The penetration of ciprofloxacin into bronchial mucosa,lung parenchyma,and pleural tissue after intravenous administration

Summary We have studied the concentrations of ciprofloxacin in serum, bronchial mucosa, lung parenchyma, and pleural tissue after a single intravenous dose of 200 mg in 20 patients subjected to lung surgery.The concentrations of ciprofloxacin in the tissues exceeded that in the serum by 3-fold to 7-fold: serum 0.6 g·ml^–1, bronchial mucosa 1.9 g·g^–1 lung parenchyma 3.4 g·g^–, and pleural tissue 1.7 g·g^–1.The achievable concentrations of ciprofloxacin in the tissues of the lower respiratory tract are above the MICs for most lung pathogens.     

Salivary nystatin concentrations after administration of an osmotic controlled release tablet and a pastille

Mucosal oral therapeutic system (MOTS) is a controlled-release osmotic system for oral cavity therapy. MOTS (nystatin) is designed to deliver approximately 200,000 units of nystatin over several hours. A crossover study was conducted in five healthy volunteers to evaluate the amount of nystatin released (based on residual drug content) when the system is held in the mouth for 30 min, 1 h, and 2 h, and to compare these concentrations with those achieved with a Mycostatin (nystatin) pastille.An average of 37% of the nystatin content was released intra-orally from MOTS during 2 h in the mouth, which was very similar to the percentage delivered in vitro. Mean salivary drug concentrations were as follows: 279 g·ml^–1 at 30 min; 654 g·ml^–1 after 1 h; and 532 g·ml^–1 at 2 h. These concentrations consistently exceeded those produced by the pastille at the same time points. Fifteen minutes after placement of the pastille in the mouth (i.e., immediately after its dissolution) mean nystatin concentrations reached 746 g·ml^–1 but fell rapidly to 13.2 g·ml^–1 at 30 min, 7.2 g·ml^–1 at 1 h, and 5.6 g·ml^–1 at 2 h.The study demonstrates that MOTS maintains high salivary nystatin concentrations throughout a 2 h dosing interval.     

Plasma concentrations of the enantiomers of halofantrine and its main metabolite in malaria patients

The plasma concentrations of the enantiomers of halofantrine and its N-desbutyl metabolite in six patients with malaria were measured after oral administration of 3×750 mg doses of micronised, racemic halofantrine hydrochloride given at 6-hour intervals.Significant differences were observed between the plasma concentrations of the enantiomers both of halofantrine and its N-monodesbutyl metabolite. AUC₀84h values were higher for (+)halofantrine (9917 g·ml^–1·h) than for (-)-halofantrine (6127 g·ml^–1·h).The clinical significance of these observations is not known. The isomers have equipotent activity in vitro but their relative toxicity has not yet been assessed.     

Lack of accumulation of midazolam in plasma and lipoprotein fractions during intravenous lipid infusions in patients on artificial respiration

Summary Severely ill patients often require total parenteral nutrition including intravenous liqid emulsions concurrently administered with lipophilic drugs. Therefore we investigated whether therapeutic application of a mixed medium chain/long chain triglyceride infusion affects the disposition of midazolam necessary for sedation in patients on artificial respiration. The concentrations of midazolam were measured in unfractionated plasma, and in lipoprotein fractions isolated from ex vivo blood samples, including determination of triglycerides and cholesterol; the albumin level was also analysed.Midazolam in the VLDL fraction was only 0.246 g·ml^–1, whereas the total plasma concentration averaged 1.101 g·ml^–1, and the midazolam content of the LDL plus HDL fractions amounted to 1.771 g·ml^–1. Albumin in these lipoprotein fractions was just as unequally distributed. A lipid infusion resulted in a significant elevation of total triglycerides from 157 to 221 mg·dl^–1 and VLDL-triglycerides from 77 to 155 mg·dl^–1. The triglyceride content of the LDL plus HDL fraction rose from 102 to 139 mg·dl^–1. At the same time the midazolam concentration in unfractionated plasma and in the VLDL and the LDL + HDL fractions decreased to 0.899 g·ml^–1, 0.130 g·ml^–1, and 1.265 g·ml^–1, respectively. Cholesterol and albumin concentrations were not affected.The data show for the first time that a significant increase in plasma triglycerides during an intravenous lipid infusion does not result in accumulation of midazolam in lipoproteins, probably because albumin binding of the drug is very strong. The lack of midazolam trapping is important with respect to the safety of concurrent use of lipophilic drugs and intravenous lipid infusions.     

