Experimental Evaluation of the Impact of Gadolinium Orthovanadate GdVO4:Eu3+ Nanoparticles on the Carrageenan-Induced Intestinal Inflammation.

AIM: To evaluate the effects of orally administered gadolinium orthovanadate GdVO4:Eu3+ nanoparticles (VNPs) on the course of chronic carrageenan-induced intestinal inflammation. METHODS: Samples of small intestinal tissue were collected from four groups of rats (intact, after administration of VNPs, with carrageenaninduced intestinal inflammation, with carrageenan-induced intestinal inflammation orally exposed to VNPs) to assess the intestinal morphology and HSP90α expression. Levels of seromucoid, C-reactive protein, TNF-α, IL-1ß and IL-10 were determined in blood serum. RESULTS: Oral exposure to VNPs was associated with neither elevation of inflammation markers in blood serum nor HSP90α overexpression in the small intestine, i.e. no toxic effects of VNPs were observed. Carrageenan-induced intestinal inflammation was accompanied by higher levels of TNF-α and IL-1ß, as well as HSP90α upregulation in the intestinal mucosa, compared with controls. Administration of VNPs to rats with enteritis did not lead to statistically significant changes in concentrations of circulating pro-inflammatory cytokines with the trend towards their increase. CONCLUSION: No adverse effects were observed in rats orally exposed to VNPs at a dose of 20 µg/kg during two weeks. Using the experimental model of carrageenan-induced enteritis, it was demonstrated that VNPs at the dose used in our study did not affect the course of intestinal inflammation.

Understanding the interaction between α-1-acid glycoprotein (AGP) and potential Cu/Zn metallo-drugs of benzimidazole derived organic motifs: A multi-spectroscopic and molecular docking study.

Drug-binding and interactions with plasma proteins strongly affect their efficiency of delivery, hence considered as a key factor in determining the overall pharmacological action. Alpha-1-acid glycoprotein (AGP), a second most abundant plasma protein in blood circulation, has unique drug binding ability and involved in the transportation of various compounds. Here, we have investigated the mechanism of interaction between AGP and potential Cu/Zn metallo-drugs of benzimidazole derived organic motifs (CuL2 and ZnL2, where L is Schiff base ligand) by applying integrated spectroscopic, biophysical techniques and computational molecular docking analyses. We found that both the metallo-drugs (CuL2 and ZnL2) were bound at the central cavity of AGP interacting with the residues of lobe I, lobe II as well as lobe III. The binding of metallo-drugs to AGP occurs in 1:1 M ratios. Hydrogen bonding, electrostatic and hydrophobic interactions played a significant role in stabilizing the AGP-metallo-drug complexes. Binding affinities of both the metallo-drugs towards AGP at 298 K were of the order of 104-105 M-1, corresponding to Gibbs free energy of stabilization of approximately -5.50 to -6.62 kcal mol-1. Furthermore, the spectroscopic investigation by circular dichroism and synchronous fluorescence analyses suggest conformational changes in AGP upon the binding of metallic compounds.

Population-Pharmacokinetic and Covariate Analysis of Lurbinectedin (PM01183), a New RNA Polymerase II Inhibitor, in Pooled Phase I/II Trials in Patients with Cancer.

BACKGROUND AND OBJECTIVES: Lurbinectedin is an inhibitor of RNA polymerase II currently under clinical development for intravenous administration as a single agent and in combination with other anti-tumor agents for the treatment of several tumor types. The objective of this work was to develop a population-pharmacokinetic model in this patient setting and to elucidate the main predictors to guide the late stages of development. METHODS: Data from 443 patients with solid and hematologic malignancies treated in six phase I and three phase II trials with lurbinectedin as a single agent or combined with other agents were included in the analysis. The potential influence of demographic, co-treatment, and laboratory characteristics on lurbinectedin pharmacokinetics was evaluated. RESULTS: The final population-pharmacokinetic model was an open three-compartment model with linear distribution and linear elimination from the central compartment. Population estimates for total plasma clearance, and apparent volume at steady state were 11.2 L/h and 438 L, respectively. Inter-individual variability was moderate for all parameters, ranging from 20.9 to 51.2%. High α-1-acid glycoprotein and C-reactive protein, and low albumin reduced clearance by 28, 20, and 20%, respectively. Co-administration of cytochrome P450 3A inhibitors reduced clearance by 30%. Combinations with other anti-tumor agents did not modify the pharmacokinetics of lurbinectedin significantly. CONCLUSION: The population-pharmacokinetic model indicated neither a dose nor time dependency, and no clinically meaningful pharmacokinetic differences were found when co-administered with other anticancer agents. A chronic inflammation pattern characterized by decreased albumin and increased C-reactive protein and α-1-acid glycoprotein levels led to high lurbinectedin exposure. Co-administration of cytochrome P450 3A inhibitors increased lurbinectedin exposure.

