Serum Alpha 1-acid Glycoprotein Levels Research Articles

Role of Serum Alpha-1-Acid Glycoprotein as a New Biomarker for Cirrhotic and Hepatocellular Carcinoma Patients

Abstract Background Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide, it is the second leading cause of malignancy related mortality all over the world and is primarily due to the hepatitis C virus (HCV) epidemic. Aim of the Work to evaluate the diagnostic value of serum AAG level as a novel biomarker for HCC and cirrhotic patients Patients and Methods This study was conducted on ninety cases chosen from El Demerdash hospital (Ain Shams University) divided into three groups group (A) ten normal control people, group (B) forty known HCC patients which was further subdivided into two small subgroups B (I) twenty with low AFP level and B (II) twenty with high AFP level, as well as forty patients with liver cirrhosis group (C) during the period from June 2022 to December 2022. Results The mean value of AAG in HCC low AFP cases was 1307 μg/ml which was higher than that of patients with HCC high AFP (850 μg/ml) and chronic liver disease patients (309 μg/ml). AAG as a diagnostic marker for HCC the cut-off value was 740 ng/ml with sensitivity 73% and specificity 74% for HCC low AFP, which was higher than that of patients with HCC high AFP sensitivity 68% and specificity 71%. Conclusion Alpha 1 Acid Glycoprotein had better performance in diagnosing HCC patients with low AFP. Serum Alpha 1 Acid Glycoprotein (AAG) concentrations can used as a potential marker for hepatocellular carcinoma.

Serum Levels and Glycosylation Changes of Alpha-1-Acid Glycoprotein According to Severity of Breast Cancer in Korean Women.

Elevated serum levels of alpha-1-acid glycoprotein (AGP) are known to be associated with several types of cancer. In addition, some reports have indicated that changes in glycosylation of AGP are associated with cancer progression. However, changes in AGP levels of serum and changes in glycosylation of AGPs in breast cancer have not been specifically studied. In the present study, serum AGP levels in benign (BN) cancer and breast cancer stage I (BC I), BC IIA, BC IIB, and BC III in Korean women were measured using an enzyme-linked immunosorbent assay (ELISA). AGP was purified from individual sera by hot phenol extraction and then subjected to AGP glycosylation analysis. Three types of AGP glycosylation (fucosylation, high-mannose-type and sialylation) were detected using enzyme-linked lectin assays (ELLAs). Serum AGP levels were higher in BC I, BC IIA, BC IIB, and BC III, than in the BN group, and the level in BC I and BC IIA was high enough to be distinguished from BN. Meanwhile, terminal fucosylation and high-mannose-type glycans appeared to be lowest in BC I. The glycosylation levels of BC I provide sensitivity and specificity that make BC I clearly distinguishable from BC IIA, BC IIB, and BC III as well as BN. Therefore, determination of serum AGP or AGP glycosylation level could be useful for detecting the early stages of breast cancer.

Serum levels of alpha-1 acid glycoprotein and pentraxin 3 in patients with Behçet's disease and relationship with disease activity.

To evaluate the relationship between disease activity and levels of alpha 1-acid glycoprotein and pentraxin 3 in patients with Behçet's disease (BD). Forty-eight patients with BD and 29 age- and gender-matched healthy control subjects were included in the study. Serum pentraxin 3 levels were measured using enzyme-linked immunosorbent assay (ng/ml), and alpha 1-acid glycoprotein levels were measured using nephelometry (mg/dl). Disease activity was assessed using the BD Current Activity Form (BDCAF). Serum alpha-1 acid glycoprotein levels were significantly higher in patients with BD compared to the control group (P = 0.048). There were no significant differences between two groups in terms of levels of pentraxin 3 (P = 0.697). According to Pearson's analysis, alpha 1-acid levels are significantly positively correlated with erythrocyte sedimentation rate, C-reactive protein, and skin lesions and arthritis of BDCAF scores. Pentraxin 3 levels did not correlate with erythrocyte sedimentation rate, C-reactive protein, or any domains of BDCAF scores. The results of the present study demonstrate that serum levels of alpha-1 acid glycoprotein were significantly higher in patients with BD relative to the control group. Alpha-1 acid glycoprotein is greatly associated with skin lesions and arthritis in patients with BD. We did not find high serum levels of PTX3 in patients with BD compared to healthy controls, and pentraxin 3 is not associated with disease activity in BD.