5-HT-induced neurogenic relaxations of the guinea-pig proximal colon: investigation into the role of ATP and VIP in addition to nitric oxide

In the guinea-pig proximal colon, 5-hydroxytryptamine (5-HT) relaxes the longitudinal muscle by stimulating neuronal 5-HT receptors, which induces the release of nitric oxide (NO). It was investigated whether the inhibitory neurotransmitters adenosine 5-triphosphate (ATP) and/or vasoactive intestinal polypeptide (VIP) could be involved as well.Antagonists to block the contractile response to 5-HT via 5-HT₂, 5-HT₃ or 5-HT₄ receptors were present throughout the experiments and methacholine was administered to precontract the strips. ATP, VIP and 5-HT induced concentration-dependent relaxations, in the case of 5-HT yielding a non-monophasic concentration-response curve. Tetrodotoxin (TTX; 300 nM), N^G-nitro-l-arginine (l-NNA, 100 M) and their combination did not inhibit the relaxations induced by VIP (up to 0.3 M) or 0.3–3 M ATP but reduced those by 10 M ATP. Suramin (300 M) strongly inhibited the relaxations to ATP and VIP. l-NNA and suramin also inhibited the relaxations to 5-HT. In the presence of l-NNA (100 M), suramin did not significantly inhibit the relaxations to 5-HT. Suramin did not affect the relaxations to isoprenaline, nitroglycerin or exogenous NO (1 M), demonstrating its specificity. Apamin (30 nM) inhibited both the relaxations to ATP (by 70–100%) and to 5-HT; relaxations to isoprenaline were partially inhibited, indicating a non-specific component in the inhibitory action of apamin. However, relaxations to exogenous VIP (up to 0.3 M), NO (1 ,M) and to nitroglycerin were not inhibit ed. In the presence of l-NNA (100 M), apamin inhibited the relaxations to 5-HT only at 30 M. ,\-methylene-ATP (,-Me-ATP; 100 M) did not desensitize the responses to ATP. Reactive blue 2 affected the relaxations to isoprenaline at concentrations necessary to significantly inhibit the relaxations to ATP (i.e. from 10 M onwards). Thus, it was not possible to test either ,-Me-ATP or reactive blue 2 against the relaxations to 5-HT. -Chymotrypsin (0.015 mg·ml^–1) and trypsin (0.005 mg·ml^–1) almost abolished the relaxations to VIP, but did not affect those to isoprenaline and 5-HT. The VIP receptor antagonists [p-Cl-d-Phe⁶, Leu¹⁷]VIP (1 M) and VIP_10–28 (1 and 3 M) did not affect the concentration-response curve to VIP and were hence not tested against 5-HT. Phosphoramidon (1 M) had no effect on the relaxations to VIP or 5-HT.It can be concluded that in the guinea-pig colon longitudinal muscle, VIP and ATP induce relaxation via a direct effect on the smooth muscle, not involving NO. 5-HT-induced relaxations are mediated by NO as well as by a substance which is sensitive to inhibition by suramin but not apamin. It is suggested that this substance is ATP and not a peptide.     

Lack of a pharmacokinetic interaction between oral famciclovir and allopurinol in healthy volunteers

