P. du Souich

Radioimmunoassay of atrial natriuretic factor: Human plasma levels

A simple and sensitive radioimmunoassay procedure has been developed for the determination of atrial natriuretic factor (ANF) in human plasma. The rabbit antiserum was obtained from a commercial source. ANF was extracted from plasma using an octadecasilyl silica cartridge with a recovery of 78.7%. HPLC of the plasma extract showed the presence of one immunoreactive peak of ANF corresponding to its low molecular weight form. Plasma ANF in humans increased from 8.0 +/- 2.2 in upright position to 20.0 +/- 5.9 fmol/ml (n = 6) in downward position (p less than 0.005).

Modulation of inflammation by chondroitin sulfate

OBJECTIVE AND METHODS To evaluate the immune-modulator effect of chondroitin sulfate (CS) by means of the review of the literature. RESULTS Inflammatory reactions are primarily originated by infectious agents, immune reactions and by sterile tissue lesions that activate membrane receptors by means of pathogen-associated molecular patterns, tissue breakdown products and cytokines. The activation of membrane receptors triggers the phosphorylation of mitogen activated protein kinases and of the nuclear factor kappaB (NF-kappaB). The binding of NF-kappaB to the promoter of target genes enhances the expression of pro-inflammatory cytokines, inducible nitric oxide synthase, cyclooxygenase 2, phospholipase A2, and matrix metalloproteases, proteins that contribute to tissue damage and to the inflammatory reaction. The activation of NF-kappaB has a key role in the immune homeostasis and the inflammatory response and therefore, in the pathogenesis of numerous diseases. Chondroitin sulfate (CS) is able to diminish NF-kappaB activation and nuclear translocation in chondrocytes and synovial membrane, effects that may explain the benefits of CS in osteoarthritis. In addition, systemic CS reduces NF-kappaB nuclear translocation in macrophages and hepatocytes, raising the hypothesis that CS might be of benefit to treat other diseases with a strong inflammatory component. There is preliminary evidence in humans that CS improves moderate to severe psoriasis. Moreover, experimental and clinical data suggest that CS might be a useful therapeutic agent in diseases such as inflammatory bowel diseases, atherosclerosis, Parkinsons and Alzheimers diseases, multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis and systemic lupus erythematosus. DISCUSSION These results urge for double blinded placebo-controlled trials to confirm the utility of CS in diseases with immune and inflammatory components.

Tixocortol pivalate, a corticosteroid with no systemic glucocorticoid effect after oral, intrarectal, and intranasal application

Tixocortol pivalate is a corticosteroid with topical anti‐inflammatory activity equal to that of hydrocortisone. It was evaluated in a group of 18 normal subjects to determine whether it exerted any systemic glucocorticoid activity after single oral or intrarectal doses and after short‐term dosing by the intranasal route. Effects of tixocortol pivalate were compared to those of oral dexamethasone and intrarectal betamethasone 21‐phosphate. By the three routes, tixocortol pivalate does not induce any changes in plasma Cortisol, leukocyte counts (neutrophils, lymphocytes, monocytes, eosinophils), blood glucose, or 24‐hr urinary excretion of sodium and potassium, whereas there were changes after dexamethasone and betamethasone. Tixocortol pivalate, however, increased urinary free cortisol‐like substances. It is concluded that tixocortol pivalate given for short periods by nonparenteral routes does not induce a measurable systemic glucocorticoid effect.

Effect of hypoxia alone or combined with inflammation and 3-methylcholanthrene on hepatic cytochrome P450 in conscious rabbits