Genetic variations of orosomucoid genes associated with serum alpha‐1‐acid glycoprotein level and the pharmacokinetics of paclitaxel in Japanese cancer

Alpha‐1‐acid glycoprotein (AGP) encoded by orosomucoid genes (ORM1 and ORM2) is an acute‐phase response protein and functions as a drug‐binding protein that affects pharmacokinetics (PK)/pharmacodynamics of binding drugs. To explore the effects of genetic variations of ORMs and a role of AGP on paclitaxel (PTX) therapy, we analyzed the duplication and genetic variations/haplotypes of ORMs in 165 Japanese cancer patients and then investigated their associations with serum AGP levels and the PK parameters of PTX. No effects of ORM duplications on serum AGP levels at baseline or PK of PTX were observed, but close associations of ORM1 −559T > A with the increases of AGP levels and area under the curve (AUC) of PTX metabolites were detected. In addition, a significant correlation between the serum AGP level and the AUCs of PTX metabolites was observed, suggesting that AGP may function as a carrier of PTX from the blood into the liver via putative receptors. This study provided useful information on the possible clinical importance of ORM genetic polymorphisms and a novel role of AGP in PTX therapy. © 2011 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:4546–4559, 2011

Relationship between serum acute-phase proteins and high disease activity in patients with rheumatoid arthritis

The aim of this study was to assess the relationship between serum acute-phase proteins and high disease activity evaluated by activity score (DAS28) in patients with rheumatoid arthritis. Studies were carried out on 27 females with RA and 32 control women. Acute-phase proteins were divided into 4 fractions as follows: alpha1-globulins represented by alpha1-acid glycoprotein (AGP) and alpha1-antitrypsin (AAT); alpha2-globulins - haptoglobin (Hp); beta-globulins - complement C3 (C3) and total transferrin (Tf); gamma-globulins - C reactive protein (CRP), rheumatoid factor (RF) and immunoglobulin G (IgG), and determined by immunoturbidimetric methods. The serum levels of acute-phase proteins changed in RA patients. On account of the alterations of concentration, acute-phase proteins are placed in the downgrade scale as follows: CRP, Hp, AGP, C3, AAT and Tf. None of the acute-phase proteins correlated with the RF and the majority of them were closely related to ESR. Almost all of the acute-phase proteins (without C3) were closely related to RA activity (based on DAS28) and their places in the downgrade scale were as follows: CRP, Tf, AGP, Hp and AAT. The degree of disability evaluated by Health Assessment Questionnaire has affected on the concentrations of AGP, Tf and CRP. Serum AGP, AAT and RF levels significantly correlated with the patient's age. No correlations were observed between IgG, TP levels, and clinical data. Among the entire panel, the CRP and AGP appeared to be the most useful biochemical markers for evaluation of the disease activity of patients with RA.

Serum α1-Acid Glycoprotein Level Associate with Imatinib Trough Plasma Concentration and Clinical Outcome in CML Patients Treated with Imatinib: Blood Level Testing of Imatinib in Nagoya (BINGO) Study.