Famciclovir has been shown to have potent and selective activity against herpesviruses. The possibility of a pharmacokinetic interaction between the anti-viral agent, famciclovir and allopurinol has been investigated in twelve healthy male volunteers following a single oral dose of famciclovir (500 mg) in the presence and absence of steady-state levels of allopurinol (300 mg). Similarly, the pharmacokinetic profiles of allopurinol and oxypurinol prior to and following a single dose of famciclovir were compared.Mean values of C_max, AUC and terminal-phase half-life for penciclovir following administration of famciclovir alone at 3.3 g·ml^-1, 8.8 ·h·ml^-1 and 2.1 h, respectively were unchanged by co-administration of allopurinol. Similarly, mean urinary recovery and renal clearance values of penciclovir following famciclovir alone were 56.8% and 271·h^-1, and when given with allopurinol 59.7% and 27.51·h^-1, respectively. No evidence of accumulation of the inactive precursor to penciclovir, BRL 42359, was noted as a result of co-administration of the two drugs.Mean steady-state C_max, AUC and terminal-phase half-life values for allopurinol after co-administration of allopurinol with famciclovir also appeared unchanged from values obtained after dosing of allopurinol alone, at 2.12 g·ml^-1, 5.73 g·h·ml^-1 and 1.38h, respectively. Mean C_max and AUC values of the active metabolite of allopurinol, oxypurinol were 11.2 g·ml^-1 and 96.0 g·h·ml^-1, respectively, and these were also unaltered by co-administration of famciclovir with allopurinol, with values of 10.6 g/ml and 89.8 g·h/ml, respectively.In summary, no evidence of a pharmacokinetic interaction between allopurinol and famciclovir was observed when the two drugs were given concomitantly to healthy volunteers.     

Facilitatory and inhibitory modulation by endogenous adenosine of noradrenaline release in the epididymal portion of rat vas deferens

Summary The present study aimed at determining the modulation by adenosine of the release of noradrenaline in the epididymal portion of the rat vas deferens. The tissues were treated with pargyline and perifused in the presence of desipramine and yohimbine. Up to four periods of electrical stimulation were applied (5 Hz, 9 min).The A₁-adenosine receptor selective agonist R-N⁶-phenylisopropyladenosine (R-PIA; 100–900 nmol·l^–1) reduced, whereas the A_2A-receptor selective agonist 2-p-(2-carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine (CGS21680; 3–30nmol·l^–1) increased the electrically-evoked noradrenaline overflow in a concentration-dependent manner. The nonselective agonist 5-N-ethy1carboxamidoadenosine (NECA; 30–300 nmol·l^–1) reduced noradrenaline overflow, but the effect did not depend on the concentration. Adenosine deaminase at the concentration of 0.5 ·ml^–1 decreased but at that of 2.0 ·ml^–1 increased noradrenaline overflow. The inhibitors of adenosine uptake, S-(4-nitrobenzyl)-6-thioinosine (NBTI; 50 nmol·l^–1) and dipyridamole (3 mol·l^–1), increased the electrically-evoked noradrenaline overflow. The A₁-adenosine receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 20 nmol·l^–1) caused an increase whereas the A₂-adenosine receptor antagonist 3,7-dimethyl-1-(2-propynyl)xanthine (DMPX; 0.1 mol·l^–1) caused a decrease. NBTI (50 nmol·l^–1), partially antagonized the effect of both DPCPX (20 nmol·l^–1) and DMPX (0.1 mol·l^–1).It is concluded that, in the epididymal portion of the rat vas deferens, endogenous adenosine tonically modulates the release of noradrenaline evoked by electrical stimulation, through activation of both inhibitory (A₁) and facilitatory (A_2A) adenosine receptors.Abbreviations CGS 21680 2-p-(2-carboxyethyl)phenethylamino-5-N-ethylcarboxamidoadenosine - DMPX 3,7-dimethyl-l-(2-propynyl)xanthine - DPCPX 1,3-dipropyl-8-cyclopentylxanthine - NBTI S-(4-nitrobenzyl)-6-thioinosine - NECA 5-N-ethylcarboxamidoadenosine - R-PIA R-N⁶-phenylisopropyladenosine Correspondence to J. Gongalves at the above address     

Whole blood concentrations of mefloquine enantiomers in healthy Thai volunteers

We studied the pharmacokinetics of the enantiomers of mefloquine in whole blood in healthy Thai volunteers after administration of a single oral dose of 750 mg of the racemic mixture.Mefloquine pharmacokinetics were stereoselective. The peak concentrations and areas under the curve of the (–) enantiomer were significantly higher than those of its antipode (0.79 versus 0.46 g · ml^-1 and 402 versus 94 g · h · ml^-1). The half-lives of (–)MQ were significantly longer than those of (+)MQ (531 versus 206 h). No stereoselectivity was observed for t_max values.     

