bluuebunny/crossref_metadata_2025 huggingface dataset:
Are young adults with asthma treated sufficiently with inhaled steroids? A population‐based study of prescription data from 1991 and 1994
Authors: GAIST DAVID , HALLAS JESPER , HANSEN NIELS‐CHR. G. , GRAM LARS F.
Published: October 2003

1 We conducted a descriptive cross‐sectional study of asthma therapy among young adults to assess to what extent the current guidelines for asthma therapy have been implemented. In particular, we examined the use of inhaled corticosteroids in heavy users of inhaled β‐adrenoceptor agonists.

2 Data were retrieved from a population‐based prescription database. For each of the years 1991 and 1994, all 20 to 44‐year‐olds who redeemed anti‐asthma medication in the Odense area (210 000 inhabitants) were studied.

3 We identified the number of users and total sales volume for specific anti‐asthma medications in defined daily doses (DDD) as well as the number of users and median annual doses of common regimens. Combined use of inhaled corticosteroids and inhaled β‐adrenoceptor agonists was also described.

4 The annual sales volume of anti‐asthma drugs increased by 23% to 927 636 DDD from 1991 to 1994. Inhaled corticosteroids were mainly responsible for this with a 52% increase in number of users and an 88% increase in DDD. Inhaled β‐adrenoceptor agonists used in monotherapy remained the most popular regimen in 1994 (1685 users=39%). Inhaled corticosteroids in combination with inhaled β‐adrenoceptor agonist were the second most popular regimen in 1994 (1308 users=30%), increasing by 64% as compared with 1991. However, among patients with an annual use of inhaled β‐adrenoceptor agonist of 200 DDD (1600 ‘puffs’) or more the percent of patients not receiving inhaled corticosteroids at all only fell from 37 to 33%.

5 Though the number of patients being treated with inhaled corticosteroids has increased, there is still evidence of a substantial underuse.
Pharmacodynamics and pharmacokinetics of BAY x 7195 aerosol, a new and selective receptor antagonist of cysteinyl‐leukotrienes, in normal volunteers
Authors: WENSING G. , HEINIG R. , KUHLMANN J.
Published: October 2003

1The safety, tolerability and pharmacokinetics of BAY x 7195 aerosol, a new selective receptor antagonist of cysteinyl‐leukotrienes, were investigated in healthy male volunteers in two observational studies (1 and 2 mg; n=5 each) and two double blind, placebo‐controlled two way crossover studies (4 and 8 mg; n=6 each) using the commercially available Inhaler Ingelheim M.

2The pharmacodynamic effect was assessed by testing the ability of BAY x 7195 aerosol to inhibit leukotriene‐D4 (LTD4) induced bronchoconstriction in healthy volunteers. Using a double‐blind, placebo‐controlled three way crossover design, volunteers received 2 and 4 mg of BAY x 7195 by means of a newly developed metered dose dry powder inhaler. Bronchoprovocation with nebulized LTD4 was performed 20 min and 8 h (n=6 each) after drug administration. Specific airways conductance (SGaw) served to assess the airway's response.

3BAY x 7195 aerosol was safe and well tolerated. Inhalation of the aerosol had no effect on baseline lung function. Only one volunteer reported cough following the inhalation of the 8 mg dose.

4The pharmacokinetics of unchanged drug following the administration of BAY x 7195 aerosol were linear in the investigated range of doses and in general very similar to a previously investigated tablet formulation. Plasma‐concentration vs time courses followed a two‐compartment body model. Compared with oral administration of the tablet formulation absorption tended to be more rapid with the aerosol formulation.

5Compared with placebo, 2 and 4 mg BAY x 7195 increased the concentration of LTD4 needed to produce a 35% decrease in SGaw 20 min after drug administration by a mean (geometric) of 14.2 and 29.7 fold, respectively. For both doses only three volunteers showed a protective effect against LTD4 induced bronchoconstriction 8 h after drug administration. Individual shifts in the concentration‐response curve ranged between 0.4 and 7.2 fold.

6In conclusion, the present results suggest that BAY x 7195 aerosol is a safe and potent but short acting receptor antagonist of cysteinyl leukotrienes in man.
The causes of essential hypertension
Authors: BROWN MORRIS J.
Published: October 2003

1Confusion between the criteria for defining and diagnosing hypertension may have misled the search for the causes of hypertension.

