A placebo-controlled, double-blind, randomized trial of cyclosporine therapy in active chronic Crohn's disease.

We randomly assigned 71 patients with active chronic Crohn's disease who were resistant to or intolerant of corticosteroids to treatment with oral cyclosporine (5 to 7.5 mg per kilogram of body weight per day) or placebo for three months. Disease activity was assessed on a clinical grading scale without knowledge of the treatment given. At the end of the treatment period, 22 of the 37 cyclosporine-treated patients (59 percent) had improvement, as compared with 11 of the 34 placebo-treated patients (32 percent) (P = 0.032). During cyclosporine treatment, there was significant improvement in plasma orosomucoid levels (P = 0.0025) and the Crohn's Disease Activity Index (P = 0.00012). The effect of treatment became evident after two weeks. In the subsequent three months, during which the patients were gradually withdrawn from treatment, the improvement continued in 14 of the 37 patients (38 percent) in the cyclosporine group and in 5 of the 34 (15 percent) in the placebo group (P = 0.034). No serious adverse events were observed. We conclude that cyclosporine has a beneficial therapeutic effect in patients with active chronic Crohn's disease and resistance to or intolerance of corticosteroids.

Changes in rat liver mRNA for alpha-1-acid-glycoprotein, apolipoprotein E, apolipoprotein B and beta-actin after mouse recombinant tumor necrosis factor injection.

Hybridization studies using specific cDNA probes have been used to determine the specific mRNA levels for apolipoproteins B and E, alpha 1 acid glycoprotein and beta actin in extracts of rat liver. Injection of rats with recombinant mouse tumor necrosis factor had led to a rapid increase in liver mRNA levels for alpha 1 acid glycoprotein (x 12) and for beta actin (x 2.5) whereas mRNA levels for Apolipoprotein B and E remained stable over the same period.

[Roxithromycin passage in the cervix mucus]. / Passage de la roxithromycine dans la glaire cervicale.

We studied the diffusion of roxithromycin in the cervix mucus of fifteen healthy normal women, aged 24 to 44 (median 37). They were consulting physician to have an IUD. After this intervention (between the 4 to 7 days of menstrual cycle) they received an antibiotic treatment with the standard dose of roxithromycin: 150 mg bd for a week. At the end of this treatment the cervix mucus was taken 1 to 12 hours after the last antibiotic dose. We dose the roxithromycin by a microbial assay (Bacillus subtilis ATCC 6633, antibiotic medium 1, pH 8) and the acid alpha-1-glycoprotein by an immunodiffusion assay. All women had drug measurable with levels from 0.45 to 2.07 mg/l (median: 0.80 mg/l). The acid alpha-1-glycoprotein levels were quite constant (median: 0.19 mg/l). The antibiotic concentrations observed are above the MIC of the major genital pathogens, mainly C. trachomatis, G. vaginalis, H. ducreyi and U. urealyticum, but lower than the MIC ov N. gonorrhoeae and M. hominis.

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.

Placental transfer of alfentanil at caesarean section.

Twenty-one women about to undergo elective Caesarean section were given intravenous alfentanil 10 micrograms kg-1 1 min prior to induction of anaesthesia in order to obtund the pressor response to laryngoscopy and endotracheal intubation. Compared with a control group of 16 patients, alfentanil significantly reduced the pressor response to endotracheal intubation (P less than 0.01), without any detectable adverse effect upon the neonate. At delivery, mean maternal alfentanil plasma concentration was 23.5 ng ml-1 (SD 7.5, range 9.8-41.2 ng ml-1) and the mean maternal venous plasma alpha 1-acid glycoprotein (alpha 1-AGP) was 576 mg l-1 (SD 208, range 230-1200 mg l-1). Mean neonatal umbilical venous alfentanil plasma concentration was 7.5 ng ml-1 (SD 1.8, range 3.6-10.6 ng ml-1), while the mean umbilical venous alpha 1-AGP concentration was 189 mg l-1 (SD 76, range 80-410 mg l-1). At delivery, the calculated unbound maternal and foetal plasma alfentanil concentrations were similar.