Periodontal and serum protein profiles in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor adalimumab.

BACKGROUND: Tumor necrosis factor (TNF)-α inhibitor has been shown to affect the periodontal condition of patients with rheumatoid arthritis (RA). The aim of the present study is to assess the effect of a fully humanized anti-TNF-α monoclonal antibody, adalimumab (ADA), on the periodontal condition of patients with RA and to compare serum protein profiles before and after ADA therapy. METHODS: The study participants consisted of 20 patients with RA treated with ADA. Clinical periodontal and rheumatologic parameters and serum cytokine levels were evaluated at baseline and 3 months later. Serum protein spot volume was examined with two-dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. Proteins with significant difference in abundance before and after ADA therapy were found and identified using mass spectrometry and protein databases. RESULTS: The patients showed a significant decrease in gingival index (P = 0.002), bleeding on probing (P = 0.003), probing depth (P = 0.002), disease activity score including 28 joints using C-reactive protein (P <0.001), and serum levels of TNF-α (P <0.001) and interleukin-6 (P <0.001) after ADA medication, although plaque levels were comparable. Among a total of 495 protein spots obtained, nine spots were significantly decreased in abundance at reassessment, corresponding to complement factor H, phospholipase D, serum amyloid A, complement component 4, and α-1-acid glycoprotein (P <0.01). CONCLUSION: These results suggest a beneficial effect of ADA therapy on the periodontal condition of patients with RA, which might be related to differences in serum protein profiles before and after ADA therapy.

Role of alpha1-acid glycoprotein in therapeutic antifibrotic effects of imatinib with macrolides in mice.

RATIONALE: Imatinib is an inhibitor of platelet-derived growth factor receptors. We have reported that treatment with imatinib inhibited bleomycin-induced pulmonary fibrosis in mice. However, late treatment with imatinib had no effect. OBJECTIVES: To clarify why imatinib had no antifibrotic effect when its administration was delayed, we focused on alpha(1)-acid glycoprotein (AGP), because it was reported to bind imatinib and mediate drug resistance. METHODS: The concentration of AGP in serum of mice and patients with idiopathic pulmonary fibrosis was measured by radial immunodiffusion testing. The effects of AGP in vitro were evaluated by assaying the growth of lung fibroblasts. We examined the combined effects of erythromycin (EM) or clarithromycin (CAM) on bleomycin-induced pulmonary fibrosis in mice. MEASUREMENTS AND MAIN RESULTS: Addition of AGP abrogated imatinib-mediated inhibition of the growth of fibroblasts. However, treatment with EM or CAM restored the growth-inhibitory effects of imatinib. The elevated level of AGP was detected in serum and lung homogenates in bleomycin-exposed mice and reached a plateau on Day 14. Imatinib alone did not ameliorate pulmonary fibrosis when treatment was started on Day 15, whereas coadministration of imatinib and EM or CAM significantly reduced the fibrogenesis via inhibition of the growth of fibroblasts in vivo. Serum levels of AGP were higher in patients with idiopathic pulmonary fibrosis than in healthy subjects. CONCLUSIONS: AGP is an important regulatory factor modulating the ability of imatinib to prevent pulmonary fibrosis in mice, and combined therapy with imatinib and EM or CAM might be useful for treatment of pulmonary fibrosis.

