Protein binding of disopyramide in liver cirrhosis and in nephrotic syndrome.

The plasma protein binding of disopyramide (D) was determined in seven patients with cirrhosis, six with nephrotic syndrome, and seven healthy subjects. Plasma samples containing concentrations of 0.2 to 12.0 micrograms/ml were ultrafiltered and the free fractions were measured with fluorescence polarization immunoassay. The mean free fractions at D concentrations ranging from 1 to 6 micrograms/ml were significantly (P less than 0.01) greater in patients with cirrhosis than in healthy subjects. No difference was observed between patients with nephrotic syndrome and healthy subjects. The free fraction at D 3 micrograms/ml correlated better with alpha 1-acid glycoprotein (r = -0.77) than with albumin (r = -0.46). Patients with cirrhosis had significantly (P less than 0.01) lower capacity constants as compared with the other two study groups. There was a significant (P less than 0.01) correlation between capacity constant and alpha 1-acid glycoprotein (r = 0.71). Our results suggest that the D therapeutic range measured as the total plasma concentration in cirrhosis, but not in nephrosis, should be approximately 50% lower than previously believed.

Urine and plasma propranolol.

Eight hypertensive patients who had been followed in an outpatient clinic during long-term therapy with propranolol (40 to 160 mg twice daily) were studied during a 24-hr stay in the ward. The usual oral dose was given and the total and free plasma concentrations were determined during the 24 hr and the urinary excretion of unchanged drug was measured. Average free plasma concentration of propranolol (y free) was calculated from: y free = Excreted propranolol (ng/24 hr)/Creatinine clearance (ml/24 hr). There was a significant relationship between log y free and average free plasma concentration (means free) determined from the directly measured plasma concentration curve: log y free = 0.0743 means free - 0.0466 (r = 0.98, P less than 0.001). In another group of propranolol-treated hypertensive patients there was a significant positive relationship between orosomucoid concentration and reciprocal of the free propranolol fraction in plasma. From this relationship the average total drug concentration (y total) was calculated from y free; there was a significant correlation with directly measured total plasma level: log y total = 0.0038 . means total + 1.0895 (r = 0.91, P less than 0.001). It is suggested that individually determined values of y free below 30 ng/ml and y total below 400 ng/ml (the concentration range studied) can be used to calculate the average mean 24-hr free and total plasma concentrations.

Wheat gluten challenge in schizophrenic patients.

Eight chronic schizophrenic patients were maintained on a diet free of gluten, cereal grains, and milk (CM-F diet) and challenged in a double-blind manner with dietary wheat gluten and placebo. While on the CM-F diet, each patient received a daily challenge of 30 g of gluten for 5 weeks and a placebo challenge for 8 weeks. No deterioration in clinical status as measured by the BPRS was noted on gluten challenge. Serum alpha 1 acid glycoprotein measurement demonstrated no evidence of inflammatory response to gluten challenge. The data suggest that sensitivity to dietary gluten is not characteristic of young chronic schizophrenic patients.

Pharmacokinetics of intravenously administered 125I-labelled human alpha 1-acid glycoprotein.

The volumes of distribution of many acidic drugs have been shown to be close to that of their binding protein, i.e. serum albumin. The distribution of basic drugs mainly bound to alpha 1-acid glycoprotein (AAG) can be questioned with respect to its dependency upon the distribution of this plasma protein. So, a pharmacokinetic study was performed in 7 subjects with human 125I-labelled alpha 1-acid glycoprotein. The steady-state volume of distribution was found to be 5.37 +/- 0.82L. The central volume was 3.23 +/- 0.33L, close to that of plasma volume and the peripheral volume was 2.14 +/- 0.63L. These data allowed the establishment of an equation giving access to the volume of distribution of a basic drug by relating its unbound fraction to physiological distribution of alpha 1-acid glycoprotein. The values yielded by this equation show that the actual and calculated volumes of distribution of basic drugs mainly bound to AAG are discrepant. This protein is thus not the main factor controlling the distribution of basic drugs within the body.

Effects of alpha-1-acid glycoprotein administration on propranolol binding and beta blockade in rats.