Interleukin-6 (IL-6) and acute phase proteins in the disease course of patients with systemic lupus erythematosus.

One of the mediators responsible for the induction of the production of acute phase proteins by hepatocytes is interleukin-6 (IL-6), formally known as hybridoma growth factor (HGF). In a prospective study the biological significance of IL-6, but also the relationship with the acute phase response (C-reactive protein [CRP], alpha 1-antitrypsin and alpha 1-acid glycoprotein) during flare-ups in 12 systemic lupus erythematosus (SLE) patients was investigated. Only 2 SLE patients showed sustained elevated IL-6 levels, and in one of these patients a clear correlation was found between the increases in IL-6 and the acute phase response. In the other SLE patients hardly any response or change in the levels of IL-6, CRP, and/or alpha 1-antitrypsin was found. In contrast to the profiles of alpha 1-acid glycoprotein, in seven of the SLE patients a significant increase in the serum levels took place in the period preceding the exacerbation. This difference between the three acute phase proteins suggests that the regulatory mechanisms are different. Our results are in agreement with the findings that IL-6 might be responsible for the CRP response.

The prognostic influence of serum neuron specific enolase in small cell lung cancer.

An analysis of prognostic factors in small cell lung cancer has been made using presentation data from 86 of 101 consecutive patients referred to The Finsen Institute for chemotherapy. Prognosis was in univariate analysis significantly correlated with performance status (PS), disease extent, serum lactate dehydrogenase (LDH), neuron specific enolase (NSE), alpha-1-acid glycoprotein and plasma sodium. Multivariate analysis, taking stage of disease into account, resulted in selection of PS and NSE as the most influential of the investigated variables. LDH was excluded as an independent prognosticator, but there was a strong correlation between the influence of LDH and NSE (coefficient: -0.38) as well as between their serum concentrations (coefficient: 0.72). LDH and NSE apparently have similar prognostic influence, and NSE seems superior to LDH. A firm conclusion should, however, await our investigation of a large series of patients.

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.

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).

A competitive enzyme-linked immunosorbent assay for alpha 1-acid glycoprotein in serum and urine samples.

In this solid-phase competitive enzyme-linked immunosorbent assay for alpha 1-acid glycoprotein in serum or urine, antiserum to human alpha 1-acid glycoprotein is incubated with solid-phase-bound alpha 1-acid glycoprotein in the presence of standard or sample. Incubation with second antibody labeled with alkaline phosphatase then follows, before development with substrate. Results obtained correlate well with a fluorescent assay involving the dye Auramine O (r = 0.953) and with radial immunodiffusion (r = 0.921). The present assay covers the range 0.2 to 5 mg/L and 16 samples take 2.5 h to complete. This assay is useful for measuring concentrations of alpha 1-acid glycoprotein in serum and also in urine, for which other assay methods are not sufficiently sensitive.

Dose-response behavior of the induction of alpha 1-acid glycoprotein by phenobarbital in the dog.

Three-week dosing periods at one of six oral phenobarbital doses between 15 and 400 mg/day were used to achieve steady states for induction of plasma alpha 1-acid glycoprotein concentration (AGP) in beagle dogs. In this way, the characteristics of the dose-response relationship between phenobarbital concentration and the extent of induction could be evaluated. With the 400 mg/day dose of phenobarbital, AGP increased nearly 13-fold. The response of AGP was found to depend on the square of the phenobarbital concentration. Analysis of the decay of AGP when phenobarbital dosing was discontinued showed a kinetic pattern governed by multiple rate processes. This was the result of persistence of the phenobarbital, the turnover of some metabolic precursor to AGP, and the turnover of AGP itself.

Species-dependent binding of disopyramide enantiomers.