The pharmacokinetics of theβ 2-adrenoceptor agonist fenoterol in healthy women

Summary We have studied the pharmacokinetics of fenoterol in healthy women during and after a 3 h intravenous infusion of different doses within the therapeutic range for tocolysis (0.5 g·min^–1, 1.0 g·min^–1, and 2.0 g·min^–1). A specific and sensitive radioimmuno-assay was used for the determination of fenoterol. For compartmental analysis the plasma concentration time data were fitted with the TOPFIT program, assuming two exponentials.The total clearance of fenoterol increased with dose (1299 ml·min^–1 at 0.5 g·min^–1, 1483 ml·min^–1 at 1.0 g·min^–1, and 1924 ml·min^–1 at 2.0 g·min^–1), as did the apparent volume of distribution (from 491 at the lowest to 851 at the highest dose).In contrast, the apparent half-lives were not dose-dependent, with t_{1/2· 1} 4.8 min and t_{1/2· 2} 52 min.This paper is dedicated to Prof. Dr. Ellen Weber, Heidelberg, FRG     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

Pharmacokinetics of exogenous adenosine in man after infusion

Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 g·kg^–1 respectively) and after infusion of 200 g·kg^–1 in 10 min followed by 400 g·kg^–1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min^–1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 g·ml^–1), but the mean clearance and half-life were significantly different (12.1 l·min^–1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.     

Binding of a metabolite of triflusal (2-hydroxy-4-trifluoromethylbenzoic acid) to serum proteins in rat and man

Summary 2-hydroxy-4-trifluoromethylbenzoic acid (HTB) is the main active metabolite of the platelet anti-aggregant drug triflusal. Its binding to plasma proteins of rats and healthy volunteers in vitro and in vivo has been studied.Rats were given a single oral dose of 50 mg·kg^–1 triflusal and the healthy volunteers received 300 mg as a single oral dose or a multiple dose regimen of 600 mg every 24 h and 300 mg every 8 h, both for 13 days. Protein-free HTB was obtained by ultrafiltration. Unbound and total HTB concentrations were determined by HPLC.HTB was primarily bound to albumin in plasma. The Scatchard plots suggested two types of binding sites for HTB on the albumin molecule. In rats, the binding constants (K=intrinsic affinity constant, n=number of binding sites) were K₁=1.4×10⁵ l·mol^–1, n₁=1.23, and K₂=4.1×10³ l·mol^–1 and n₂=3.77. The mean plasma concentration in rats after oral administration was 185 (37) g·ml^–1 (protein-free HTB: 2.44 (0.77)%). The binding constants in human plasma were K₁=4.7×10⁵ l·mol^–1, n₁=1.93, K₂=4.3 l·mol^–1 and n₂=4.28.The plasma HTB concentration in man (n=8) was 35 g·ml^–1 (C_max) after a single oral dose of triflusal 300 mg, 172.96 g·ml^–1 (C_max·ss) during the multiple dosage regimen of 300 mg every 8 h, and 131 g·ml^–1 (C_max·ss) during the multiple oral dose regimen of 600 mg every 24 h. Unbound HTB ranged from 0.27 to 0.43%, depending on dose. HTB had high affinity for plasma albumin, which was not saturable after therapeutic doses. It showed linear elimination.     

Opioid peptides decrease noradrenaline release and blood pressure in the rabbit at peripheral receptors