The influence of a multifunctional, polymeric biomaterial on the concentration of acute phase proteins in an animal model.

The concentrations of the acute phase proteins alpha1-Acid Glycoprotein (AAG) and haptoglobin were determined in Sprague-Dawley-rats after implantation of a novel biodegradable multifunctional polymeric biomaterial for the reconstruction of a gastric wall defect (polymer group; n=42). For comparison, the concentrations of AAG and haptoglobin were measured as well after primary wound closure of the gastric wall defect without biomaterial implantation (control group; n=21) and in rats without any surgical procedure (baseline group; n=21). The implantation periods were 1 week, 4 weeks and 6 months. The concentrations of AAG and haptoglobin were measured by an ELISA assay. Gastrointestinal complications like fistula, perforation or peritonitis did not occur in any of the animals. No statistically significant differences in the concentrations of AAG and haptoglobin were detected between the polymer and the control group. An adequate mechanical stability of the polymeric biomaterial was detectable under the extreme pathophysiological conditions of the stomach milieu. In further examinations the correlation between the intraperitoneal cytokine levels of the animals and the following systemic inflammatory markers should be analysed. Further investigations are needed to analyse the mechanisms of the tissue integration of a biomaterial as well as the process of the tissue remodeling and the influence of the immune system on these mechanisms. The knowledge of these processes is necessary to adapt the multifunctional biomaterial and prepare it thus for the use and implantation in different body locations and to develop novel therapeutical options in medicine.

Selective binding of imatinib to the genetic variants of human alpha1-acid glycoprotein.

Imatinib is a selective tyrosine kinase inhibitor, successfully used for the treatment of chronic myelogenous leukaemia. Its strong plasma protein binding referred to alpha1-acid glycoprotein (AGP) component was found to inhibit the pharmacological activity. AGP shows genetic polymorphism and the two main genetic variants have different drug binding properties. The binding characteristics of imatinib to AGP genetic variants and the possibility of its binding interactions were investigated by various methods. The results proved that binding of imatinib to the two main genetic variants is very different, the high affinity binding belongs dominantly to the F1-S variant. This interaction is accompanied with specific spectral changes (induced circular dichroism, UV change, intrinsic fluorescence quenching), suggesting that the bound ligand has chiral conformation that would largely overlap with other ligands inside the protein cavity. Binding parameters of Ka=1.7(+/-0.2)x10(6)M(-1) and n=0.94 could be determined for the binding on the F1-S variant at 37 degrees . Imatinib binding on the A variant is weaker and less specific. The binding affinity of imatinib to human serum albumin (nKa approximately 3 x 10(4)M(-1)) is low. Pharmacologically relevant binding interactions with other drugs can be expected on the F1-S variant of AGP.

Resistance-modifying agents. 11.(1) Pyrimido[5,4-d]pyrimidine modulators of antitumor drug activity. Synthesis and structure-activity relationships for nucleoside transport inhibition and binding to alpha1-acid glycoprotein.

The cardiovascular and antithrombotic agent dipyridamole (DP) has potential therapeutic utility as a modulator of the activity of antimetabolite antitumor agents by virtue of its inhibition of nucleoside transport. However, the activity of DP can be compromised by binding to the acute phase serum protein, alpha(1)-acid glycoprotein (AGP). Analogues of DP were synthesized and evaluated as inhibitors of (3)H-thymidine uptake into L1210 leukamia cells in the presence and absence of 5 mg/mL AGP. Compounds with potency similar to that of DP were identified where the piperidino substituents at the 4,8-positions were replaced by 4'-methoxybenzylamino, 3',4'-dimethoxybenzylamino, or piperonylamino groups. Replacement of the diethanolamino groups at the 2,6-positions of DP by alkylamino or alkoxy substituents was tolerated, although at least one oxygen-bearing function (hydroxyl or alkoxy) was required in the side chain for activity comparable to that of DP. Whereas AGP completely ablated the activity of DP, the majority of the newer compounds synthesized retained significant activity in the presence of excess AGP, although replacement of the piperidino groups at the 4,8-positions by N-methylbenzylamino substituents did, in some cases, restore susceptibility to AGP. Selected compounds have been demonstrated to prevent rescue from antifolate cytotoxicity, mediated by nucleoside salvage.