Abstract 4266 IntroductionImatinib, which is the most successful molecularly targeting drug, is the first-line agent for the treatment of chronic myeloid leukemia patients (CML) in chronic phase (CP). However, some patients show poor response against imatinib therapy, resulting in the progression to blastic phase. To date, several reports showed that imatinib trough plasma concentration (Cmin) was associated with the clinical response in CML patients, while it remains unclear whether Cmin reflects the actual inhibitory effect on the BCR-ABL kinase activity. In human plasma, imatinib binds to several plasma proteins, such as albumin (ALB) and alpha1-acid glycoprotein (AGP), and the protein-binding-imatinib lacks the kinase inhibitory activity. Especially, AGP is a major imatinib-binding protein, and the high plasma AGP concentration reportedly reduces the clinical efficacy of imatinib. These results indicate that the free-imatinib concentration is a more reliable surrogate marker for predicting the clinical efficacy than the total imatinib concentration. However, since routine measurements of the free-imatinib concentration is difficult, the inhibitory activity of the patient's plasma (PIA) against the BCR-ABL kinase is proposed to be a direct marker reflecting the actual inhibitory effects of the free-imatinib. In this study, we analyzed the association between Cmin of total imatinib and the clinical response in CML-CP patients in considering the AGP concentration. Furthermore, we evaluate the usefulness of PIA for predicting the clinical response in the CML patients treated with imatinib. MethodsWe measured Cmin of the total imatinib and AGP and ALB concentrations at the different two points in CML-CP patients who were treated with imatinib alone. The PIA was quantified by determining the de-phosphorylation levels of BCR-ABL and STAT5 in BCR-ABL-expressing Ba/F3 cells after the treatment with patients' plasma. We evaluated the association of these parameters with clinical response. Informed consent was obtained from all patients to use their samples for this study. This study was approved by the ethical committee of Nagoya university school of medicine. ResultsThe study population included 65 CML-CP patients. The mean Cmin of imatinib was 1070 ± 362 ng/ml. Clinical response was evaluated by the achievement of the complete cytogenetic response (CCR) and major molecular response (MMR) at 12 months after the start of imatinib therapy. The CCR and MMR were achieved in 63 (96.9%) and 40 (61.5%) patients, respectively. The mean Cmin of the patients who achieved MMR was significantly higher than that of those who did not (1167 ± 386 ng/ml vs. 913 ± 257ng/ml, P=0.012). The differences of Cmin between the two different points (median interval 28 ± 20 days) in the same patient were not so little (median 123 ± 198 ng/ml, range 12 to 923 ng/ml), but were not associated with clinical outcomes. The PIA was statistically correlated with the Cmin (P=0.018). Although serum AGP level was within normal range (72.8 ± 13.9 mg/dl, range 44 to 106 mg/dl) in most patients, it was notable that the serum AGP level correlated with Cmin of imatinib and clinical outcomes. The Cmin of patients with high AGP level was significantly higher than that of low AGP level (1237 ± 379ng/ml vs. 907 ± 260ng/ml, P=0.0003) and the MMR rate was significantly higher in patients with high AGP level (78%) than in those with low AGP level (45%, P=0.007). ConclusionsWe demonstrate that the Cmin of imatinib predicts clinical response and reflects the actual kinase inhibitory effects in CML patients treated with imatinib. However, the Cmin is not necessarily stable during the treatment in a part of patients, suggesting that it is recommended to examine Cmin at more than two different points for evaluating its suitability. The serum AGP and ALB levels did not affect the relationship between Cmin and PIA. However, since the serum AGP level was correlated with Cmin and clinical response, the AGP level might influence the kinase inhibitory activity in the patients whose Cmin of imatinib were low. Disclosures:Kiyoi:Novartis Pharma : Research Funding; Kyowa Hakko Kirin Co., Ltd. : Consultancy. Naoe:Kyowa Hakko Kirin Co., Ltd. : Research Funding; Chugai Pharmaceutical Co.,Ltd.: Research Funding; Wyeth K.K.: Research Funding.

Serum alpha-1 acid glycoprotein levels in patients with idiopathic peripheral retinal vasculitis (Eales' disease).