Alpha-1-acid glycoprotein (AAG), 750 mg/kg, was administered to rats to determine its effect on propranolol binding and beta blockade. Anesthetized rats received [3H]propranolol i.v., followed in 15 min by human AAG or bovine serum albumin, 750 mg/kg. AAG treatment produced a human AAG concentration in serum of 7.76 +/- 1.17 mg/ml, several times higher than the endogenous serum AAG concentration in stressed rats. AAG treatment significantly increased the heart rate response to isoproterenol, compared to albumin (95.4 +/- 19.6 vs 28.3 +/- 16.7% of baseline value, measured 45 min after propranolol, P less than 0.001). AAG-treated rats had greater [3H]propranolol binding in serum (93.0 +/- 3.2 vs 76.7 +/- 3.0%, P less than 0.01) and a lower calculated unbound [3H]propranolol concentration in serum (2.7 +/- 1.3 vs 7.4 +/- 3.1 X 10(6) dpm/ml, P less than 0.001) than albumin-treated rats. These data demonstrate that AAG can alter propranolol pharmacokinetics and pharmacodynamics even when administered after the propranolol effect is evident. Because the reported affinity of propranolol for cardiac beta receptors is 10,000 times greater than its affinity for AAG, these data suggest that AAG acted by altering propranolol disposition rather than by directly competing with beta receptors for drug.

Early plasma protein and mineral changes after surgery: a two stage process.

Sequential changes in albumin, transferrin, alpha 1-acid glycoprotein, C reactive protein, fibrinogen, copper, iron, and zinc in plasma up to 24 h after hysterectomy were measured. No increases in the concentrations of the acute phase proteins alpha 1-acid glycoprotein, C reactive protein, and fibrinogen were observed until 6 h after the skin incision. These increases were preceded by significant falls at 2-4 h, and this was shown also by albumin, transferrin, iron, zinc, and copper. The ratios of iron and zinc to their binding proteins, transferrin and albumin, did not decrease until 4-6 h and their concentrations remained low for at least 24 h. These patterns suggest that at least two mechanisms operate after trauma. The early fall in the concentrations of the proteins in plasma is consistent with a prompt increase in microvascular permeability. The later decrease in binding of the metals iron and zinc to their transport proteins and the increase in concentrations of the acute phase proteins could be initiated by a common mediator.

Immunochemical and electrophoretic study of glycoproteins in cancer patients.

Glycoproteins have been studied in the past and found to be elevated in human malignancies, as well as degenerative, traumatic or inflammatory diseases. In order to obtain insight into the relationship of these plasma proteins to malignancy, we studied 78 patients with various neoplasms and compared the values of alpha 1-acid glycoprotein (orosomucoid), alpha 1 glycoprotein and carcinoembryonic antigen (CEA). Normal values were calculated for these parameters in sera of 100 normal individuals.

The contribution of alpha 1-acid glycoprotein, lipoproteins, and albumin to the plasma binding of perazine, amitriptyline, and nortriptyline in healthy man.

Parameters for the binding of perazine (PER), amitriptyline (AT) and nortriptyline (NT) to plasma and to single plasma proteins were determined by equilibrium dialysis. The highest affinity (K at least 10(5) M-1) and lowest capacity (first site 1 mol/mol) towards all three drugs was exhibited by alpha 1-acid glycoprotein (alpha 1-AGP). From the parameters, alpha 1-AGP was estimated to contribute 43% to total binding of PER and 49 and 31%, respectively, to AT and NT binding in samples with normal protein concentrations. Fractions bound to total lipoproteins would amount to 32% (PER), 40 (AT) and 52% (NT), respectively, while the contribution of albumin would range from 11% (AT) to 25% (PER). The extent of the binding to plasma was compared with that to single proteins and their mixtures. Binding to combinations of alpha 1-AGP, lipoproteins and albumin exceeded that to plasma with PER but not with AT and NT. This leads to the assumption that additional plasma constituents interfere with PER binding.

Acute phase reactants in the elderly.

The erythrocyte sedimentation rate (ESR), plasma fibrinogen, serum orosomucoid, serum alpha 1-antitrypsin and serum haptoglobin were measured in 267 apparently healthy elderly subjects (median age 79 years, range 60-93), and compared to the values in 58 healthy younger subjects (median age 27 years, range 18-50). The acute phase reactants displayed no sex differences, but were significantly higher in elderly than in younger persons (mean +/- SD): ESR 13 +/- 10 mm/h vs 4 +/- 3 mm/h (p less than 0.001); fibrinogen 4.35 +/- 0.95 g/l vs 3.33 +/- 0.54 g/l (p less than 0.001); orosomucoid 0.68 +/- 0.20 g/l vs 0.60 +/- 0.16 g/l (p less than 0.01); alpha 1-antitrypsin 2.16 +/- 0.38 g/l vs 1.84 +/- 0.43 g/l (p less than 0.001); haptoglobin 1.30 +/- 0.50 g/l vs 1.00 +/- 0.30 g/l (p less than 0.001). Correlations existed between the acute phase reactants, being highest between ESR and fibrinogen (r = 0.53, p less than 0.001).

Regulation of alpha 1-acid glycoprotein plasma concentration by sex steroids and adrenal-cortical hormones during experimental inflammation in the rat.