2The systematic approach of molecular genetics appears to offer the best chance of explaining hypertension, but the attractions are partly offset by the large numbers required, and unproven record of the genetic techniques in finding functional mutations in complex human disorders.

3Part of the evidence for the polygenic nature of essential hypertension derives from the variable response to a large number of different anti‐hypertensive agents. Systematic investigation of this variability may provide a basis for dividing patients into genetically more homogeneous sub‐groups, within which smaller numbers will be required to detect the genes responsible for the susceptibility to hypertension.

4The proportion of hypertensive patients with affected siblings has been studied in 6000 patients from Addenbrookes Hospital and local general practices. A recurrence risk for hypertension of∼3.5 was found.

5Approximately two‐thirds of patients have no known affected siblings. The next largest group, about one third, is patients whose siblings are all hypertensive. In a small group, <10% of all patients, half the siblings are hypertensive.

6We conclude from these surprising findings that hypertension is not a continuous, multifactorial part of the normal blood pressure distribution. They suggest that several more single‐gene disorders causing hypertension will be found. The sibships where all members are hypertensive are inconsistent with the segregation of Mendelian genetics and suggest the selection of some genes linked to hypertension at the time of gamete maturation.
A randomized, double‐blind, placebo‐controlled trial comparing pethidine to metamizol for treatment of post‐anaesthetic shivering
Authors: MONSÓ A. , RIUDEUBAS J. , BARBAL F. , LAPORTE J‐R. , ARNAU J. M.
Published: October 2003

1Shivering is frequent during the post‐anaesthetic recovery period, and there is no clear consensus about the best strategy for its treatment. We tested the efficacy of two commonly used analgesic drugs, pethidine and metamizol.

2A randomized, double‐blind, placebo‐controlled clinical trial was performed, including 104 adult patients who presented with post‐anaesthetic shivering during the recovery from general anaesthesia. They were randomized to receive placebo (n=32), metamizol 25 mg kg−1 (n=37), or pethidine 0.4 mg kg−1 (n=35). The response to treatment was assessed 5, 15 and 45 min after drug administration, and the main outcome variable was complete suppression of shivering.

3The efficacy at 5, 15 and 45 min was as follows: placebo 6%, 16% and 37%; metamizol 13.5%, 32% and 76%, and pethidine 89%, 91% and 89%. With both active drugs the efficacy at all three time intervals was significantly higher than that with placebo (P<0.05). The differences (at 5 and 15, but not at 45 min) between pethidine and metamizol were statistically significant (P<0.05). Both drugs were well tolerated.

4The persistence of shivering at 45 min in two thirds of placebo‐treated patients indicates that drug treatment is worthwhile; metamizol produces a better post‐anaesthetic shivering response than placebo, especially 15 and 45 min after drug administration; the efficacy of pethidine was the highest and the response to it appeared more quickly; however, at 45 min it was similar to that observed with metamizol.

5Both metamizol and pethidine suppress postanaesthetic shivering, but the latter induces a quicker and more reliable response.
Enzyme kinetic modelling as a tool to analyse the behaviour of cytochrome P450 catalysed reactions: application to amitriptyline N‐demethylation
Authors: SCHMIDER JÜRGEN , GREENBLATT DAVID J. , HARMATZ JEROLD S. , SHADER RICHARD I.
Published: October 2003

1To determine kinetic parameters (Vmax, Km) for cytochrome P450 (CYP) mediated metabolic pathways, nonlinear least squares regression is commonly used to fit a model equation (e.g., Michaelis Menten [MM]) to sets of data points (reaction velocity vs substrate concentration). This method can also be utilized to determine the parameters for more complex mechanisms involving allosteric or multi‐enzyme systems. Akaike's Information Criterion (AIC), or an estimation of improvement of fit as successive parameters are introduced in the model (F‐test), can be used to determine whether application of more complex models is helpful. To evaluate these approaches, we have examined the complex enzyme kinetics of amitriptyline (AMI) N‐demethylation in vitro by human liver microsomes.

2For a 15‐point nortriptyline (NT) formation rate vs substrate (AMI) concentration curve, a two enzyme model, consisting of one enzyme with MM kinetics (Vmax=1.2 nmol min−1 mg−1, Km=24 μm) together with a sigmoidal component (described by an equation equivalent to the Hill equation for cooperative substrate binding; Vmax=2.1 nmol min−1 mg−1, K′=70 μm; Hill exponent n=2.34), was favoured according to AIC and the F‐test.