Serum alpha-1 acid glycoprotein levels were measured in 27 patients with idiopathic peripheral retinal vasculitis (Eales' disease) and 31 healthy subjects by single radial immunodiffusion technique. The levels were found to be significantly increased in both moderate and severe types of the disease. The serum levels of this protein paralleled the severity of the disease. The increased alpha-1 acid glycoprotein in serum showed a significant fall to near normal levels during the quiescent stage. Our observations support the hypothesis that idiopathic peripheral retinal vasculitis is an immune mediated disease. It is proposed that serum alpha-1 acid glycoprotein may be considered as a reliable parameter of the activity and the degree of severity of the disease, as well as an useful tool for monitoring the efficacy of treatment.

Isolation, characterization and quantitation of canine alpha-1-acid glycoprotein

The present study was designed to investigate the physicochemical properties of canine alpha-1-acid glycoprotein (AGP), and to establish a method for measuring serum AGP in canine. Fifty-three normal beagles were used in the study. AGP was purified from normal canine sera by successive ammonium sulfate precipitation, ion-exchange chromatography and gel filtration. The serum AGP concentration was measured by single radial immunodiffusion (SRID). Canine AGP had a molecular weight of 42,000 +/- 2,000 Da and contained 40.9% carbohydrate. Gel isoelectric focusing revealed microheterogeneity with 6-7 bands in a pI range (isoelectric points) of 3.2-3.8. AGP migrated to the alpha1-globulin region on immunoelectrophoresis. The serum AGP level of 35 normal beagles was 283.4 +/- 113.3 microg/ml. Canine AGP was isolated, and its physicochemical properties were clarified. SRID may be a useful method for quantification of serum AGP in canine.

Critical Assessment of the Diagnostic Value of Feline α1-Acid Glycoprotein for Feline Infectious Peritonitis Using the Likelihood Ratios Approach

Alpha-1-acid glycoprotein (AGP) increases in the blood of cats with feline infectious peritonitis (FIP), a lethal disease caused by feline coronavirus (FCoV). However, the diagnostic potential of AGP might be limited because AGP also increases in pathophysiological conditions other than FIP. In this retrospective study, the diagnostic potential of serum AGP concentration was evaluated on the basis of the pretest probability of disease, according to the Bayesian approach. Serum AGP levels from cats with FIP (group 1; n = 58) and without FIP (group 2; n = 104) were evaluated. Non-FIP cats were further subgrouped as follows: 2a) inflammation (n = 26), 2b) asymptomatic FCoV infection (n = 49), 2c) injection-site sarcoma (n = 19), 2d) postvaccination (n = 7), and 2e) specific pathogen free (n = 3). Standard descriptive analyses by group and empirical receiver-operating characteristic (ROC) curve estimation were performed. Ordinary logistic regression analysis was performed to derive an estimate of the continuous likelihood ratio to produce the posttest probability of disease for any combination of pretest probability and serum AGP value. The comparison of serum AGP levels in the different groups and the analysis of the ROC curve confirmed that serum AGP is a powerful discriminating marker for FIP. The Bayesian approach demonstrated that when the pretest probability of FIP is high, based on history and clinical signs (groups 1 or 2a), moderate serum AGP levels (1.5-2 mg/ml) can discriminate cats with FIP from others, while only high serum AGP levels (>3 mg/ml) can support a diagnosis of FIP in cats with a low pretest probability of disease (groups 2b to 2e).