Treatment of adult intact rats with sex steroids (estradiol-17 beta, ethynylestradiol, dihydrotestosterone) raises the concentration of serum acute-phase alpha 1-acid glycoprotein (AGP). Estrogens are more effective than dexamethasone, and experimental inflammation causes an additive effect on AGP synthesis when ethynylestradiol is given simultaneously. Adrenaline is also able to increase the AGP level. Experiments with adrenalectomized and adrenalectomized plus castrated rats result in a 50% reduction in the serum level of AGP as compared with that in normal and hypophysectomized rats. Although ethynylestradiol is the strongest inducer of AGP synthesis in intact animals, it is unable to enhance significantly the AGP level in adrenalectomized rats, contrary to dexamethasone. Adrenalectomized rats are incapable of undergoing a substantial increase in plasma AGP level following experimental inflammation, and ethynylestradiol or adrenaline cannot take the place of dexamethasone in inducing high levels of AGP in these inflamed rats. These results indicate that glucocorticoids play an obligatory role in modulating AGP synthesis either by directly regulating the AGP gene or in modulating AGP synthesis by increasing the stability of AGP mRNA. Finally, it is suggested that glucocorticoids may also act in unmasking receptor binding sites at the AGP gene level for other mediators such as sex steroids and putative inflammatory factors.

Quantitative and qualitative biochemical parameters for alcohol abuse.

Blood from alcoholics, non-alcoholic patients and healthy controls were analyzed for various biochemical markers. Follow-up measurements were made during about 3 months of abstention. While a gradual increase in aldehyde dehydrogenase activity (ALDH) in red cell was noted in alcoholic patients serum alpha 1-acid glycoprotein (AAG) values returned to normal range within 8 weeks during abstinence. An additional minor band for alpha 1-antitrypsin (AAT) was observed after isoelectric focusing of sera from alcoholics; this band disappeared after 3 weeks of abstinence. However, no such unusual AAT band was found in non-alcoholic patients with liver disorders.

Biological measurements of Crohn's disease activity--a reassessment.

Fifty-eight patients with Crohn's disease were studied in order to compare disease activity as measured by a clinical scoring system, with nutritional status, the laboratory measurements reflecting nutritional status, and the serum levels of acute phase proteins, using principal component analysis and stepwise multiple regression analysis. We confirmed that orosomucoid is the laboratory measurement which correlates best with clinical assessment of disease activity, followed by ESR and C-reactive protein. Serum albumin correlated poorly with clinical disease activity, although body weight showed an inverse correlation. Serum fibronectin, a protein involved in the production of fibrous tissue, did not detect the presence of fibrous strictures in the intestine.

[Alpha 1-acid glycoprotein and carbamazepine]. / Alpha 1-glycoprotéine acide et carbamazépine.

Levels of alpha 1-acid glycoprotein (alpha 1-AGP) were determined in 40 epileptic patients who had been also treated with carbamazepine (CBZ) and, in some patients, phenobarbital (PB) for at least 3 months. alpha 1-AGP levels were also determined in 28 controls. CBZ dit not alter blood levels of alpha 1-AGP while CBZ-PB decreased them. Such results are at variance with recent studies which suggested an increase of alpha 1-AGP in epileptic patients treated either with phenytoin or phenytoin + PB, or + CBZ, or + primidone.

The effects of phenytoin dosage on the induction of alpha 1-acid glycoprotein and antipyrine clearance in the dog.

Doses of phenytoin from 90 to 800 mg/d were used to study induction of hepatic cytochrome P-450 and plasma alpha 1-acid glycoprotein in dogs. The antipyrine clearance was increased by 80%, which is equivalent to an increase in cytochrome P-450 of 140%, and the plasma glycoprotein concentration rose 200% at the highest dose of phenytoin used. Plasma concentrations of phenytoin were measured at each dose level to provide a definitive value for the amount of inducer present. These data were used to assess the concentration-response relationship for phenytoin inducing either cytochrome P-450 or the glycoprotein. A simple relationship between concentration and effect was not observed, suggesting a complex mechanism of induction.

[Early diagnosis of sepsis in the preterm neonate]. / Diagnosi precoce di sepsi nel neonato pretermine.

The usefulness of the neutrophil blood cell count, the ratio of band forms to total neutrophils, the platelet count, the quantitative determination of serum IgM, C-reactive protein, alpha-1-acid glycoprotein and haptoglobin for the early identification of the serious neonatal infections was evaluated in 70 preterm newborns: 15 with sepsis, 2 with serious infections, 53 without infections. None of these tests has proved sensitive and predictive enough to be used as a single measure. The combination of 2 or more of them had improve the sensitivity (76.4%) and the predictive value of negative test (91.6%). The authors suggest that the greatest potential value of the tests is to exclude infections, with a more than 90% probability, if they are negative.