The pharmacokinetics of mecillinam and pivmecillinam in pregnant and non-pregnant women.

1. The pharmacokinetics of parenteral mecillinam (n = 27) and oral pivmecillinam (n = 12) were studied in pregnant (n = 27) and non-pregnant (n = 12) subjects. 2. In early pregnancy (9-14 weeks of gestation) the mean peak plasma drug concentration (Cmax = 19 +/- 9 micrograms ml-1) after an intravenous injection of 200 mg mecillinam was significantly lower (P less than 0.05) and the volume of distribution (V = 49 +/- 20.1) significantly larger (P less than 0.05) than in non-pregnant subjects (Cmax = 35 +/- 18 micrograms ml-1, V = 29 +/- 12.1). In late pregnancy (39-40 weeks of gestation) the plasma mean peak concentration (Cmax = (29 +/- 14 micrograms ml-1) after parenteral administration of 200 mg mecillinam was slightly lower and the volume of distribution (V = 65 +/- 29.1, V = 0.9 +/- 0.4 l kg-1) significantly larger than that in non-pregnant subjects (V = 0.4 +/- 0.3 l kg-1). Also after oral administration of 200 mg pivmecillinam, equimolar to 136.5 mg mecillinam, the mean peak plasma concentration in pregnant subjects (Cmax = 1.8 +/- 1.2 micrograms ml-1) was slightly lower than that in non-pregnant subjects (Cmax = 1.7 +/- 1.2 micrograms ml-1). 3. The mean half-life of elimination after parenteral administration of mecillinam was significantly longer during both early (t1/2,Z = 133 +/- 38 min, P less than 0.05) and late pregnancy (t1/2,Z = 107 +/- 41 min, P less than 0.05) as compared with the non-pregnant state (t1/2,Z = 75 +/- 21 min).(ABSTRACT TRUNCATED AT 250 WORDS)     

Plasma concentrations and pharmacokinetics of midazolam during anaesthesia

Midazolam and 1-hydroxymidazolam plasma concentrations have been monitored and pharmacokinetic parameters of midazolam estimated during anaesthesia induced and maintained by its repeated injection according to two protocols (3 X 0.3 mg kg-1 at 45 min intervals or an induction dose of 0.3 mg kg-1 with maintenance doses of 0.15 mg kg-1 at 30 min intervals). Minimum plasma concentrations of midazolam measured just before each injection were 258.8 +/- 108.4 ng ml-1 for the first protocol and 353.1 +/- 55.2 ng ml-1 for the second protocol; maximum midazolam concentrations, measured 5 min after the last administration, were 1103.1 +/- 237.9 ng ml-1 and 743.0 +/- 103.2 ng ml-1, respectively, suggesting that a continuous infusion of midazolam after a loading dose should be better than repeated injections at keeping the concentration close to the sedative level of 400 ng ml-1. The estimated pharmacokinetic parameters were similar to those already published, except for the beta elimination half-life of midazolam (3.24 +/- 0.90 h for protocol 1 and 3.34 +/- 1.47 h for protocol 2) which was slightly longer than that reported for single dose studies. The comparison of plasma determinations, obtained either by gas-liquid chromatography or by a radioreceptor assay technique, clearly showed that 1-hydroxymidazolam, even after repeated midazolam administration, was not present at a concentration sufficient to affect the overall pharmacological activity of the parent drug.     

Regulation of prostaglandin production by nitric oxide; an in vivo analysis.

1. Endotoxin E. Coli lipopolysaccharide (LPS)-treatment in conscious, restrained rats increased plasma and urinary prostaglandin (PG) and nitric oxide (NO) production. Inducible cyclo-oxygenase (COX-2) and nitric oxide synthase (iNOS) expression accounted for the LPS-induced PG and NO release since the glucocorticoid, dexamethasone inhibited both effects. Thus, LPS (4 mg kg-1) increased the plasma levels of nitrite/nitrate from 14 +/- 1 to 84 +/- 7 microM within 3 h and this rise was inhibited to 35 +/- 1 microM by dexamethasone. Levels of 6-keto PGF1 alpha in the plasma were below the detection limit of the assay (< 0.2 ng ml-1). However, 3 h after the injection of LPS these levels rose to 2.6 +/- 0.2 ng ml-1 and to 0.7 +/- 0.01 ng ml-1 after LPS in rats that received dexamethasone. 2. The induced enzymes were inhibited in vivo with selective COX and NOS inhibitors. Furthermore, NOS inhibitors, that did not affect COX activity in vitro markedly suppressed PG production in the LPS-treated animals. For instance, the LPS-induced increased in plasma nitrite/nitrate and 6-keto PGF1 alpha at 3 h was decreased to 18 +/- 2 microM and 0.5 +/- 0.02 ng ml-1, 23 +/- 1 microM and 0.7 +/- 0.01 ng ml-1, 29 +/- 2 microM and 1 +/- 0.01 ng ml-1 in rats treated with LPS in the presence of the NOS inhibitors NG-monomethyl-L-arginine, NG-nitro arginine methyl ester and aminoguanidine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of intravenous infusion of doxorubicin on blood chemistry, blood pressure and heart rate in rabbits