To investigate the effect of moderate hypoxia alone or combined with an inflammatory reaction or after 3‐methylcholanthrene (3MC) pre‐treatment on cytochrome P450 (P450), conscious rabbits were exposed for 24 h to a fractional concentration of inspired O2 of 10% (mean PaO2 of 34 mmHg). Hypoxia decreased theophylline metabolic clearance (ClM) from 1.73±0.43 to 1.48±0.13 ml min−1 kg−1 (P<0.05), and reduced (P<0.05) the formation clearance of theophylline metabolites, 3‐methylxanthine (3MX), 1‐methyluric acid (1MU) and 1,3‐dimethyluric acid (1,3DMU). Hypoxia reduced the amount of CYP1A1 and 1A2 but increased CYP3A6 proteins. Turpentine‐induced inflammatory reaction reduced (P<0.05) the formation clearance of 3MX, 1MU, and 1,3DMU, and diminished the amount of CYP1A1, 1A2 and 3A6 proteins. However, when combined with hypoxia, inflammation partially prevented the decrease in ClM, especially by impeding the reduction of 1,3DMU. The amount of CYP1A1 and 1A2 remained reduced but the amount of CYP3A6 protein returned to normal values. Pre‐treatment with 3MC augmented the ClM by 114% (P<0.05) due to the increase in the formation clearance of 3MX, 1MU and 1,3DMU. 3MC treatment increased the amount of CYP1A1 and 1A2 proteins. Pre‐treatment with 3MC prevented the hypoxia‐induced decrease in amount and activity of the P450. It is concluded that acute moderate hypoxia and an inflammatory reaction individually reduce the amount and activity of selected apoproteins of the P450. However, the combination of hypoxia and the inflammatory reaction restores P450 activity to near normal values. On the other hand, pre‐treatment with 3MC prevents the hypoxia‐induced depression of the P450.

Enhancement of nadolol elimination by activated charcoal and antibiotics

This study was carried out to assess whether nadolol undergoes enterohepatic circulation. Eight healthy subjects received 80 mg nadolol orally on three occasions at least 2 wk apart. The first experiment was a control. The second consisted of nadolol followed in 3 hr by 3 gm activated charcoal given over a 9‐hr period. In the third, the subjects received 0.5 gm erythromycin base and 0.5 gm neomycin four times a day orally for 2 days before nadolol. After the activated charcoal, the nadolol AUC fell from 2455 ± 155 to 1355 ± 123 ng · hr/ml (mean ± SE), as did the percentage nadolol recovered in urine (15.4 ± 1.4 to 10.2 ± 0.7%) and the nadolol t½ (17.3 ± 1.7 to 11.8 ± 1.6 hr). These data suggest that nonrenal elimination increased. After the antibiotics, nadolol AUC was constant, percentage of nadolol recovered in urine fell to 12.7 ± 1.7%, nadolol t½ fell to 11.6 ± 1.3 hr, and mean peak nadolol concentration rose from 146 ± 15 to 397 ± 52 nglml. These results suggest that there is an enterohepatic circulation for nadolol, that activated charcoal may decrease nadolol bioavailability, and that antibiotics may increase the nadolol effect.

Effect of moderate hypoxemia on atrial natriuretic factor and arginine vasopressine in normal man

The object of this study was to assess the effect of moderate acute hypoxemia on plasma concentrations of atrial natriuretic factor (ANF), arginine vasopressin (AVP), plasma renin activity (PRA) and urinary excretion of prostaglandin E2 (UPGE2V). Eight volunteers were exposed for 2 hours to a gas mixture containing 10% O2, 4.5% CO2 and 85.5% N2. Hypoxia increased diastolic blood pressure and free water clearance. Hypoxia did not change the AVP, PRA or UPG2V, although increased ANF from 17.7 +/- 3.4 pg/mL to 27.2 +/- 1.7 pg/mL (p less than 0.005) at 120 minutes. ANF changes were closely associated with the rise in blood pressure.

Effect of hypercapnia and/or hypoxemia and metabolic acidosis on kinetics and concentrations of phenytoin in the cerebrospinal fluid of conscious rabbits

The present study was designed to determine the effect of changes in gases and pH in the blood on kinetics and passage to the cerebrospinal fluid (CSF) of phenytoin (DPH). Five groups of 6 rabbits were used, a control [with a mean partial pressure (Pa) of oxygen of 84 +/- 2 (SEM) mmHg, partial pressure of carbon dioxide (PaCO2) of 23 +/- 1 mmHg and pH = 7.512 +/- 0.018], a second group with hypercapnia (PaCO2 = 65 +/- 3 mmHg, pH = 7.244 +/- 0.008), a third group with hypoxemia (PaO2 = 48 +/- 2 mmHg), a fourth group with hypercapnia combined with hypoxemia (PaCO2 = 72 +/- 3 mmHg, PaO2 = 51 +/- 1 mmHg and pH = 7.252 +/- 0.008) and a fifth group with metabolic acidosis (pH = 7.232 +/- 0.011). All animals were conscious during the experiments following the administration of 10 mg/kg (i.v.) of phenytoin, hypoxemia decreased the clearance of phenytoin from 4.20 +/- 0.55 to 2.65 +/- 0.44 ml/min per kg (P less than 0.05) and consequently the area under the plasma concentration/time curve (AUC) for phenytoin increased (2575 +/- 319 to 4316 +/- 740 micrograms min/ml; P less than 0.05). Metabolic acidosis increased the volume of distribution of phenytoin from 780 +/- 70 to 1103 +/- 65 ml/kg (P less than 0.01). The protein binding of phenytoin was not affected by any of the experimental conditions.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of acute and chronic moderate hypoxia on the kinetics of lidocaine and its metabolites and on regional blood flow