Dexamethasone as a probe for CYP3A4 metabolism: evidence of gender effect

A study was conducted to evaluate prospectively the correlation between docetaxel clearance and pharmacokinetics of dexamethasone previously obtained in 21 patients. Dexamethasone pharmacokinetics were performed in 17 patients 24 h before docetaxel treatment as monochemotherapy. Dexamethasone and docetaxel plasma concentrations were determined by HPLC methods. Determination of docetaxel unbound fraction in plasma was performed using microequilibrium dialysis. Significant correlation was observed between observed plasma docetaxel clearances (CL(docetaxel)) and values predicted from dexamethasone plasma clearance (CL(dexa)), unbound plasma docetaxel fraction estimated from serum alpha1-acid glycoprotein level (fu(alpha1-AAG)), and hepatic metastasis status. However, after splitting of the prospective data set according to gender, no correlation was observed for males (R(2) = 0.08, NS, n = 10), then strong correlation was observed for females (R(2) = 0.78, P < 0.01, n = 7). Multivariate analysis was performed from data obtained in the women included in the first study and those of this prospective study (n = 18). Docetaxel CL was significantly correlated with CL(dexa) (P = 0.001) and fu(alpha1-AAG) (P = 0.01) according to the relationship (with +/-95% confidence intervals): CL(docetaxel) (l/h) = 1.92 (+/-0.94) x CL(dexa) (l/h) + 2.68 (+/-1.95) x fu(alpha1-AAG) (%) (R(2) = 0.68). Dexamethasone may be used to predict docetaxel clearances in females, but not in males.

Alpha 1-acid glycoprotein (AGP): a possible carrier of sialyl lewis X (slewis X) antigen in colorectal carcinoma.

1- to detect alpha 1-acid glycoprotein (AGP) and sialyl Lewis x (sLex) in colorectal malignant, benign and normal samples; 2- to isolate AGP from colorectal cancer and 3- to study its immunoreactivity with an anti-sLex monoclonal antibody (MAb). tissue and serum samples from 88 patients with colorectal cancer, 22 adenomas and 23 normal were included. Expression of AGP and sLex was studied by immunohistochemistry (IHC); isolation approach: AGP was precipitated with ammonium sulphate and immunoprecipitated with anti-AGP MAb. The immune complex formed was isolated by protein A-Sepharose CL-4B affinity chromatography and further eluted; fractions were analysed by SDS-PAGE and Western-blot. Statistical analysis was performed by means of Principal Component Analysis. By Western blot employing anti-AGP MAb and sLex MAbs, isolated fractions from malignant samples showed a band at about 45 kD. IHC revealed that AGP was expressed in 70% of colorectal carcinoma samples, 50% of benign and 35% of normals. SLex was detected in 31% of malignant samples, 41% of benign and in one normal sample. In malignant samples, AGP reaction comprised the whole specimen with a strong and homogeneous staining while normal and benign samples showed a restricted reaction. In cancer, sLex expression consisted in an intense reactivity in membrane, cellular debris and some cytoplasmic foci while normal and benign samples were occasionally stained. A statistically significant positive correlation was found between AGP and sLex expression. Serum AGP levels were measured by radial immunodiffusion and statistical comparative analysis with tissue expression did not show a correlation between both parameters. AGP may constitute a carrier of sLex in colorectal cancer.

α1‐Acid glycoprotein fucosylation as a marker of carcinoma progression and prognosis

Serum alpha1-acid glycoprotein (AGP), an acute-phase protein secreted by the liver, carries alpha(1,3)-fucosylated structures on its 5 highly branched, N-linked sugar chains. Serum AGP levels in patients with various types of malignancies (n=214 patients) were measured using an enzyme-linked immunosorbent assay with anti-AGP antibody. To investigate glycoforms that differed in their degree of branching and extent of fucosylation, serum AGP samples were analyzed by crossed affinoimmunoelectrophoresis (CAIE) with concanavalin A, and Aleuria aurantia lectin (AAL), and anti-AGP antibody. A significant difference (P <0.001) in serum AGP levels was observed in preoperative patients compared with levels in the healthy control group, but the levels in individual patients did not reflect their clinical status. Conversely, it was found not only that the patterns of AGP glycoforms differed widely in the patient group compared with the healthy control group, but they also changed depending on each patient's clinical status. Furthermore, AGP glycoforms seemed to be appropriate markers of disease progression and prognosis according to follow-up studies of 45 patients during prolonged preoperative and postoperative periods. Patients with advanced malignancies who had AGP glycoforms that contained highly fucosylated triantennary and tetraantennary sugar chains for long periods after surgery were likely to have a poor prognosis. However, patients who had AGP glycoforms without such changes were expected to have a good prognosis.