The effects of a 1 h continuous infusion of doxorubicin (12.5 mg kg-1, 200 mg M-2) on blood chemistry was examined in rabbits over a 6-h period. Plasma glucose levels remained unchanged while insulin levels were significantly decreased to 39, 45 and 61% of the zero time value (12.8 +/- 2.9 ng ml-1) at 30, 60 and 120 min, respectively, after starting the drug infusion. Plasma cortisol levels were increased to 141, 140 and 131% of the initial zero time value (12.3 +/- 2.2 ng ml-1) at 120, 240 and 360 min, respectively. Doxorubicin had no effect on plasma electrolytes, osmolality and urea nitrogen but significantly increased plasma creatinine over the corresponding control value (2.2 +/- 0.8 micrograms ml-1 to 4.9 +/- 0.7 micrograms ml-1) at 120 min and the level remained elevated for the remaining period of the study. Systolic and diastolic pressure, and heart rate were also depressed at 240 and 360 min. The data collected in the present study indicate that the doxorubicin infusion might have a direct effect on beta cells in the pancreas as well as muscle tissue. Changes in cortisol, blood pressure and heart rate appear to be secondary to other effects produced by doxorubicin.     

Dose-dependent pharmacokinetics of zoxazolamine in the rat

Zoxazolamine (ZX) is a model substrate frequently used in studies on (methylcholanthrene-inducible) hepatic cytochrome P-450 activity. The iv pharmacokinetics of ZX were studied in rats at four dose levels: 5 mg X kg-1 (n = 6), 25 mg X kg-1 (n = 6), 50 mg X kg-1 (n = 5), and 60 mg X kg-1 (n = 4). Concentrations of ZX in blood, as well as the urinary excretion of unchanged ZX and chlorzoxazone, were determined. The apparent systemic clearance (CLs,app) decreased with increasing dose from 52.6 +/- 3.9 at 5 mg X kg-1 to 9.3 +/- 0.4 ml X min-1 X kg-1 at 60 mg X kg-1. The apparent elimination half-life, t1/2,app, increased from 16.1 +/- 0.3 min to 141 +/- 28.5 min. There was only slight concentration dependency of plasma protein binding: 86.0 +/- 0.9% at 4.2 +/- 0.2 micrograms X ml-1 (n = 6) vs. 80.4 +/- 0.4% at 27.1 +/- 1.1 micrograms X ml-1 (n = 6). Since from clearance and protein binding data nonrestrictive clearance of ZX could be inferred, this small change in binding was regarded as irrelevant for the interpretation of pharmacokinetic data of ZX. The blood-plasma concentration ratio was larger than unity: 2.11 +/- 0.09 at 5.4 +/- 0.9 micrograms X ml-1, and 1.85 +/- 0.08 at 47.9 +/- 4.9 micrograms X ml-1 (n = 5).(ABSTRACT TRUNCATED AT 250 WORDS)     

Absorption of clonazepam after intranasal and buccal administration.

Serum concentrations of clonazepam after intranasal, buccal and intravenous administration were compared in a cross-over study in seven healthy male volunteers. Each subject received a 1.0 mg dose of clonazepam intranasally and buccally and 0.5 mg intravenously. A Cmax of 6.3 +/- 1.0 ng ml-1 (mean; +/- s.d.) was measured 17.5 min (median) (range 15-20 min) after intranasal administration. A second peak (4.6 +/- 1.3 ng ml-1) caused by oral absorption was seen after 1.7 h (range 0.7-3.0 h). After buccal administration a Cmax of 6.0 +/- 3.0 ng ml-1 was measured after 50 min (range 30-90 min) with a second peak of 6.5 +/- 2.5 ng ml-1 after 3.0 h (range 2.0-4.0 h). Two minutes after i.v. injection of 0.5 mg clonazepam the serum concentration was 27 +/- 18 ng ml-1. It is concluded that intranasal clonazepam is an alternative to buccal administration. However, the Cmax of clonazepam after intranasal administration is not high enough to recommend the intranasal route as an alternative to intravenous injection.     

