摘要:

Summary—Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first‐pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine‐induced inflammation: propranolol, which is bound extensively to α1‐acid glycoprotein (α1‐AGP); metoprolol, another high extraction drug, but which is negligibly bound to α1‐AGP; and antipyrine, a low extraction drug, not bound to serum proteins.After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half‐life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20‐fold in rats with inflammation; as the decrease in free fraction was only 4‐fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance. The differential effect of turpentine on the intravenous kinetics of propranolol and metoprolol can be explained by the fact that propranolol binding is increased by turpentine treatment.For antipyrine, systemic clearance was decreased, the volume of distribution was unchanged, and the half‐life was increased in the turpentine‐treated rats. As antipyrine is not bound in serum, one can conclude that its hepatic intrinsic clearance was decreased.Inflammation induced by turpentine treatment decreases the metabolism of high

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00667.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Thirty‐two neonates were treated with netilmicin 3 mg/kg every 12 h by IV infusion for 30 min for suspected infections, colonization, or proven infections. Pharmacokinetic studies were performed in order to define the situations in which monitoring of plasma levels would be appropriate.Mean plasma levels were within the therapeutic range and did not differ in fullterms and preterms. In the 4 children who had 2 successive pharmacokinetic studies, plasma levels were increased between H1 and H5 at the second evaluation due to netilmicin accumulation.Plasma half‐life was longer in proven infections and seemed to decrease in preterms with increased gestational age.These results suggest that the dosage schedule should be left inchanged, but that administration time should be reduced from 30 to 20 min and that peak and trough plasma levels should be measured only in proven infections, in very premature babies (gestational age<33 wk), and during netilmicin treatment longer tha

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00668.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Analgesia can be obtained during ophthalmic surgery by regional anesthesia using local anesthetic agents. As in other indications, neurological complications may occur, especially because the site of injection is close to the central nervous system. In order to evaluate the risk of retrobulbar and facial block obtained after 40 mg lidocaine and 20 mg bupivacaine injection, pharmacokinetics of both drugs was evaluated in plasma obtained from 11 patients. In addition, 3 cerebrospinal fluid samples were analyzed.Maximal plasma concentration was 0.73 ± 0.33 μg.ml‐1for lidocaine and 0.19 ± 0.06/ng‐ml‐1for bupivacaine, obtained 24.7 ± 23.0 min and 12.0 ± 3.7 min after the end of injection, respectively. CSF/plasma ratio was in the range 0.05–0.26 for lidocaine and 0.56– 1.33 for bupivacaine.In all patients, regional anesthesia was sufficient to perform surgery without any other analgesic drug. No sign of cardiovascular or respiratory toxicity was observed

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00669.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—The aim of this study was to investigate quantitatively the action of and the interaction between beta‐adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 times 10−5M) or acetylcholine (5×10−5M) and concentration‐response (C/R) curves for various beta‐adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta‐adrenoceptor agonist (autodesensitization), with other beta‐adrenoceptor agonists (cross‐desensitization), or with a beta‐adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 ± 0.06 (N= 5) for salbutamol (10−5M), 0.78 ± 0.09 (N= 5) for fenoterol (10−6M), 0.30 ± 0.04 (N= 9) for isoprenaline (10−5M), and 0.33 ± 0.05 (N= 5) for adrenaline (10−5M). Our studies of cross‐desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10−5M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 ± 0.08,N= 5) and salbutamol (0.62 ± 0.05,N= 5) than for adrenaline (0.35 ± 0.07,N= 5) and isoprenaline itself (0.30 ± 0.05,N= 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10−8M) reduced it significantly, although to a negligible extent. Adenosine (3 times 10−4M) did not shift the C/R curve to isoprenaline by itself, but incubation of trachea! strips with adenosine and isoprenaline caused a significantly greater shift of C/R curves to isoprenaline (0.30 ± 0.04) than incubation with isoprenaline alone (0.20 ± 0.04) (P<0.05,N= 5). These experiments suggest that adenosine may have increased the uncoupling and/or down‐regulation phenomena induced by isoprenal

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00670.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Summary—Contractile responses of left extrapulmonary artery segments with either intact or damaged endothelium were examined with changes in PO2at constant pH. Hypoxia consistently reduced noradrenaline‐induced contractions. This hypoxia‐induced relaxation was sometimes followed by a contraction and a second relaxation. Hypoxia‐induced relaxations were also obtained if precontraction was elicited with KC1 (40 mM), but no triphasic response was observed. Relaxations faded away with time and only contractions were then observed. Relaxations were more considerable in rings from young animals and, although always present, decreased with the age of the animal. Endothelium damage reduced hypoxia‐induced relaxations. Indomethacin, a potent blocker of cyclooxygenase, increased hypoxia‐induced contraction and reduced relaxation in segments with intact endothelium. Without endothelium the indomethacin effect was less significant. It is concluded that the response to hypoxia of the pulmonary artery is similar to that of systemic vessels. Endothelium seems to play a modulatory role in the hypoxia‐induced response in extrapulmonary artery. Prostaglandin metabolism seems to play a minor role in th

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00671.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0767-3981    

DOI:10.1111/j.1472-8206.1989.tb00672.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY