Correlation between adriamycin-induced augmentation of interleukin 2 production and of cell-mediated cytotoxicity in mice

Based on the observation that spleen cells from Adriamycin-treated mice could develop augmented levels of cytotoxic T-lymphocyte activity in response to heat-treated and/or X-irradiated alloantigens, it was postulated that modulations in soluble mediators could be involved in this phenomenon. In fact, in this study Adriamycin-induced increases in the levels of prostaglandin E2 and interleukin 2 activity have been observed with isolated cells. The "interleukin 2-like" activity was indistinguishable from that of partially purified interleukin 2 in terms of ability to restore responsiveness to experimentally inhibited primary alloantigen response cultures and to maintain long-term cultures of activated T-cells. Furthermore this latter activity was completely ablated by antiinterleukin 2 monoclonal antibody. While the modification in prostaglandin E2 production did not appear to play a role in determining augmentation of cytotoxic T-cell activity, the modification in interleukin 2 production was consistent with the possibility that this is a primary mechanism of Adriamycin-induced augmented cell-mediated cytotoxicity.     

DNA adduct formation in precision-cut rat liver and lung slices exposed to benzo[a]pyrene.

Chemical-DNA adducts provide an integrated measure of exposure, absorption, bioactivation, detoxification, and DNA repair following exposure to a genotoxic agent. Benzo[a]pyrene (BaP), a prototypical polycyclic aromatic hydrocarbon (PAH), can be bioactivated by cytochrome P-450s (CYPs) and epoxide hydrolase to genotoxic metabolites which form covalent adducts with DNA. In this study, we utilized precision-cut rat liver and lung slices exposed to BaP to investigate tissue-specific differences in chemical absorption and formation of DNA adducts. To investigate the contribution of bioactivating CYPs (such as CYP1A1 and CYP1B1) on the formation of BaP-DNA adducts, animals were also pretreated in vivo with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, dioxin) prior to in vitro incubation of tissue slices with BaP. Furthermore, the tissue distribution of BaP and BaP-DNA adduct levels from in vivo studies were compared with those from the in vitro tissue slice experiments. The results indicate a time- and concentration-dependent increase in tissue-associated BaP following exposure of rat liver and lung tissue slices to BaP in vitro, with generally higher levels of BaP retained in lung tissue. Furthermore, rat liver and lung slices metabolized BaP to reactive intermediates that formed covalent adducts with DNA. Total BaP-DNA adducts increased with concentration and incubation time. Adduct levels (fmol adduct/microg DNA) in lung slices were greater than liver at all doses. Liver slices contained one major and two minor adducts, while lung slices contained two major and 3 minor adducts. The tissue-specific qualitative profile of these adducts in tissue slices was similar to that observed from in vivo studies, further validating the use of this model. Pretreatment of animals with TCDD prior to in vitro incubation with BaP potentiated the levels of DNA adduct formation. TCDD pretreatment altered the adduct distribution in lung but not in liver slices. Together, the results suggest that tissue-specific qualitative and quantitative differences in BaP-DNA adducts could contribute to the lung being a target tissue for BaP carcinogenesis. Furthermore, the results validate the use of precision-cut tissue slices incubated in dynamic organ culture as a useful model for the study of chemical-DNA adduct formation.     

Effects of simvastatin,an HMG-CoA reductase inhibitor,in patients with hypertriglyceridemia

BACKGROUND: Patients with elevated levels of serum triglycerides (TG) often have other associated lipid abnormalities (e.g., low levels of high-density lipoprotein cholesterol [HDL-C]) and are at increased risk of developing coronary heart disease. Although the therapeutic benefits of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in hypercholesterolemic patients have been well established, less is known about the effects of statins in patient populations with hypertriglyceridemia. HYPOTHESIS: The purpose of this study was to evaluate the lipoprotein-altering efficacy of simvastatin in hypertriglyceridemic patients. METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study. In all, 195 patients with fasting serum triglyceride levels between 300 and 900 mg/dl received once daily doses of placebo or simvastatin 20, 40, or 80 mg for 6 weeks. RESULTS: Compared with placebo, simvastatin treatment across all doses resulted in significant reductions (p < 0.05 - < 0.001) in serum levels of triglycerides (-20 to -31% decrease) and TG-rich lipoprotein particles. Significant (p < 0.001) reductions were also seen in low-density lipoprotein cholesterol (-25 to -35%) and non-HDL-C (-26 to -40%). Levels of HDL-C were increased (7-11%) in the simvastatin groups compared with placebo (p < 0.05 - < 0.001). CONCLUSION: The results of this study demonstrate the beneficial effects of simvastatin in patients with hypertriglyceridemia.     

The Fears,Phobias and Anxieties of Children with Autism Spectrum Disorders and Down Syndrome: Comparisons with Developmentally and Chronologically Age Matched Children

This study compared the fears and behavior problems of 25 children with an autism spectrum disorder (ASD), 43 children with Down syndrome (DS), 45 mental age (MA) matched children, and 37 chronologically age (CA) matched children. Children’s fears, phobias, anxieties and behavioral problems were assessed using parent reports. Significant differences emerged across the diagnostic groups on a variety of fears. Children with ASD were reported to have more situation phobias and medical fears, but fewer fears of harm/injury compared to all other groups. The groups also differed in terms of the pattern of correlations between fears, phobias, anxieties and behavior problems. For children with ASD, fears, phobias and anxieties were closely related to problem behaviors, whereas fears, phobias, and anxieties were less related to behavioral symptoms for the other groups of subjects. Such findings suggest that children with ASD exhibit a distinct profile of fear and anxiety compared to other mental age and chronologically age-matched children, and these fears are related to the symptoms associated with ASD.     