Systemic low-grade inflammation is related to both circulating and adipose tissue TNFalpha, leptin and IL-6 levels in obese women.

We assessed the relationships between four circulating acute phase proteins and the circulating and adipose tissue levels of three adipocytokines. In all, 15 nondiabetic obese women with a body mass index (BMI) above 32 kg/m(2) were investigated. Circulating concentrations of C-reactive protein (CRP), alpha 1 acid glycoprotein (AAG), fibrinogen, alpha 1 antitrypsin and both circulating and adipose tissue levels of interleukin (IL)-6, tumor necrosis factor (TNF)alpha and leptin were measured by either nephelometry or enzyme-linked immunosorbent assay. We found a strong positive correlation between both circulating and adipose tissue levels of IL-6, TNFalpha and leptin and serum CRP levels. All these adipose tissue adipocytokines were also positively correlated with serum AAG levels. These correlations disappeared when adjusted for fat mass, suggesting that the relationship observed was dependent on fat amount. Our results indicate a strong relationship between adipocytokines and inflammatory markers, and suggest that cytokines secreted by adipose tissue in obese subjects could play a role in increased inflammatory proteins secretion by the liver.

Alpha 1-acid glycoprotein (AAG) levels in healthy and pregnant beagle dogs.

Serum alpha 1-acid glycoprotein (AAG) levels were measured in healthy beagles of various ages (66 male and 74 female) by turbidimetric immunoassay (TIA), and then separately--in pregnant beagles--by single radial immunodiffusion (SRID). The first experiment revealed that serum AAG levels ranged from 40 to 960 microg/ml (mean of 322 +/- 202 microg/ml) in male dogs, and from 47 to 833 microg/ml--in female dogs (mean of 316 +/- 199 microg/ml), without any significant sex- or age-related variation. The second experiment, however, revealed that serum AAG levels increased in all pregnant beagles and peaked in the middle of gestation at 250-1,000 microg/ml (mean of 634 +/- 246 microg/ml). In 7 of 8 dogs the AAG levels peaked about 45 days after ovulation. Despite a high value of 1,210-1,360 microg/ml being observed for serum AAG levels in 3 pregnant beagles inoculated with Staphylococcus aureus, its levels in umbilical cord blood were below the detection limit of SRID (40 microg/ml).

Comparison of the effects of infection with Salmonella enteritidis, in combination with an induced molt, on serum levels of the acute phase protein, alpha1 acid glycoprotein, in hens

Periods of inflammation due to infection, injury, or malignancy are marked by increases in serum constituents known as acute phase proteins (APP), and these proteins have been used as markers for early stages of disease. Four experiments were performed to examine whether levels in chickens of one such APP, alpha1 acid glycoprotein (AGP), would be affected by an infection with Salmonella enteritidis (SE) and if the added stress of induced molting via 14-d feed withdrawal would increase these effects. In all experiments but Experiment 1, hens were divided into four equal groups: molted infected, nonmolted infected, molted noninfected, nonmolted non-infected (Experiment 1 lacked this last group). Blood and intestinal samples were collected at various times from the hens and assayed for AGP and SE levels, respectively. Infection with SE significantly elevated serum AGP levels above those found in the noninfected groups of hens in two of four experiments, whereas in molted infected hens, serum AGP levels were significantly higher than those found in the noninfected counterparts in all four experiments. Comparison of AGP titer between the infected groups of hens revealed that significantly higher SE levels generally did not guarantee significantly higher AGP levels, although when individual values were plotted, a trend was observed toward increasing serum levels concomitant with increasing SE counts. Serum AGP levels show promise as a method to detect infection problems in hens, especially when the severity of the infection is exacerbated by stress situations. However, more work is needed to determine what other factors may elevate serum AGP levels and potentially confound the picture.

Utilization of alpha-1-acid glycoprotein levels in the serum as a parameter for in vivo assay of influenza virus inhibitors.

