Effects of purified and technical piperonyl butoxide on drug-metabolizing enzymes and ultrastructure of rat liver

Weanling male rats were fed technical grade piperonyl butoxide at dietary levels of 1000, 5000 and 10,000 ppm for 1, 4 and 8 weeks and 100 ppm for 1 week. Activities of hexobarbital oxidase, aniline hydroxylase, p-nitroanisole-demethylase, nitroreductase, glucuronyltransferase and P-450 content were increased 2- to 4-fold by 5000 or 10,000 ppm technical grade piperonyl butoxide. Liver weight and microsomal protein were increased a maximum of 50–70% by piperonyl butoxide. Electron microscopy showed enlargement and extensive proliferation of the smooth endoplasmic reticulum (SER) in liver parenchymal cells of rats fed 5000 or 10,000 ppm technical grade piperonyl butoxide. A dose of 1000 ppm produced minimal effects on liver weight, P-450, and glucuronyltransferase activity, but no effects of this dose could be detected on proliferation of the SER. Maximum induction of P-450 and the drug-metabolizing enzymes which require P-450 occurred after 1 week of exposure with all doses of piperonyl butoxide. In contrast, the effects of 10,000 ppm piperonyl-butoxide on liver weight, cellular hypertrophy and SER proliferation appeared greater after 8 weeks than after 1 week. No differences in the degree of SER proliferation could be detected after different lengths of exposure to 5000 ppm piperonyl butoxide. Glucuronyl transferase activity was induced maximally between 4 and 8 weeks at all dose levels. Purified and technical grade piperonyl butoxide (10,000 ppm) were equally effective in increasing liver drug-metabolizing enzymes and producing proliferation of the SER.     

The effect of technical and purified pentachlorophenol on the rat liver

Dietary concentrations of 0, 20, 100, and 500 ppm of technical grade pentachlorophenol were fed to male and female Sherman strain rats for 8 months. The same experiment using purified pentachlorophenol was carried out. The food consumption was measured in all rats during the second week of exposure and for one week every 6 weeks thereafter. An autopsy was performed on all rats at the end of the experiment. The brain, lungs, spleen, liver, kidneys, heart, and testes were weighed and examined grossly and microscopically in all rats fed purified pentachlorophenol, all female rats fed technical pentachlorophenol, and in the male rats fed the highest dose of technical pentachlorophenol and the controls. Only the kidneys and livers were examined microscopically in the male rats fed 20 and 100 ppm of technical pentachlorophenol. Although the food intake was comparable, male and female rats fed 500 ppm of technical and male rats fed 500 ppm of purified pentachlorophenol gained less weight. The livers of the male and female rats fed 500 ppm technical pentachlorophenol weighed significantly more than those of the controls. The kidneys of all male rats fed purified pentachlorophenol weighed significantly more than those of the controls; however, there was no dose-related increase. No morphological changes were seen in the kidneys. At the 500-ppm dietary concentrations, technical pentachlorophenol produced a severe effect in the liver of female rats characterized by vacuolation of the hepatocytes, an increase in fibroblasts and other mononuclear cells within sinusoids, bile duct proliferation, periportal fibrosis, degenerated liver cells, increased mitotic figures, and an accumulation of brown pigment in macrophages and in Kupffer cells. In male rats at the 100- or 500-ppm dietary concentrations of technical pentachlorophenol, the predominant lesion consisted of enlarged pleomorphic hepatocytes which had foamy cytoplasm or cytoplasm with large vacuoles. The walls of the hepatic central veins of the livers in animals of both sexes were thickened. At the 100-ppm dietary concentrations similar but less pronounced effects were observed in the livers. Only mild alterations were noted at the 20-ppm dietary concentration. Purified pentachlorophenol caused slightly enlarged liver cells with occasional eosinophilic cytoplasmic inclusions at 500 ppm but no alterations were observed in the livers of rats fed the 100- and 20-ppm dietary concentrations. The results suggest that most of the toxicity associated with feeding technical grade pentachlorophenol to rats at these dietary concentrations stems from toxic contaminants rather than from pentachlorophenol.     