Kupffer cell-depleted rats have a diminished acute-phase response following major liver resection.

Partial hepatectomy (PH)-induced Kupffer cell (KC) activation results in a rapid release of cytokines inducing the acute-phase response (APR). This study was done to evaluate the role of Kupffer cells (KCs) in the course of the APR following PH and a consecutive endotoxin challenge. KC depletion was performed in rats by i.v. administration of 1 mL liposome-encapsulated dichloromethylene diphosohonate (Cl2MDP). Control rats received 1 mL NaCl 0.9%. Forty-eight hours later, PH was performed. At 24 h after PH, rats were randomized to receive either 1 mL NaCl 0.9% (saline) or 50 microg/kg LPS i.v. in 1 mL. Animals were sacrificed at 4 h after LPS or saline infusion. The APR was determined by measuring hepatic gene expression of alpha 2-macroglobulin, alpha 1-acid glycoprotein, and IL-6 and expression of hepatic albumin. The APR was significantly depressed in KC-depleted rats. Despite increased IL-6 mRNA synthesis in response to low-dose LPS, no enhancement of acute-phase protein synthesis (APP) was found in KC-depleted rats. Hepatic failure was most profound in KC-depleted rats, as indicated by elevated plasma levels of liver transaminases and ammonia. We conclude that after PH, KC function in the remnant liver is important for the acute-phase reaction and reduces endotoxin-induced hepatocyte damage.

Plasma levels of retinol, carotenoids, and tocopherols in relation to dietary pattern among pregnant Tanzanian women.

In Tanzania, as in other developing countries, dietary intake of nutrients in pregnant women is marginal or lower than the recommended intakes and therefore these women are at high risk for deficiencies. Our aim was to evaluate the relationship between diet and plasma levels of retinol, carotenoids, and alpha-tocopherol in the third trimester of pregnancy. Ninety pregnant women aged between 18 and 45 years were equally recruited from three villages. Seven-day food frequency data was collected by questionnaire. Plasma levels of retinol, carotenoids, and tocopherols were assessed by high-performance liquid chromatography (HPLC). Results indicated that cooked green leafy vegetables constituted the major source of provitamin A carotenoids, with low intake of yellow/orange fruits and preformed vitamin A. Lutein, lycopene, and beta-carotene were the predominant carotenoids in the plasma with mean values of 1.61, 0.84, and 0.63 mumol/L, respectively. There was no significant correlation between frequencies of vegetable consumption and either plasma retinol or carotenoids. However, increased consumption of green leafy vegetables with oil, which increases bioavailability, was correlated with high plasma retinol levels (p = 0.03). Low retinol levels (< or = 0.70 mumol/L) were present in 26% of women. The mean plasma retinol concentration was 0.89 mumol/L and 63% of the women had values below 1.05 mumol/L. The mean plasma alpha-tocopherol concentration was 15.4 mumol/L and women with plasma retinol concentration > 1.05 mumol/L had significantly higher mean alpha-tocopherol than women with plasma retinol concentration < or = 0.70 mumol/L (p < or = 0.01). Twenty-four percent of the women were anemic (hemoglobin: Hb < 110 g/L) and the mean Hb value was 116.3 g/L.

Enzyme and plasma protein induction by multiple oral administrations of phenobarbital at a therapeutic dosage regimen in dogs.