A cyclophosphamide/DNA phosphoester adduct formed in vitro and in vivo

The antitumor activity of cyclophosphamide is thought to be due to the alkylating activity of phosphoramide mustard, a metabolite of cyclophosphamide. Reaction of 2'-deoxyguanosine 3'-monophosphate and phosphoramide mustard resulted in the formation of several adducts that could be detected by high performance liquid chromatography (HPLC). One of these adducts, isolated and purified by HPLC, could be detected by 32P postlabeling. This product was identified by UV, nuclear magnetic resonance, and mass spectrometry and by acid, base, and enzymatic hydrolysis to be 2'-deoxyguanosine 3'-monophosphate 2-(2-hydroxyethyl)aminoethyl ester. A combination of HPLC fractionation of digested DNA and 32P postlabeling was used to detect this adduct in calf thymus DNA incubated in vitro with metabolically activated cyclophosphamide and in DNA from the liver of mice treated with cyclophosphamide. In these DNA samples the adduct occurred at a level of 1/10(5) and 1/3 x 10(7) nucleotides, respectively.     

Achieving lipoprotein goals in patients at high risk with severe hypercholesterolemia: efficacy and safety of ezetimibe co-administered with atorvastatin

Background

Despite the efficacy of statins in lowering low-density lipoprotein cholesterol (LDL-C) levels, many patients who are at high risk for heart disease with hypercholesterolemia require additional LDL-C level reduction. The cholesterol absorption inhibitor, ezetimibe, has been shown to provide significant incremental reductions in LDL-C levels when co-administered with statins. This study was performed to compare the efficacy and safety of ezetimibe (10 mg) plus response-based atorvastatin titration versus response-based atorvastatin titration alone in the attainment of LDL-C goals in subjects who are at high risk for coronary heart disease (CHD) and are not at their LDL-C goal on the starting dose of atorvastatin.

Methods

This was a 14-week, multicenter, randomized, double-blind, active-controlled study conducted in 113 clinical research centers in 21 countries. Participants were adults with heterozygous familial hypercholesterolemia (HeFH), CHD, or multiple (≥2) cardiovascular risk factors, and a LDL-C level ≥130 mg/dL after a 6- to10-week dietary stabilization and atorvastatin (10 mg/day) open-label run-in period. Eligible subjects continued to receive atorvastatin (10 mg) and were randomized to receive blinded treatment with ezetimibe (10 mg/day; n = 305) or an additional 10 mg/day of atorvastatin (n = 316). The atorvastatin dose in both groups was doubled after 4 weeks, 9 weeks, or both when the LDL-C level was not at its goal (≤100 mg/dL), so that patients receiving combined therapy could reach 40 mg/day and patients receiving atorvastatin alone could reach 80 mg/day. The primary end point was the proportion of subjects achieving their LDL-C level goal at week 14. A secondary end point was the change in LDL-C level and other lipid parameters at 4 weeks after ezetimibe co-administration with 10 mg/day of atorvastatin versus 20 mg/day of atorvastatin monotherapy.

Results

The proportion of subjects reaching their target LDL-C level goal of ≤100 mg/dL was significantly higher in the co-administration group than in the atorvastatin monotherapy group (22% vs 7%; P <.01). At 4 weeks, levels of LDL-C, triglycerides, and non-high-density lipoprotein cholesterol were reduced significantly more by combination therapy than by doubling the dose of atorvastatin (LDL-C −22.8% versus −8.6%; P <.01). The combination regimen had a safety and tolerability profile similar to that of atorvastatin alone.

Conclusions

The addition of ezetimibe to the starting dose of 10 mg/day of atorvastatin followed by response-based atorvastatin dose titration to a maximum of 40 mg/day provides a more effective means for reducing LDL-C levels in patients at high risk for CHD than continued doubling of atorvastatin as high as 80 mg/day alone.     

Comparison of effects of ezetimibe/simvastatin versus simvastatin versus atorvastatin in reducing C-reactive protein and low-density lipoprotein cholesterol levels

The lowering effects of ezetimibe/simvastatin combination therapy on low-density lipoprotein (LDL) cholesterol and high-sensitivity C-reactive protein (CRP) were compared with those of simvastatin or atorvastatin monotherapy in a large cohort of patients with primary hypercholesterolemia. To compare ezetimibe/simvastatin with simvastatin, data were combined from 3 identical, prospective 12-week trials in which patients were randomized to receive placebo; ezetimibe 10 mg; ezetimibe 10 mg added to simvastatin 10, 20, 40, or 80 mg; or simvastatin 10, 20, 40, or 80 mg. To compare ezetimibe/simvastatin with atorvastatin, data were analyzed from a phase III double-blind, active-controlled study in which patients were randomized equally to receive ezetimibe/simvastatin 10/10, 10/20, 10/40, or 10/80 mg or atorvastatin 10, 20, 40, or 80 mg for 6 weeks. When averaged across doses, ezetimibe/simvastatin produced significantly greater reductions compared with simvastatin alone in LDL cholesterol (52.5% vs 38.0%, respectively) and CRP levels (31.0% vs 14.3%, respectively). At each individual simvastatin dose, co-administration with ezetimibe produced significant further CRP reductions versus simvastatin alone. Ezetimibe/simvastatin was significantly more effective at lowering LDL cholesterol than atorvastatin when pooled across doses (53.4% vs 45.3%, respectively) and in each milligram-equivalent dose comparison. Reductions in CRP of similar magnitude were observed with ezetimibe/simvastatin and atorvastatin when averaged across doses and at each milligram-equivalent statin dose comparison. In conclusion, the lipid-modulating and anti-inflammatory effects of ezetimibe/simvastatin provide additional benefits not realized by statin monotherapy alone.