Summary Effects of dynorphin-(1–13), Leu⁵-enkephalin,d-Ala²,d-Leu⁵-enkephalin (DADLE), and for comparison bremazocine, on plasma noradrenaline concentration and mean arterial pressure (MAP) were studied in pithed rabbits. In the first series of experiments, the sympathetic outflow was stimulated electrically via the pithing rod at 2 Hz twice for 3 min each (S₁, S₂). Drugs were administered before S₂. Bremazocine 10 g/kg+2g/kg/h and 100 g/kg+20 g/kg/h, dynorphin 1 and 3 g/kg/min, Leu⁵-enkephalin 100 g/kg/min and DADLE 10 and 30 g/kg/min all diminished the electrically-evoked increase in plasma noradrenaline and MAP. The effects were antagonized by naloxone. In the second series, an infusion of noradrenaline (2 g/kg/min) was given twice for 3 min each (N₁, N₂). Drugs were administered before N₂. Bremazocine 100 g/kg+20 g/kg/h slightly enhanced the pressor effect of exogenous noradrenaline, whereas dynorphin 3 g/kg/min, Leu⁵-enkephalin 100 g/kg/min and DADLE 30 g/kg/min caused no significant change. In the third series, the sympathetic outflow was stimulated continuously at 2 Hz, and the interaction of dynorphin and DADLE was studied. Dynorphin 1 g/kg/min and DADLE 10g/kg/min initially decreased MAP to a similar extent. The effect of DADLE faded with time. When, during continuous infusion of DADLE 10 g/kg/min, and after return of MAP to the pre-DADLE level, dynorphin 1 g/kg/min or DADLE 10 g/kg/min was infused additionally, the effect of dynorphin was unchanged, whereas that of DADLE was almost abolished. We conclude that the opioid peptides as well as bremazocine decrease action potential-evoked release of noradrenaline and, secondarily, blood pressure. They act at peripheral sites, presumably prejunctional opioid receptors at postganglionic sympathetic axons. Dynorphin on the one hand, and Leu⁵-enkephalin and DADLE on the other hand, appear to act at different receptors, dynorphin probably at a - and DADLE and Leu⁵-enkephalin at a -receptor.     

Esmolol,an ultrashort-acting,selective β1-adrenoceptor antagonist: pharmacodynamic and pharmacokinetic properties

The effects of esmolol at different rates of infusion (100, 250 and 500 g·kg^–1 BW·min^–1) were compared with -adrenoceptor occupancy (₁ and ₂, estimated by a subtype selective radioreceptor assay) and plasma concentrations of esmolol and its acid metabolite were measured by HPLC. Up to a rate of infusion of esmolol of 500 g·kg^–1 BW·min^–1 there was a maximal ₁-receptor occupancy of 84.7% while ₂-receptor occupancy was below the detection limit; confirming the ₁ selectivity of esmolol. Exercise-induced increases in heart rate and systolic blood pressure were reduced by esmolol in a dose-dependent manner. The estimated EC₅₀ values of rate of infusion for the reduction in heart rate and systolic blood pressure during exercise were 113 and 134 g·kg^–1 BW · min^–1, respectively. Additionally, heart rate and systolic blood pressure were reduced moderately at rest. Because of the short elimination half-life of esmolol caused by the rapid hydrolysis to its acid metabolite, 45 min after end of infusion high plasma concentrations of the metabolite (maximally 80 g·ml^–1) but no esmolol were detectable. Since no in vivo effects have been observed, despite the presence of high plasma concentrations of the metabolite, the metabolite did not participate in the observed effects up to an infusion rate of esmolol of 500 g·kg^–1 BW·min^–1. The plasma concentrations of antagonist detected by radioreceptor assay and plasma concentrations of esmolol detected by HPLC showed a good correlation (r=0.97). Since the cardiovascular effects, determined before and 45 min after termination of infusion of esmolol were similar, it can be concluded that the observed effects on heart rate and systolic blood pressure are exclusively mediated by esmolol.Dedicated to Dr. P.Rajagopal, Kuantan Specialist Hospital, Kuantan, Malaysia     

Inhibition by ethanol of excitatory amino acid receptors and nicotinic acetylcholine receptors at rat locus coeruleus neurons

The frequency of spontaneous action potentials of locus coeruleus (LC) neurons was recorded extracellularly in pontine slices of the rat brain. Ethanol (1–100 mM) elevated the firing rate in most neurons; this effect was concentration-dependent. (S)--amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 0.03–1 M), kainate ( 0.1–3 M), N-methyl-D-aspartate (NMDA; 1–30 M), substance P 0.01–1 M, nicotine 0.1–10 M and ,-methylene ATP ,-meATP; 0.3–30 M, all increased the firing. Application of ethanol g10–100 mM to the superfusion medium for 10 min, reproducibly and concentration-dependently inhibited the facilitatory effect of NMDA g10 M. However, the inhibitory effect of ethanol (100 mM) decreased during a 30-min superfusion period and after the washout of ethanol the sensitivity of LC neurons to NMDA (10 M) tended to overshoot above their initial level. Although NMDA was more potent in the absence than in the presence of external Mg²⁺, ethanol (100 mM) continued to depress the facilitatory effect of a low concentration of NMDA (EM) in a Mg²⁺-free medium. By contrast, in a medium containing normal Mg²⁺, ethanol (100 mM) failed to significantly interfere with the increase in firing rate induced by a high concentration of NMDA (30 M). The effects of kainate (0.5 M), AMPA (0.3 M) and nicotine (1 M) were also depressed by ethanol (100 M), while the effects of substance P (0.03 M) and ,-meATP (30 M) were not changed. In conclusion, ethanol selectively counteracts the opening of cationic channels caused by excitatory amino acid (EAA) receptor agonists and nicotinic acetylcholine receptor agonists. During a longer lasting incubation with ethanol, the inhibition of the NMDA-induced excitatory effect declines, indicating the development of tolerance. Correspondence to: P. Illes at the above address     