In dogs effects of phenobarbital (PB) on hepatic cytochrome P450 (CYP) activities and on concentrations of plasma alpha 1-acid glycoprotein (AGP) were examined. Total body clearance (Cl(B)) of antipyrine and plasma AGP concentrations were monitored during oral PB treatment at a therapeutic dose for 35 days. Cl(B) of antipyrine, which reflects hepatic CYP activities, gradually increased and was maintained at about threefold concentrations compared with that before treatment, suggesting that PB induced CYP activities at a large extent even in a therapeutic dose, necessary for an antiepileptic effect. Plasma AGP concentrations also increased significantly (about fourfold). Dogs were killed at the 35th day of the PB treatment, and hepatic CYP content and enzyme kinetics of several CYPs were determined using liver microsomes. CYP content was about twofold higher than that from untreated dogs. The V(max) values for CYP1A-like activity (ethoxyresorufin O-deethylation), 2B-like activity (ethoxycoumarin O-deethylation), 2C-like activity (tolbutamide hydroxylation) and 3A-like activity (midazolam 4-hydroxylation) were higher (2-4-fold) than that in untreated dogs. In summary, a therapeutic dose of PB for antiepileptic therapy significantly induced hepatic CYPs and plasma AGP in dogs. Therefore, during antiepileptic therapy with PB, special attention must be paid to the pharmacokinetics of drugs simultaneously administered.

Role of alpha1 acid glycoprotein in the in vivo resistance of human BCR-ABL(+) leukemic cells to the abl inhibitor STI571.

BACKGROUND: Chronic myeloid leukemia is caused by a chromosomal translocation that results in an oncogenic fusion protein, Bcr-Abl. Bcr-Abl is a tyrosine kinase whose activity is inhibited by the antineoplastic drug STI571. This drug can cure mice given an injection of human leukemic cells, but treatment ultimately fails in animals that have large tumors when treatment is initiated. We created a mouse model to explore the mechanism of resistance in vivo. METHODS Nude mice were injected with KU812 Bcr-Abl(+) human leukemic cells. After 1 day (no evident tumors), 8 days, or 15 days (tumors >1 g), mice were treated with STI571 (160 mg/kg every 8 hours). Cells recovered from relapsing animals were used for in vitro experiments. Statistical tests were two-sided. RESULTS: Tumors regressed initially in all STI571-treated mice, but all mice treated 15 days after injection of tumor cells eventually relapsed. Relapsed animals did not respond to further STI571 treatment, and their Bcr-Abl kinase activity in vivo was not inhibited by STI571, despite high plasma concentrations of the drug. However, tumor cells from resistant animals were sensitive to STI571 in vitro, suggesting that a molecule in the plasma of relapsed animals may inactivate the drug. The plasma protein alpha1 acid glycoprotein (AGP) bound STI571 at physiologic concentrations in vitro and blocked the ability of STI571 to inhibit Bcr-Abl kinase activity in a dose-dependent manner. Plasma AGP concentrations were strongly associated with tumor load. Erythromycin competed with STI571 for AGP binding. When animals bearing large tumors were treated with STI571 alone or with a combination of STI571 and erythromycin, greater tumor reductions and better long-term tumor-free survival (10 of 12 versus one of 13 at day 180; P:<.001) were observed after the combination treatment. CONCLUSION: AGP in the plasma of relapsed animals binds to STI571, preventing this compound from inhibiting the Bcr/Abl tyrosine kinase. Molecules such as erythromycin that compete with STI571 for binding to AGP may enhance the therapeutic potential of this drug.

Alpha-1-acid glycoprotein in major depressive disorder. Relationships to severity, response to treatment and imipramine plasma levels.

BACKGROUND: Increased plasma levels of alpha-1-acid glycoprotein (AGP) were reported in major depressive disorder. However, the relationship between AGP levels, severity of depression, treatment response and antidepressant levels are still unclear. METHODS: Plasma AGP levels were measured in 36 subjects with major depressive disorder before and after a 6-week treatment with imipramine and in 30 controls. Free imipramine plasma levels of depressed patients were measured at 6 weeks. Comparative analysis between depressed patients and controls, between non-responders (N = 12) and responders (N = 24), and between severely depressed patients (N = 14) and moderately depressed patients (N = 22) were made. RESULTS: Depressed patients had significantly higher mean values of AGP than control subjects. Imipramine non-responders and specially severely depressed patients had significantly greater increases of AGP levels during treatment than other depressed subgroups. There was no correlation between baseline AGP levels and severity of depression or free imipramine levels. LIMITATIONS: The most significant limitations of this study are the small sample size and the fact that all the subjects were out-patients. Results should not be generalized to in-patient populations. CONCLUSIONS: Depressed patients showed high baseline concentrations of AGP. AGP levels did not predict either free imipramine plasma levels or differential response after 6 weeks of treatment with imipramine. A greater increase of AGP during treatment was associated with severity of depression and treatment non-response. CLINICAL IMPLICATIONS: The relationship between high plasma levels of AGP, severity of depression and lack of treatment response is clarified. The influence of imipramine levels is minimized.