Alpha-1-acid glycoprotein (AGP), an acute phase protein in serum assayed by single radial immunodiffusion using a commercially available kit, was found to significantly increase in mice infected with influenza A and B viruses. Experiments were run to determine the rate of increase of serum AGP and its relation to other influenza disease parameters, including lung consolidation, development of lung virus titres, decline in arterial oxygen saturation (SaO2), histopathological changes in the lung, and death of the animal. Maximal AGP levels occurred by day 3 in the animals, at about the same time lung virus titres reached their peak and inflammatory effects were evident in the lung. Serum levels of AGP were then compared with other disease parameters in the evaluation of the anti-influenza A and B virus efficacy of oseltamivir and ribavirin in mice. Treatment was by oral gavage twice daily for 5 days, beginning 4 h before virus exposure using doses of 100, 10, and 1 mg/kg per day of oseltamivir and 75 mg/kg per day of ribavirin. Against the influenza A infection, significant inhibition of death, SaO2 decline, and lung consolidation was seen at all doses of each compound; day-6 AGP levels were reduced in a dose-responsive manner. Lung virus titres were lessened at this time, but to a significant degree only at the high dose of oseltamivir and by ribavirin. The influenza B virus infection, which appeared more severe than the influenza A infection, was also significantly inhibited by both compounds, but to a lesser extent. The serum AGP levels were again lessened by therapy with both compounds. The influence of challenge dose of influenza A virus on AGP level and on the antiviral activity of 20 mg/kg per day of oseltamivir, administered by oral gavage, was determined in mice. The AGP level was in proportion to the viral challenge dose; oseltamivir significantly inhibited AGP levels and all other disease parameters regardless of size of viral inoculum. These data indicate murine AGP levels to be markedly stimulated by infection with influenza A and B viruses, and the level of the protein to be an additional measure of antiviral efficacy.

Attenuation of the acute-phase response in thermally injured rats by cholesterol-containing cationic liposomes used as a delivery system for gene therapy.

Cholesterol-containing cationic liposomes alone modulate the acute-phase response and cytokine expression in thermally injured rats and are an effective delivery system for gene therapy in trauma. Laboratory. Fifty-six adult male Sprague-Dawley rats with a full-thickness scald burn covering 60% of total body surface area were randomly divided into 2 groups to receive either intravenous injections of cholesterol-containing cationic liposomes or saline (control). Body weights, muscle and liver dry-wet weights, serum levels of constitutive hepatic proteins, acute-phase protein levels, and cytokine levels were determined at 1, 2, 5, and 7 days after thermal injury. Rats receiving cholesterol-containing cationic liposomes had less body weight loss, increased serum transferrin levels, and decreased serum alpha1-acid glycoprotein levels when compared with controls (P<.05). Serum interleukin 1beta and tumor necrosis factor alpha levels were decreased in rats receiving liposomes at 1 and 2 days after burn compared with controls (P<.05). These results suggest that cholesterol-containing cationic liposomes alone may have a beneficial effect in modulating the hypermetabolic response after burn injury by decreasing type 1 acute-phase proteins and the expression of the proinflammatory cytokines interleukin 1beta and tumor necrosis factor alpha. Therefore, cholesterol-containing cationic liposomes appear to be suitable as a delivery system for gene therapy in trauma.

Kinetic interaction between fluoxetine and imipramine as a function of elevated serum alpha-1-acid glycoprotein levels.

