Short-term dermal toxicity and mutagenicity of coal coprocessing products in the rat.

The present study was conducted to determine the dermal toxicity of coal coprocessing products and to assess their potential health hazards. Groups of 10 male and 10 female Sprague-Dawley rats were administered dermally coal coprocessing products (light gas oil, LGO; heavy gas oil I, HGOI; heavy gas oil II, HGOII) at 1 g/kg body weight/d for 14 d. The control and positive control groups received normal saline and a coal liquefaction product (CLP) at the same dose level, respectively. Treatment with either the three fractions of coprocessing products or CLP caused decreased growth rate and food consumption in animals of both sexes. Liver enlargement occurred in groups treated with HGOI, HGOII, and CLP. Decreased serum glucose was observed in animals of both sexes treated with the three fractions and CLP. Treatment with HGOI and CLP caused an elevation of hepatic microsomal ethoxyresorufin deethylase activity in the rat of both sexes. The three fractions and CLP caused mild anemia. Mild treatment-related histological changes were observed in the liver, spleen, thyroid, bone marrow, and kidney. All three fractions of coprocessing products were tested for their mutagenicity in five strains of Salmonella typhimurium: TA98, TA100, TA1535, TA1537, and TA1538. HGOI, after metabolic activation, was found to be mutagenic in the strains of TA98, TA100, and TA1538. In contrast, HGOII was mutagenic in the five strains with or without metabolic activation. These data indicate that HGOI and HGOII are more toxic than LGO, and should be subjected to further studies to determine their long-term effects.     

Kinetics and dynamics of triamterene at steady-state in patients with cirrhosis

Triamterene is a potassium-sparing diuretic used in patients with cirrhosis for the treatment of ascites. It is extensively metabolized by the liver and is subject to an important first-pass effect after oral dosing. We examined the disposition and diuretic effect of triamterene after repeated oral administration (200 mg daily for 10 days) in 7 healthy controls and 6 patients with cirrhosis and ascites. In the controls the average plasma concentration of triamterene during a dosage interval was 45 +/- 8 ng/ml and that of hydroxy-triamterene sulfate, an active metabolite of triamterene, was 967 +/- 177 ng/ml. In the cirrhotics, the mean concentration of triamterene was 586 +/- 126 ng/ml (a 13-fold increase as compared with the controls) and that of hydroxy-triamterene sulfate was 747 +/- 502 ng/ml. Sodium excretion was correlated with hydroxy-triamterene sulfate levels in the controls (r = 0.81), but in the cirrhotics the diuretic response was correlated with basal sodium excretion (r = 0.86) and was not related to either triamterene or hydroxy-triamterene plasma concentrations. Our results indicate that chronic treatment with triamterene in patients with cirrhosis and ascites results in markedly elevated plasma levels, but these changes do not have a major influence on the magnitude of the diuretic response.     

Uroscopy in the 21st century: high-field NMR spectroscopy

From the experiments described, it can be seen that there are different research approaches that can be taken and these are summarized in Table 1. Whereas much scientific research is principally hypothesis led, there remains, nevertheless, an important place for exploratory research. High resolution NMR can measure, directly and simultaneously, a wide range of endogenous metabolites in biological fluids and has the unique capability of providing structural information on the metabolites detected. It has proved to be a powerful research tool with which to study inherited metabolic diseases, renal disease, drug metabolism, and toxicity, and can be used to monitor the effects of drug therapy. For instance, by using a library of experimental toxins one can map the metabolic profile of site-specific nephron injury. With this approach in man one could eventually take an unknown disease such as Balkan nephropathy and predict the initial site of tubular injury, the mode of injury and therefore the kind of toxin capable of producing that injury. NMR spectroscopic techniques are still advancing rapidly, with ever increasing sensitivity and sophistication of NMR pulse sequences to enhance structural elucidation in complex mixtures. Given the advances in directly coupled HPLC-NMR and even HPLC-NMR-mass spectroscopy it is likely that these technologies in conjunction with pattern recognition will make major contribution to our understanding of renal processes and provide new diagnostic insights in the 21st century.      

Activation of guinea pig eosinophil respiratory burst by leukotriene B4: role of protein kinase C

Leukotriene B4 (LTB4) and the protein kinase C activator, 4-beta-phorbol dibutyrate (PDBu), both induced a pronounced and concentration-dependent stimulation of hydrogen peroxide (H2O2) generation by purified guinea pig peritoneal eosinophils in the concentration range 1 nM-1 microM. The LTB4 response was inhibited competitively by the specific LTB4 receptor antagonist, U-75302, with a KB of 25 nM, while the concentration-response curves for both stimuli were shifted rightwards (3.8-fold and 2.8-fold for LTB4 and PDBu, respectively) by the competitive protein kinase C inhibitor, 1-O-hexadecyl-2-O-methylglycerol at a concentration of 300 microM. LTB4 appears, therefore, to induce respiratory burst in eosinophils via a receptor-mediated mechanism involving protein kinase C.     

Tissue distribution metabolism and excretion of 2,2′,4,4′, 5-pentachlorodiphenyl ether in the rat

The tissue distribution, metabolism and excretion of ¹⁴C-2,2,4,4,5-pentachlorodiphenyl ether (PCDE) were studied in the rat. Radioactivity was distributed in all tissues examined, with the highest concentrations being found in the fat followed by the skin, liver, kidney and muscle. Most of the radioactivity found in the tissues was due to unchanged PCDE. Decay of PCDE in the blood was fitted to a four-compartment pharmacokinetic model, and the last compartment had a half-life of 5.8 days. A total of 55% and 1.3% of an orally administered dose was excreted in feces and urine, respectively, in 7 days. More than 64% of the fecal radioactivity was due to unchanged PCDE, while hydroxylated PCDE accounted for 23%.     

Effects of short-duration transients on cardiac rhythm

Cardiac stimulation thresholds of short-duration large-amplitude electrical transients were studied. An isolated rabbit heart model was used and transients were applied directly to the heart through electrodes of 1 mm² and 1 cm² surface area. A variety of oscillatory waveforms and pulse configurations were studied and indicated that, for transients shorter than 100 μs, stimulation thresholds approach a constant charge-transfer density of 3·4 μC cm⁻².