The effect of an individual's cytochrome CYP3A4 activity on docetaxel clearance.

Docetaxel is a chemotherapeutic agent effective in the treatment of various solid tumors. Patients given a standard dose of docetaxel exhibit wide interpatient variation in clearance (CL) and toxic effects. Docetaxel undergoes metabolism by cytochrome CYP3A4. Thus, interpatient variability in CYP3A4 activity may account in part for differences in toxicity and CL. Twenty-one heavily pretreated patients with metastatic sarcomas received docetaxel (100 mg/m2). Hepatic CYP3A4 activity in each patient was measured by the [14C-N-methyl]erythromycin breath test (ERMBT). Blood samples were taken at selected times over the next 24 h for pharmacokinetic analysis. Phenotypic expression of hepatic CYP3A4 activity measured by the ERMBT varied over 20-fold (administered 14C exhaled in 1 h: mean, 2.53%; range, 0.25-5.35%), which is similar to a normal control population. CL of docetaxel varied nearly 6-fold (mean, 21.0 liters/h/m2; range, 5.4-29.1 liters/h/m2). The ERMBT was the best predictor of CL when compared with serum alanine aminotransferase, albumin, alkaline phosphatase, or serum alpha-1-acidic glycoprotein. The natural log of ERMBT accounted for 67% of the interpatient variation in CL. Multivariate analysis showed that the natural log of ERMBT and albumin together accounted for 72% of the interpatient variation in CL. The greatest toxicity was seen in patients with the lowest ERMBT. Hepatic CYP3A4 activity is the strongest predictor of docetaxel CL and accounts for the majority of interpatient differences in CL. Patients with low CYP3A4 activity are at risk for having decreased CL and may thus experience increased toxicity from docetaxel. Those with high activity may be receiving a suboptimal dose. By measuring CYP3A4 activity, the ERMBT may be clinically useful in tailoring doses of CYP3A4 substrates, such as docetaxel, in certain individuals.

Separation of enantiomers on HPLC chiral stationary phases based on human plasma alpha1-acid glycoprotein: effect of sugar moiety on chiral recognition ability.

HPLC chiral stationary phases based on human plasma alpha1-acid glycoprotein (AGP) and partially deglycosylated AGP (pd-AGP) were prepared to investigate the effects of sugar moiety of AGP on chiral discrimination of various solutes. Removal of a sugar moiety of AGP by treatment with N-glycosidase was confirmed by high-performance capillary electrophoresis, reversed-phase HPLC and matrix-assisted laser desorption-time of flight (MALDI-TOF) mass spectrometry. The average molecular weights of AGP and pd-AGP were estimated to be ca. 33,000 and 30,600, respectively, by MALDI-TOF mass spectrometry. Next, AGP and pd-AGP were bound to aminopropyl-silica gels activated with N,N '-disuccinimidylcarbonate. The retentivity+ and enantioselectivity of the neutral, acidic and basic solutes tested on the pd-AGP column were significantly or not significantly larger in most solutes than those on the AGP column. This is ascribable to that by cleavage of a sugar chain(s) by N-glycosidase, pd-AGP could become more hydrophobic than AGP, and/ or that a solute could be easily accessible to the specific and/or non-specific binding sites of pd-AGP. It is interesting that warfarin enantiomers are not resolved on the pd-AGP column, but resolved on the AGP column. A sugar chain(s) of AGP cleaved by N-glycosidase might be involved in the enantioselective binding of warfarin enantiomers.

Effect of short-term aspirin use on C-reactive protein.