The effect of elevated serum alpha-1-acid glycoprotein (AAG) levels on the pharmacokinetic interaction between imipramine and fluoxetine has been examined by utilizing a novel strain of transgenic mice which express serum AAG levels several times greater than normal. Before fluoxetine treatment, serum imipramine levels were approximately three times greater in transgenic mice than in control mice. Despite higher serum imipramine levels in transgenic mice, brain drug levels were lower than those found in control mice. Fluoxetine pre-treatment (20 mg kg(-1) for 5 days) resulted in an increase in serum imipramine levels in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (4.5-fold increase compared with 3.1-fold). Similarly, fluoxetine pre-treatment resulted in an increase in brain levels of imipramine in both groups of mice and the extent of the increase was greater in transgenic mice than in control mice (3.0-fold increase compared with 2.0-fold). Similar trends were observed for levels of desipramine in the serum and brain. Serum imipramine and desipramine levels did not correlate with their respective brain levels in the presence of elevated serum AAG levels before and after pre-treatment. These findings indicate that the extent of increases in imipramine and desipramine serum and brain levels are greater during elevated serum AAG states than during normal AAG states when imipramine is co-administered with fluoxetine.

Growth hormone attenuates the acute-phase response to thermal injury.

To determine the effects of growth hormone (GH) on the hepatic acute-phase response (APR) in a burned rat model. Laboratory. Male Sprague-Dawley rats (weight, 300-350 g). Rats underwent a 40% total body surface area burn injury and received GH or saline solution daily by subcutaneous injection. Unburned rats served as controls. Hepatic messenger RNA (mRNA) expression and serum levels of alpha 1-acid glycoprotein and albumin were determined 2, 7, and 14 days after injury. The serum alpha 1-acid glycoprotein levels in GH-treated animals did not increase on days 2 and 7, whereas saline-treated animals showed a major increase. Hepatic mRNA expression increased dramatically on day 2 for burned groups; however, the mRNA pool levels of GH-treated animals showed a faster rate of decline to control levels on days 7 and 14. The albumin mRNA pool levels of GH-treated and control animals did not show significant differences, whereas the negative APR, indicated by loss of albumin mRNA, was more pronounced on day 7 in the saline-treated animals. By day 14, mRNA levels were comparable in all 3 groups. Growth hormone attenuated the positive APR, as indicated by a decrease in alpha 1-acid glycoprotein expression and production, and prevented the negative APR, as seen by an absence of a decline of albumin mRNA pool levels and serum concentration. We conclude that the beneficial effects of GH on thermal injury may be due in part to a modification of the APR.

Microheterogeneity of acute-phase glycoproteins in patients with pulmonary sarcoidosis.

This study was designed to investigate qualitative changes in the carbohydrate side-chains of two acute-phase glycoproteins, alpha 1-acid glycoprotein (AGP) and alpha 1-antichymotrypsin (ACT), in 37 patients with pulmonary sarcoidosis. The glycosylation profile of AGP and ACT was studied using affinity immunoelectrophoresis with the lectin concanavalin A (conA). Serum concentration of soluble receptor for interleukin-2 (sIL-2R) and activity of serum angiotensin converting enzyme (ACE) were measured by specific enzyme-linked immunosorbent assay (ELISA) and enzyme kinetic assay, respectively. Rocket immunoelectrophoresis and nephelometric assay were used to determine serum concentration of AGP, ACT and C-reactive protein (CRP). In 11 patients with active disease, a decreased reactivity of AGP with conA was found as compared with controls (n = 44) and patients with nonactive sarcoidosis (n = 26). A similar tendency was seen with ACT. In the same group, increased concentrations of serum AGP and higher levels of sIL-2R were detected compared with patients with nonactive sarcoidosis. In the entire sarcoidosis group, there was a negative correlation between ACE activity and AGP and ACT affinity for conA (r = -0.6358, and r = -0.5019, respectively) and a positive correlation with sIL-2R level (r = 0.8241). In nine patients with elevated concentrations of serum CRP, no differences were found in disease activity and glycosylation profile of AGP and ACT when compared to patients with normal serum CRP. The results suggest that in active pulmonary sarcoidosis changes in the glycosylation pattern of acute-phase glycoproteins exist, which are similar in trend and magnitude to those found in other chronic inflammatory diseases. The synthesis and glycosylation of acute-phase proteins in pulmonary sarcoidosis are probably regulated independently.