Successful treatment of pure red cell aplasia associated with systemic lupus erythematosus with oral danazol and steroid

We describe a middle-aged Chinese systemic lupus erythematosus (SLE) patient developing steroid refractory and transfusion dependent red cell aplasia. Oral danazol 200 mg twice per day was started together with low-dose prednisolone therapy. There was no further recurrence of anemia 1 month after this combined therapy.     

A randomised trial of povidone-iodine to reduce visual impairment from corneal ulcers in rural Nepal

AIM: To assess whether povidone-iodine provided any benefit over and above a standard regimen of antibiotic therapy for the treatment of corneal ulcers. METHODS: All patients diagnosed with corneal ulcers presenting for care at a primary eye care clinic in rural Nepal were randomised to a standard protocol of antibiotic therapy versus standard therapy plus 2.5% povidone-iodine every 2 hours for 2 weeks. The main outcomes were corrected visual acuity and presence, size, and position of corneal scarring in the affected eye at 2-4 months following treatment initiation. RESULTS: 358 patients were randomised and 81% were examined at follow up. The two groups were comparable before treatment. At follow up, 3.9% in the standard therapy and 6.9% in the povidone-iodine group had corrected visual acuity worse than 20/400 (relative risk (RR) 1.77, 95% confidence interval (CI) 0.62 to 5.03). 9.4% in the standard therapy and 13.1% in the povidone-iodine group had corrected visual acuity worse than 20/60 (RR 1.39, 95% CI 0.71 to 2.77), and 17.0% and 18.8% had scars in the visual axis in each of these groups, respectively (RR 1.11, 95% CI 0.67 to 1.82). CONCLUSIONS: A small proportion of patients with corneal ulceration treated in this setting had poor visual outcomes. The addition of povidone-iodine to standard antibiotic therapy did not improve visual outcomes, although this design was unable to assess whether povidone-iodine on its own would have resulted in comparable visual outcomes to that of standard therapy.     

A mortality update of male and female capacitor workers exposed to polychlorinated biphenyls

This analysis represents a 5-year update of our mortality study of 7075 PCB exposed capacitor workers that now includes 1654 deaths and 235,984 person-years of observation with follow-up through 1998. In hourly males and females the observed number of deaths from all-cancers and all-causes were similar to the expected numbers. In salaried males all-cause and all-cancer mortality were significantly below the expected. In salaried females, all-cause mortality was significantly below the expected and all-cancer mortality was below the expected, but not significantly. We again failed to find any significant excess mortality in the a priori cancers of concern or in any other cancers in the total cohort or in the highly exposed portion of the cohort. These results expand on our previous observations and as before the data fail to demonstrate any causal association between occupational PCB exposure and excess cancer mortality or any other causes of death.     

Emerging drugs for prevention of T-cell mediated rejection in liver and kidney transplantation

Introduction: Acute and chronic graft rejection continues to be an important problem after solid organ transplantation. With the introduction of potent immunosuppressive agents such as calcineurin inhibitors, the risk of rejection has been significantly reduced. However, the adverse effects of life-long immunosuppression remain a concern, and there exist a fine balance between over-immunosuppression and risk of rejection.

Areas covered: In this review, the current standard of care in immunosuppressive therapy, including the use of steroids, calcineurin inhibitors, mycophenolate prodrugs and mammalian target of rapamycin inhibitors, will be discussed. Newer immunosuppressive agents showing promising early data after liver and kidney transplantation will also be explored.

Expert Opinion: Currently, calcineurin inhibitors continue to be a vital component of immunosuppressive therapy after solid organ transplantation. Although minimization and avoidance strategies have been developed, the ultimate goal of inducing tolerance remains elusive. Newer emerging agents should have potent and specific immunosuppressive activity, with minimal associated side effects. An individualized approach should be adopted to tailor immunosuppression according to the different needs of recipients.