficients and rates of in vitro metabolism of glyoxylic acid to oxalic acid, glycine and other metabolites using primary hepatocytes isolated from male Wistar rats and humans. Precipitation of oxalic acid with calcium in the kidneys was assumed to occur only at concentrations exceeding the thermodynamic solubility product for calcium oxalate. This solubility product can be affected by local concentrations of calcium and other ions that are expressed in the model using an ion activity product estimated from toxicity studies such that calcium oxalate precipitation would be minimal at dietary exposures below the NOAEL for kidney toxicity in the sensitive male Wistar rat. The resulting integrated PBPK predicts that bolus oral or dietary exposures to ethylene glycol would result in typically 1.4-1.6-fold higher peak oxalate levels and 1.6-2-fold higher AUC's for calcium oxalate in kidneys of humans as compared with comparably exposed male Wistar rats over a dose range of 1-1000 mg/kg. The converse (male Wistar rats predicted to have greater oxalate levels in the kidneys than humans) was found for inhalation exposures although no accumulation of calcium oxalate is predicted to occur until exposures are well in excess of the theoretical saturated vapor concentration of 200mg/m(3). While the current model is capable of such cross-species, dose, and route-of-exposure comparisons, it also highlights several areas of potential research that will improve confidence in such predictions, especially at low doses relevant for most human exposures.

Immunopotentiation of hepatitis B vaccine using biodegradable polymers as an adjuvant.

BACKGROUND/PURPOSE: The purpose of this research was to develop an alternative adjuvant for hepatitis B vaccine (HBsAg) that elicits a long-lasting immune response after a single administration. In this study, the suitability of Poly (D, L)-lactide-co-glycolic acid (PLGA), Poly lactic acid (PLA) and Chitosan polymers as adjuvants for HBsAg were investigated. METHODS: We used solvent evaporation and emulsion cross-linking techniques to encapsulate HBsAg into the different polymeric systems. The newly developed microparticles were evaluated for vaccine content, particle size distribution, in vitro release and immunogenicity. RESULTS: HBsAg-encapsulated PLGA and PLA microparticles were smooth and spherical. However, Chitosan microparticles were homogeneous, and almost spherical, with rough surfaces. The vaccine loading and release patterns varied with the type of polymer used. In this study, Chitosan polymeric microparticles released antigen until day 63 post-injection; however, the release period of the PLGA and PLA systems was shorter. A significant increase in the level of antibodies to HBsAg was induced by all the polymeric microparticles. CONCLUSION: The results indicate that Chitosan microparticles are a more efficient adjuvant for HBsAg than PLGA and PLA polymeric microparticles.

Correlation of hydrolytic degradation with structure for copolyesters produced from glycolic and adipic acids.

Copolyesters based on glycolic acid (G) combined with adipic acid (A) and ethylene glycol (E) were synthesized in different percentage of molar ratios (A: 100-50% and G: 100%) and their hydrolytic degradation was studied and correlated with their structures. According to the DSC, the production of polyesters leads to the formation of copolyesters and not to mixtures of homopolyesters. The crystallites in the copolyesters mainly consist of continuous sequences of ethylene adipate structural units. The hydrolytic degradation of the polyesters was followed by their weight loss during hydrolysis and by the FTIR spectra of the initial polyesters compared with that of the degraded polyesters at equilibrium. The region between 1142 and 800 cm(-1) can be utilized to evaluate the extent of degradation of polyesters after their hydrolysis. The absorption bands at 1142, 1077 and 850 cm(-1) due to the amorphous region decrease after hydrolysis, whereas those at 972, 901 and 806 cm(-1) due to the crystalline region increase. The experimental data of the hydrolytic degradation were fitted with exponential rise to maximum type functions using two-parameter model, which describes very well mainly the initial part of the degradation, and four-parameter model (containing two exponential terms), which is appropriate for fitting the hydrolytic degradation on the entire time period (including the equilibrium). Furthermore, the kinetics of the hydrolytic degradation of the polyesters for the initial time period based on both models results to similar values of the rate constant, k. The synthesized copolyesters of glycolic acid combined with adipic acid and ethylene glycol are soluble in many common organic solvents opposite to PGA, leading to modified biodegradable polyesters and therefore they can be easily processed.