Serum protein binding of the basic enantiomers of disopyramide were studied in several animal species. (S)-(+)-Disopyramide was more highly bound than the (R)-(-)-enantiomer to serum protein in the man, gorilla, and pig. The reverse was true in cow serum, and in serum and albumin from sheep. Enantioselective differences in binding were due to differences in association constants. No enantioselective differences in binding were observed in serum protein from horse and goat, or in albumin from cow and pig. Disopyramide was highly bound to two sites on horse albumin. The association constant characterizing the binding of disopyramide to the first (major) site on horse albumin was 1.3 x 10(7) M-1. At predialysis concentrations of 10(-7) M, tris-(2-butoxyethyl)phosphate displaced disopyramide from sites on horse albumin and from sites on serum protein from the horse, man, gorilla, cow, and pig. At predialysis concentrations of 10(-5) M, warfarin and diazepam had no effect on disopyramide binding in these animal species. It is concluded that the enantioselective binding of disopyramide is species dependent, the site that is responsible for the moderate to high binding of disopyramide enantiomers is probably located on alpha 1-acid glycoprotein, and the sites that bind disopyramide in the horse are located on albumin and may be unique.

Radiographic assessment in relation to clinical and biochemical variables in rheumatoid arthritis.

Radiographs of hands and feet were obtained from 125 consecutive patients with rheumatoid arthritis (RA) and the degree of destruction was assessed numerically on a 200-point scale using Larsen's standard radiographs as reference. The method is shown to possess a satisfactory degree of reproducibility. In 96 of these 125 patients, values of another 15 simultaneously determined clinical and biochemical variables were obtained. On applying linear and quadratic multiple regression analysis to this set as well as to the male and female subsets, an 'automatic' selection procedure (stepwise regression) proved duration of disease to be the most important factor relating to the 'Larsen index'. The 96 patients were therefore ranked with respect to duration of disease and divided into 4 subsets of equal magnitude. In the 3 subsets with duration of disease less than 21 years, stepwise regression produced in the final step linear or quadratic combinations not containing duration of disease but correlating quite well with the 'Larsen index' (R = 0.64-0.96). A similar result was obtained upon performing an analogous procedure in the female subset. In all instances, positive contributions of varying degree were obtained from Ritchie's index, ESR, a-antitrypsin (A1-AT), orosomucoid, fibrinogen, and IgM, while negative correlations were associated with ceruloplasmin, IgG, and IgA.

Influence of continuous ambulatory peritoneal dialysis on serum alpha 1-acid glycoprotein concentration and drug binding.

The influence of continuous ambulatory peritoneal dialysis (CAPD) on the concentrations of alpha 1-acid glycoprotein in serum and dialysate and on the serum binding of oxprenolol, propranolol and phenytoin has been studied. Before starting CAPD treatment, the serum binding of oxprenolol and propranolol was higher and that of phenytoin lower than in healthy volunteers, and the serum alpha 1-AGP concentration was higher. During the first days to weeks after starting CAPD, the serum alpha 1-AGP concentration rose with a concomitant increase in the binding of oxprenolol and propranolol. Subsequently, the alpha 1-AGP level and the binding of oxprenolol and propranolol decreased to the values found before starting CAPD. The binding of phenytoin showed little change. The concentration of alpha 1-AGP in dialysate was 2 to 5% of that in serum.

Acute phase reactants and complement activation in patients with acute myocardial infarction.

The acute phase proteins, C-reactive protein (CRP), orosomucoid, alpha 1-antitrypsin and haptoglobin, the native complement components C3 and C4, activation products of C3, and the terminal SC5b-9 complement complex were quantified in samples obtained on admittance and on days 1, 2, 3 and 6 in 21 patients with non-complicated acute myocardial infarction (AMI) and in 22 controls. For all proteins peak and median concentrations were higher in the AMI group than in the controls, but the difference was significant only for CRP and orosomucoid. Median CRP concentration was 46 mg/l in the AMI group and 2.5 in the control group. The corresponding orosomucoid concentrations were 1.6 and 1.2 g/l. There was no correlation between the concentration of CRP in peripheral blood and the degree of complement activation. Furthermore, no correlation was observed between complement activation and the size of infarction. The present study cannot demonstrate that the increased concentrations of CRP and other acute phase reactants observed in patients with AMI, are associated with systemic fluid-phase complement activation. Furthermore, the complement activation previously shown locally in infarcted myocardium cannot be demonstrated systemically in non-complicated AMI.

Does alpha 1-acid glycoprotein reduce the unbound metabolic clearance of disopyramide in patients with renal impairment?