Growth hormone-releasing activity of hexarelin in humans

Hexarelin is a new hexapeptide (His-d-2-methyl-Trp-Ala-Trp-d-Phe-Lys-NH₂) that stimulates the release of growth hormone both in vitro and in vivo. In this double-blind, placebo-controlled, rising-dose study we evaluated the growth hormone releasing activity of hexarelin in healthy human subjects. Twelve adult male volunteers received single intravenous boluses of 0.5, 1 and 2 ·g·kg^–1 hexarelin as well as placebo. For safety, drug doses were given in a rising-dose fashion with placebo randomly inserted into the sequence. Plasma growth hormone concentrations increased dose-dependently after the injection of the peptide, peaking at about 30 min and then decreasing to baseline values within 240 min with a half-life of about 55 min. The mean peak plasma growth hormone concentrations (C_max) were 3.9, 26.9, 52.3, 55.0 ng·ml^–1 after 0, 0.5, 1 and 2 g·kg^–1, respectively. The corresponding areas under the curve of growth hormone plasma levels from drug injection to 180 min (AUC_0–180) were 0.135, 1.412, 2.918 and 3.695 g·min·ml^–1. The theoretical maximum response (E_max) and the dose that produces half of the maximum response (ED₅₀) were estimated using logistic regression. The calculated ED₅₀ values were 0.50 and 0.64 g·kg^–1 for C_max and AUC_0–180, respectively. The corresponding E_maxs were 55.1 ng·ml^–1 and 3936 ng·min·ml^–1, thus indicating that the effect after the 2 g·kg^–1 dose is very close to the maximal response. Plasma glucose, luteinising hormone, follicle-stimulating hormone, thyroid-stimulating hormone and insulin-like growth factor I were unaffected by hexarelin administration, while the peptide caused a slight increase in prolactin, cortisol and adrenocorticotropic hormone levels. Hexarelin was well tolerated in all subjects. The results of this study indicate that intravenous administration of hexarelin in man produces a substantial and dose-dependent increase of growth hormone plasma concentrations.     

Effect of salbutamol on digoxin pharmacokinetics

Summary A single dose of the ₂-adrenoceptor agonist salbutamol has previously been shown to decrease serum digoxin concentration in healthy volunteers. A possible explanation of the phenomenon is a ₂-adrenoceptor-mediated increase in the specific binding of digoxin to skeletal muscle. The present study was undertaken to further elucidate the effect of salbutamol on the pharmacokinetics of digoxin in man.Nine volunteers were studied on two occasions during salbutamol or placebo treatment. On test days salbutamol, 4 g·kg^–1·h^–1 or saline was infused for 10 h, preceded and followed by four and three days, respectively, of oral administration. A single i. v. injection of digoxin 15 g·kg^–1, was given 20 min after starting the infusion. At the end of the infusion a muscle biopsy was taken from the vastus lateralis. Blood samples for the analysis of serum digoxin and potassium were repeatedly taken over 72 h. Urine was collected over a period of 24 h for determination of the renal excretion of digoxin and potassium. The serum digoxin concentration, expressed as the AUC 0–6 h was 15% lower during salbutamol infusion than during saline infusion. Salbutamol caused significantly faster elimination of digoxin from the central volume of distribution to deeper compartments. Salbutamol had no effect on the renal clearance of digoxin. The skeletal muscle digoxin concentration tended to be higher (48%) during salbutamol compared to placebo treatment. The serum potassium concentration was significantly lower after salbutamol compared to placebo, as was the rate of renal excretion of potassium. The results support the hypothesis that the salbutamol-induced decrease in serum digoxin is caused by increased distribution of digoxin to skeletal muscle (and possibly other tissues), and that this may be secondary to a ₂-adrenoceptor-mediated increase in Na-K-ATPase activity.     