Alinidine pharmacokinetics following acute and chronic dosing.

1 Alinidine (N-allyl clonidine) pharmacokinetics were investigated in healthy volunteers following acute administration of 40 mg orally and intravenously (i.v.) and chronic administration of 40 mg daily and twice daily for 8 days. 2 After acute oral administration the following values were obtained; Cmax -- 166.5 +/- 18.5 ng/ml at 1.8 +/- 0.7 h (mean +/- s.d., n = 5); AUC -- 1122.9 ng ml-1 h; VdSS -- 190.71 and T1/2 -- 4.2 h, and after i.v. administration: AUC -- 1046.7 ng ml-1 h; VdSS -- 190.71 and T1/2 4.2 h. 3 Clonidine was identified in plasma and urine samples following oral and i.v. administration; clonidine Cmax was 0.26 +/- 0.06 ng/ml at 8.4 +/- 2.2 h and 0.5 +/- 0.2 ng/ml at 4.8 +/- 2.5 following oral and i.v. alinidine respectively. Urinary excretion of clonidine represented 0.1% of the administered dose of alinidine. 4 During administration of alinidine 40 mg daily for 8 days, peak and trough plasma levels reached steady state after day 2 (223.1 +/- 123.9 and 9.03 +/- 6.7 ng/ml respectively). During alinidine 40 mg twice daily for 8 days peak and trough plasma levels on day 2 were 356.2 +/- 92.0 and 80.0 +/- 35.8 ng/ml respectively, these levels did not change (P greater than 0.05) between days 2 and 8. Urine elimination of alinidine did not change (P greater than 0.05) between days 5, 6, 7 and 8. 5 Clonidine plasma concentration following alinidine 40 mg daily and twice daily were 0.47 +/- 0.18 and 0.84 +/- 0.21 ng/ml respectively 2 h after administration on day 2 and did not change (P less than 0.05) between days 2-8. 6 It is unlikely that clonidine formed from alinidine contributes to the pharmacological action of alinidine.     

Effect of dehydration and hyperosmolal hydration on lignocaine and metabolites disposition in conscious rabbits.

1. The present study aimed to investigate the effect of dehydration and hyperosmolal hydration on the disposition of lignocaine and two of its metabolites, monoethylglycinexylidide (MEGX) and glycinexylidide (GX). 2. Lignocaine was infused to three groups of conscious rabbits: controls, rabbits previously deprived of water for 48 h and rabbits receiving an infusion of 2.5% NaCl. 3. In dehydrated and hyperosmolal-hydrated rabbits, plasma osmolality was 321 +/- 1 and 313 +/- 1 mOsm kg-1, respectively (P < 0.01 compared to controls, 285 +/- 1 mOsm kg-1). In dehydrated animals, baseline values of plasma arginine vasopressin (AVP) concentrations and plasma renin activity (PRA) were higher than in controls, i.e. 12.4 +/- 1.4 pg ml-1 and 15.4 +/- 1.7 ng AI ml-1 h-1 vs. 3.4 +/- 0.2 pg ml-1 (P < 0.01), and 5.1 +/- 0.6 ng AI ml-1 h-1 (P < 0.01), respectively; atrial natriuretic peptide (ANP) decreased from 55 +/- 11 to 32 +/- 4 pg ml-1 (P < 0.05). Compared to controls, hyperosmolal hydration only increased AVP to 15.5 +/- 0.7 pg ml-1 (P < 0.01). 4. Under both experimental conditions, lignocaine plasma concentrations were almost double (P < 0.01) those in controls, due to a lower systemic clearance, e.g. 54 +/- 3 and 59 +/- 1 vs. 96 +/- 5 ml min-1 kg-1, respectively. Plasma levels of MEGX increased (P < 0.01) only in dehydrated animals, although GX plasma concentrations were augmented (P < 0.01) about three fold in both groups of animals.(ABSTRACT TRUNCATED AT 250 WORDS)