Markers of inflammation, such as C-reactive protein (CRP) and fibrinogen, have been shown to be predictive of cardiovascular disease. In the Physicians Health Study, the magnitude of reduction in the risk of myocardial infarction with aspirin therapy was related to baseline CRP levels, raising the possibility that the protective effect of aspirin may be due to antiinflammatory properties in addition to its antiplatelet effect. We therefore investigated whether aspirin therapy lowers CRP levels. Because heavy physical exertion is a well-known trigger of myocardial infarction, we also investigated the effect of aspirin on CRP levels before and after strenuous exercise. Thirty-two healthy men, aged 29 +/- 6 years, were enrolled in a randomized, double-blind, parallel study. Blood samples were obtained immediately before and after maximal treadmill exercise at baseline and following 7 days of aspirin therapy (81 or 325 mg). The levels of CRP, as measured by ELISA, increased by 13% following exercise (P < 0.0001). However, aspirin did not significantly alter CRP levels, either at rest (0.81 +/- 0.13 mg/L before aspirin vs. 0.78 +/- 0.13 mg/L on aspirin) or following exercise (0.92 +/- 0.13 mg/L before aspirin vs. 0.86 +/- 0. 13 mg/L on aspirin), P = 0.73. When the resting and postexercise data were combined, the levels were 0.87 +/- 0.13 mg/L before aspirin and 0.82 +/- 0.13 mg/L on aspirin (a nonsignificant 6% reduction, P = 0.20). In conclusion, in healthy male subjects CRP levels were not significantly reduced by short-term aspirin therapy. Our data, taking together with other reports, suggest that aspirin may not affect the levels of inflammatory markers. However, further studies are needed with a longer duration of therapy, among subjects with coronary heart disease, and using additional markers of inflammation besides CRP to determine the long-term effects of aspirin use.

Effects of ethanol on receptor-mediated endocytosis in the liver.

Ethanol administration impairs multiple aspects in the process of receptor-mediated endocytosis (RME) in the liver. Studies from our laboratory over the last 10 years have carefully examined RME by the hepatocyte-specific asialoglycoprotein receptor (ASGP-R). We have identified a time course for ethanol-induced defects in RME and established that many of the impairments occur initially in the centrilobular region of the liver and as early as one week after ethanol administration. Impaired intravesicular acidification in ethanol-fed animals has been identified, and these defects in acidification could alter multiple protein trafficking pathways including RME. In addition to altered acidification, altered receptor function (including receptor inactivation) could also contribute to impaired trafficking. Current studies in our laboratory are aimed at an examination of posttranslational modifications in the receptor (acylation and phosphorylation) that are known to affect its function. A role for the ASGP-R in the process of alcoholic apoptosis is also being examined because proper functioning of the ASGP-R is thought to be important in clearance of apoptotic cells.

Changes in plasma alpha 1-acid glycoprotein concentration and selected immune response in broiler chickens injected with Escherichia coli lipopolysaccharide.

1. Changes in plasma alpha 1-acid glycoprotein (AGP) concentration and immune responses following Escherichia coli lipopolysaccharide (LPS) injection were studied in broiler chickens. 2. Higher plasma AGP concentrations were observed from 12 to 48 h after a single injection of LPS. 3. The highest concentration of plasma AGP was observed on day 2 followed by a gradual decrease in chicks injected with 150 micrograms/kg body weight of LPS every day for 13 d. 4. Plasma AGP concentration in chicks injected daily with LPS at 900 micrograms/kg body weight for 13 d increased on day 2, and decreased on day 4 to the concentration found before the injection. The concentration increased again on day 10. 5. Changes in plasma interleukin-1 (IL-1) like activity were similar to those in plasma AGP concentration when LPS was injected daily at 900 micrograms/kg body weight for 3 d. 6. Responses of blood mononuclear cell (MNC) proliferation to mitogen or concanavalin A, (Con A), and pokeweed mitogen (PWM) were positively correlated with changes in plasma AGP concentration. 7. The results suggest that plasma AGP concentration could be used as a positive indicator of changes in blood MNC proliferation to a mitogen and in plasma IL-1 like activity.