The effect of acute and chronic hypoxia on the disposition of lidocaine and its metabolites, and on regional blood flow has been examined in conscious beagles (n = 5). Each dog received an infusion of lidocaine for 5 h under three experimental conditions: (1) breathing air; (2) following acute exposure to a FIO2 of 8% and a FICO2 of 3.5% to generate a PaO2 of 45 mmHg without hypocapnia; and (3) after 6 days of hypoxemia. Multiple blood samples were drawn to assess the kinetics of lidocaine and its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). Three hours after the end of the infusion of lidocaine, the dogs received radioactive microspheres to estimate hepatic, renal and brain blood flow. Neither acute nor chronic moderate hypoxia affected the kinetics of lidocaine, the parent compound. However, both experimental conditions increased plasma concentrations of MEGX and GX and increased the ratio of the area under their plasma concentration curves to the dose of lidocaine received. Acute moderate hypoxia increased brain blood flow, although it did not affect liver or renal perfusion. Chronic moderate hypoxia did not significantly change the blood flow to any of the organs studied. It was concluded that acute and chronic moderate hypoxia decreases the rate of elimination of both active metabolites of lidocaine without modifying the perfusion to the organs responsible for their elimination.

Effects of phenobarbital and tobacco smoking on furosemide kinetics and dynamics in normal subjects.

This study was carried out to determine whether furosemide (F) kinetics and dynamics were influenced by phenobarbital and tobacco smoking. Our subjects were 10 normal men: five nonsmokers (NS) and five smokers (S). They received a single intravenous F injection of 40 mg. Regular serum and urine collections were made. In a second study, the NS group received 100 mg phenobarbital orally for 15 days and then a second dose of F. Cumulative 8‐hr urinary excretion of sodium was identical for NS, NS with phenobarbital, and S at 345 ± 30, 357 ± 29, and 353 ± 25 mmol. Diuresis was smaller by 800 ml (20%) in S than in NS. F increased endogenous creatinine clearance from 117 ± 13 to 196 ± 17 ml/min in NS and from 110 ± 12 to 222 ± 30 ml/min in NS with phenobarbital. In the S group, endogenous creatinine clearance showed a tendency to increase only slightly, from 136 ± 23 to 180 ± 34 ml/min. The increase in free water clearance caused by F was smaller in the S group than in the NS group (P < 0.05). Protein binding and distribution of F were not affected by phenobarbital or tobacco smoking. F clearance was slightly higher in S than in NS, which was primarily the result of a slight increase in extrarenal F clearance. In the NS group, F clearance remained constant after phenobarbital. It is concluded that tobacco smoking in normal subjects affects the diuretic response to F without modifying kinetics.

Plasma atrial natriuretic peptide during spontaneous bronchoconstriction in asthmatics

The aim of this work was to establish the role of endogeneous ANP during a spontaneous asthma attack. Forced expiratory lung volume in 1 s (FEV1), cardiovascular parameters, and plasma ANP, cAMP, and cGMP were measured for 60 min before and 10 min after treatment with a bronchodilator in 10 asthmatics. The results show that in the presence of moderate bronchoconstriction, FEV1 was 54 +/- 3% (+/-SE); ANP levels initially were slightly elevated at 47 +/- 10 pg/ml and decreased to 26 +/- 3 pg/ml (p < 0.05) over 60 min, with no change in FEV1. Following salbutamol inhalation, FEV1 increased to 77 +/- 4% with no change in ANP. We conclude that endogenous ANP does not act as a bronchodilator in asthmatics with moderate bronchospasm.