Final amended report on the safety assessment of Ammonium Thioglycolate, Butyl Thioglycolate, Calcium Thioglycolate, Ethanolamine Thioglycolate, Ethyl Thioglycolate, Glyceryl Thioglycolate, Isooctyl Thioglycolate, Isopropyl Thioglycolate, Magnesium Thioglycolate, Methyl Thioglycolate, Potassium Thioglycolate, Sodium Thioglycolate, and Thioglycolic Acid.

This safety assessment includes Ammonium and Glyceryl Thioglycolate and Thioglycolic Acid Butyl, Calcium, Ethanolamine, Ethyl, Isooctyl, Isopropyl, Magnesium, Methyl, Potassium, and Sodium Thioglycolate, as used in cosmetics. Thioglycolates penetrate skin and distribute to the kidneys, lungs, small intestine, and spleen; excretion is primarily in urine. Thioglycolates were slightly toxic in rat acute oral toxicity studies. Thioglycolates are minimal to severe ocular irritants. Thioglycolates can be skin irritants in animal and in vitro tests, and can be sensitizers. A no-observable-adverse-effect level for reproductive and developmental toxicity of 100 mg/kg per day was determined using rats. Thioglycolates were not mutagenic, and there was no evidence of carcinogenicity. Thioglycolates were skin irritants in some clinical tests. Clinically significant adverse reactions to these ingredients used in depilatories are not commonly seen, suggesting current products are formulated to be practically nonirritating under conditions of recommended use. Formulators should take steps necessary to assure that current practices are followed.

PEGylated PLGA nanoparticles for the improved delivery of doxorubicin.

We hypothesize that the efficacy of doxorubicin (DOX) can be maximized and dose-limiting cardiotoxicity minimized by controlled release from PEGylated nanoparticles. To test this hypothesis, a unique surface modification technique was used to create PEGylated poly(lactic-co-glycolic acid) (PLGA) nanoparticles encapsulating DOX. An avidin-biotin coupling system was used to control poly(ethylene glycol) conjugation to the surface of PLGA nanoparticles, of diameter approximately 130 nm, loaded with DOX to 5% (wt/wt). Encapsulation in nanoparticles did not compromise the efficacy of DOX; drug-loaded nanoparticles were found to be at least as potent as free DOX against A20 murine B-cell lymphoma cells in culture and of comparable efficacy against subcutaneously implanted tumors. Cardiotoxicity in mice as measured by echocardiography, serum creatine phosphokinase (CPK), and histopathology was reduced for DOX-loaded nanoparticles as compared with free DOX. Administration of 18 mg/kg of free DOX induced a sevenfold increase in CPK levels and significant decreases in left ventricular fractional shortening over control animals, whereas nanoparticle-encapsulated DOX produced none of these pathological changes. FROM THE CLINICAL EDITOR: The efficacy of doxorubicin (DOX) may be maximized and dose-limiting cardiotoxicity minimized by controlled release from PEGylated nanoparticles. Administration of 18 mg/kg of free DOX induced a sevenfold increase in CPK levels and significant decreases in left ventricular fractional shortening in mice, whereas nanoparticle-encapsulated DOX produced none of these pathological changes.

Inhalation and epidermal exposure of volunteers to ethylene glycol: kinetics of absorption, urinary excretion, and metabolism to glycolate and oxalate.

Ethylene glycol (EG) is a widely used liquid. Limited data are published regarding inhaled EG and no data regarding transdermal EG uptake in humans. In order to gain information on the quantitative fate of EG, four male volunteers inhaled between 1340 and 1610 micromol vaporous 13C-labeled EG (13C2-EG) for 4h. Separately, three of these subjects were epidermally exposed for up to 6h to liquid 13C2-EG (skin area 66 cm2). Plasma concentrations and urinary amounts of 13C2-EG were determined by gas chromatography with mass selective detection. Additionally, plasma was assayed for 13C-labeled glycolic acid 13C2-GA) and urine for 13C2-GA and 13C-labeled oxalic acid (13C2-OA). Both EG metabolites were nephrotoxic in animals and humans and embryotoxic in rodents. 13C-labels enabled to differentiate from also determined endogenous EG, glycolic acid (GA), and oxalic acid (OA). Of 13C2-EG inhaled, 5.5+/-3.0%, 0.77+/-0.15%, and 0.10+/-0.12% were detected in urine as 13C2-EG, 13C2-GA, and 13C2-OA, respectively. The skin permeability constant of liquid EG was 2.7 x 10(-5)+/-0.5 x 10(-5)cm/h. Of the dose taken up transdermally, 8.1+/-3.2% and up to 0.4% were excreted in urine as 13C2-EG and 13C2-GA, respectively. It is calculated that equally long-lasting exposure to 10 ppm vaporous EG or wetting of both hands by liquid EG leads to about the same body burden by EG and metabolites. The amounts of GA and OA excreted daily in urine as a result of exposure (8h/day) to 10 ppm EG are about 15% and 2%, respectively, of those excreted from naturally occurring endogenous GA and OA.