The pharmacokinetics of disopyramide was studied in 15 patients with renal dysfunction (4 with pyelonephritis, 7 with glomerular nephritis and 4 with interstitial nephritis). The elimination rate constant of unbound disopyramide was 0.094 h-1 and CLu/f (unbound clearance divided by bioavailability) was 245 ml/min. Both the unbound renal clearance (CLR) and CLu/f were highly correlated with the creatinine clearance (CLCR). The apparent unbound metabolic clearance in the patients was approximately two-fold lower than that previously reported in normal subjects. The estimated unbound metabolic clearance in the renal dysfunction patients showed a significant negative correlation with the alpha 1-acid glycoprotein (AAG) concentration and only a weak, non-significant correlation with CLCR. As AAG in the renal dysfunction subjects was increased in comparison with normal values, it is possible that AAG is a factor in the decrease in the apparent unbound metabolic clearance.

Variations in alpha-2-HS glycoprotein level in neoplastic disease with and without involvement of bone.

Variations in the serum level of alpha-HS-glycoprotein may be observed in all pathological conditions which induce changes in bone turn-over, as well as in inflammatory and neoplastic diseases. This study includes 162 patients divided into four groups according to the TNM classification (tumour, lymph node metastasis). The first consisted of patients with neoplasms at TNM stages 1 and 2 with no bone metastases; the second of similar patients at TNM stages 3 and 4. The third group were patients with primary or secondary neoplasms of bone, and the fourth were patients with viral or bacterial diseases. The levels of alpha-2-HS-glycoprotein serum were determined for all the groups and these were compared with AAG (alpha-1-glycoprotein) and CEA (carcinoembryonic antigen). There were no significant differences in the levels of alpha-2-HS-glycoprotein for the first group as compared with normal controls, while in the other groups the differences were significant. The levels of alpha-2-HS-glycoprotein were diminished when the levels of CEA and AAG were both high, but increased when only one of these other parameters was high.

Serum acute phase reactants in necrotizing enterocolitis.

The serum acute phase reactants, C-reactive protein (CRP) and orosomucoid, rose significantly within 24 to 48 hours of presentation in infants with definite necrotizing enterocolitis (NEC) compared with the levels in infants with symptoms who tolerated early reintroduction of enteral feeds. A serum CRP value greater than 10 mg/l within 48 hours identified infants with definite NEC with a 92% sensitivity and an 81% specificity. Serum CRP values remained elevated at 7 to 10 days in 4 infants with late septicaemia and in 4 of 5 infants with abscess or early stricture requiring surgery. Serum acute phase reactants are a potentially valuable adjunct to clinical assessment in the management of infants with suspected NEC.

Serum protein binding of phenytoin, diazepam and propranolol in chronic renal diseases.

The effect of chronic renal disease on the serum free fraction of phenytoin, diazepam and propranolol was examined in vitro among 60 conservatively treated patients with renal insufficiency of varying degree and different etiology, and in 10 patients with a nephrotic syndrome. The control group comprised 10 age and sex-matched healthy subjects. The free fractions were separated at 37 degrees C using a pressure ultrafiltration method. The highest free fractions of phenytoin and diazepam in uremic patients were 4 to 5-fold the normal. The free fractions were about twice the normal at a creatinine concentration of 800 mumol/l, and 2 to 4-fold at an urea concentration of 20-40 mmol/l. The creatinine and urea correlated with the free fractions of phenytoin and diazepam in a similar manner. The effect of a decreased serum albumin on the free fractions of these drugs was clear when its concentration was under 30 g/l. The creatinine and urea did not correlate with the free fraction of propranolol. However, after mathematically correcting the free fraction of propranolol to correspond to an alpha 1-acid glycoprotein (alpha 1-AGP) concentration of 0.9 g/l, it correlated significantly with creatinine and urea. The concentration of alpha 1-AGP was the most important determinant for the free fraction of propranolol. For practical purposes, the change in the free fractions of phenytoin and diazepam can be adequately predicted by the serum creatinine or urea and serum albumin levels. For propranolol the only parameter which needs to be analyzed is the serum alpha 1-AGP concentration.

[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.