The effect of prostaglandin E1 during cardiopulmonary bypass on renal function after cardiac surgery

Summary We have evaluated the effect of prostaglandin E₁(PGE₁) on renal function after cardiac surgery with cardiopulmonary bypass in 20 patients, ten of whom received 0.02 g·kg^–1·min^–1 of PGE₁ by infusion into the oxygenator during bypass; ten patients served as controls.Serum ₂-microglobulin fell significantly and urine ₂-microglobulin increased significantly after surgery in both groups. Urine N-acetyl--D-glucosaminidase was high after surgery in both groups, but it was significantly lower in the PGE₁ group. Free water clearance fell significantly on the 1st, 3rd, and 5th postoperative days compared with preoperative values in the control but not in the PGE₁ group.These results suggest that PGE₁ may prevent renal dysfunction after cardiopulmonary bypass.     

Computer assisted design of a theophylline dosing regimen in acute bronchospasm: Serum concentrations and clinical outcome

Summary The effect of intravenous theophylline on the outcome of inhospital treatment of acute bronchospasm has been assessed, comparing the results achieved by computer-assisted dosing, designed to achieve and maintain a serum theophylline level of 16 g · ml^–1 (10 patients) with those of unaided physicians (15 control patients). The outcome measures compared were clinical improvement, peak expiratory flow rate and serum theophylline concentration.Loading doses of theophylline in the control and computer groups were: 167 and 437 mg, respectively. Initial serum theophylline concentrations, measured 20 min after the loading dose, were 13.6 and 17.0 g · ml^–1 in the control and computer groups, respectively. In patients who had not received theophylline prior to admission, loading doses and initial concentrations were: 200 mg and 9.4 g · ml^–1 in the control group (n = 5) versus 613 mg and 15.7 g · ml^–1 in the computer group (n = 4), respectively.During maintenance therapy, serum theophylline concentrations were kept in the therapeutic range (10–20 g · ml^–1) throughout 51 % and 77 % of the hospitalisation period, in the control and computer groups, respectively. There were no differences between the two groups in the rate or extent of clinical improvement or in change in peak expiratory flow rate.The computer assisted theophylline dosing regimen outperformed that of the unaided physicians in achieving and maintaining therapeutic serum theophylline concentrations in acute bronchospasm. There was no correlation between clinical outcome and serum theophylline concentration, but this may have been due to the small sample size and modest difference in serum theophylline between the two groups. The findings serve as an additional argument in favour of the trend away from reliance on theophylline as first line therapy in acute bronchospasm.     

A lack of pharmacokinetic interaction between ranitidine and piroxicam

Summary The effects of piroxicam (40 mg) on the pharmacokinetics of ranitidine (150 mg) and of ranitidine (150 mg bid) on the pharmacokinetics of piroxicam (20 mg) were assessed in two 2-way crossover studies in two groups of 18 healthy male subjects.In the first study there were no statistically significant differences between the pharmacokinetic variables for ranitidine in the presence or absence of piroxicam. The mean maximum plasma concentration (C_max) was 467 ng·ml^–1 for ranitidine alone and 466 ng·ml^–1 in the presence of piroxicam; mean area under the plasma concentration vs time curve (AUC) was 2460 h·ng ml^–1 and 2551 h·ng ml^–1 respectively; and the mean terminal half-life (t 1/2) was 3.6 h and 3.8 h respectively.In the second study there were no statistically significant differences between the pharmacokinetic variables for piroxicam in the presence or absence of ranitidine. The mean C_max was 2.1 ·ml^–1 in the presence of placebo and 2.0 g·ml^–1 in the presence of ranitidine respectively; mean AUC was 133 h·g ml^–1 and 137 h·g ml^–1 respectively, and the mean t 1/2 was 53.6 h and 54.5 h respectively.