Comparative pharmacokinetics and distribution kinetics in brain of phencynonate enantiomers in rats.

To investigate the pharmacokinetics in blood and the distribution kinetics in brain of enantiomers of novel anticholinergic agent phencynonate (N-methyl-9alpha-(3-azabicyclo[3,3,1]nonanyl)-2'-cyclopentyl-2'-hydroxyl-2'-phenylacetate), we collected blood and implanted microdialysis probes in the cerebral frontal cortex of rats. Phencynonate enantiomers (0.35 mg/kg, i.m.) were then cross administered, and the microdialysates were collected using in situ microdialysis sampling in the brain of freely moving rats, and the concentration of phencynonate enantiomers was determined by the validated method of liquid chromatography-mass spectrometry. Pharmacokinetic parameters were calculated from the blood and the brain dialysate concentrations of phencynonate enantiomers versus time data. The disposition profiles of the phencynonate enantiomers were best fitted to a first order absorption, two-compartment open model in rats. In general, there were some differences when comparing the mean kinetic parameters of S- and R-phencynonate in the blood and brain, but the distinct diversity between individual animals made the statistical difference not obvious. Therefore, stereoselective disposition of phencynonate isomers was not obviously observed in rat.

Priming dose of phenylhydrazine protects against hemolytic and lethal effects of 2-butoxyethanol.

Protection against a high dose of a toxicant by prior exposure to another toxicant is called heteroprotection. Our objective was to establish a heteroprotection model in RBCs. Female Sprague Dawley rats treated with an LD90 dose of 2-butoxyethanol (BE, 1500 mg/kg in water, 5 ml/kg po) 14 days after priming with 0.9% NaCl suffered 90% mortality by 15 days, whereas all rats receiving the LD90 dose of BE 14 days after priming with phenylhydrazine (PHZ, 125 mg/kg in 0.9% NaCl, 3 ml/kg po) survived. Hematocrit decreased from normal 45% to 24% by day 3 after PHZ priming and improved thereafter. Increasing the time interval between the priming and LD90 dose to 21 days abolished the heteroprotection. RBCs obtained on days 7 and 14 after PHZ priming unlike those on day 21 were resilient to the hemotoxic metabolite of BE, butoxyacetic acid (BAA). Unaltered hepatic alcohol and aldehyde dehydrogenase activities upon PHZ priming suggested that bioactivation of BE to BAA was unaffected. Lower renal (6 and 12 h) and hepatic (12 h) BAA levels and 3 fold higher excretion of BAA in PHZ-primed rat urine suggested a protective role of toxicokinetics. Higher erythropoietin, reticulocytes, and resiliency of PHZ-primed rat RBCs indicated that newly formed RBCs are resilient to hemolytic BAA. The antioxidant levels in the PHZ-primed rat RBCs did not indicate a protective role in heteroprotection. In conclusion, the resistance of PHZ-primed rats against BE-induced hemotoxicity and lethality is mediated by a combination of altered toxicokinetics, robust erythropoiesis, and resiliency of new RBCs.

Discovery of para-alkylthiophenoxyacetic acids as a novel series of potent and selective PPARdelta agonists.

A novel series of potent and selective PPARdelta agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described.

Sistema intravítreo bioerudivel de liberación prolongada de microesferas de triamcinolona (RETAAC). Comunicación preliminar de su utilidad potencial para el tratamiento del edema macular diabético / Intravitreal bioerudivel sustained-release triamcinolone microspheres system (RETAAC). Preliminary report of its potential usefulnes for the treatment of diabetic macular edema

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