3Data generated by incubating AMI under the same conditions but in the presence of 10 μm ketoconazole (KET), a CYP3A3/4 inhibitor, were consistent with a single enzyme model with substrate inhibition (Vmax=0.74 nmol min−1 mg−1, Km=186 μm, K1=0.0028 μm−1).

4Sulphaphenazole (SPA), a CYP2C9 inhibitor, decreased the rate of NT formation in a concentration dependent manner, whereas a polyclonal rat liver CYP2C11 antibody, inhibitory for S‐mephenytoin 4′‐hydroxylation in humans, had no important effect on this reaction.

5Incubation of AMI with 50 μm SPA resulted in a curve consistent with a two enzyme model, one with MM kinetics (Vmax=0.72 nmol min−1 mg−1, Km=54 μm) the other with ‘Hill‐kinetics’ (Vmax=2.1 nmol min−1 mg−1, K′=195 μm; n=2.38).

6A fourth data‐set was generated by incubating AMI with 10 μm KET and 50 μm SPA. The proposed model of best fit describes two activities, one obeying MM‐kinetics (Vmax=0.048 nmol min−1 mg−1, Km=7 μm) and the other obeying MM kinetics but with substrate inhibition (Vmax=0.8 nmol min−1 mg−1, Km=443 μm, K1=0.0041 μm−1).

7The combination of kinetic modelling tools and biological data has permitted the discrimination of at least three CYP enzymes involved in AMI N‐demethylation. Two are identified as CYP3A3/4 and CYP2C9, although further work in several more livers is required to confirm the participation of the latter.
Platelet PGI2 receptor affinity is reduced in pre‐eclampsia
Authors: KLOCKENBUSCH WALTER , HOHLFELD THOMAS , WILHELM MICHAEL , SOMVILLE THIERRY , SCHRÖR KARSTEN
Published: October 2003

Prostacyclin (PGI2) receptors were studied in platelet membrane preparations from women with normal pregnancy, pregnancy‐induced hypertension (PIH) or pre‐eclampsia. Patient groups showed no differences in gestational week at delivery. A markedly lower birth weight, however, was found in pre‐eclampsia. No differences between groups could be detected in platelet PGI2 receptor number. In contrast, the binding affinity to the PGI2 mimetic iloprost was considerably reduced in pre‐eclampsia, whereas receptor affinity between PIH and normal pregnancy did not differ significantly.
A cohort study of the ocular safety of anti‐ulcer drugs
Authors: GARCÍA RODRÍGUEZ LUIS A. , MANNINO SALVATORE , WALLANDER MARI‐ANN , LINDBLOM BERTIL
Published: October 2003

1Recently, some cases have been reported where intravenous use of omeprazole was followed by loss of vision. We followed up a cohort of close to 140 000 persons during periods of treatment and non‐treatment with five anti‐ulcer drugs.

2The relative risk of vascular disorders of the eye during use of omeprazole compared with non‐use was 1.8 (95% CI 0.5–6.0). Use of other anti‐ulcer drugs was associated with a similar risk of vascular disorders. The relative risk associated with current use of any anti‐ulcer drug was 1.9 (95% CI 1.1–3.4). We did not find a single case of optic inflammatory disorder during treatment with any of the five anti‐ulcer drugs.

3These results do not suggest a major increased risk for vascular or inflammatory disorders of the eye associated with use of omeprazole or other anti‐ulcer drugs.
Patient awareness of the adverse effects of non‐steroidal anti‐inflammatory drugs (NSAIDs)
Authors: WYNNE H. A. , LONG A.
Published: October 2003

We set out to determine the extent to which two groups of patients reported having been informed about the adverse effects of NSAIDs. These consisted of 50 patients who had suffered an acute gastrointestinal bleed while taking a NSAID, and 100 age, sex and drug matched controls who had not. Eight (16%) of the index patients, and 41 (41%) of the control patients remembered having been informed of potential adverse effects, an odds ratio of 3.65 (95% CI 1.55–8.58, P<0.002). Two (4%) of the index patients recalled having been advised what to do should adverse symptoms develop, whereas 21 (21%) of the control patients did so, an odds ratio of 6.38 (95% CI 1.4–28.4, P<0.01). Eighteen (36%) of patients who bled had experienced gastrointestinal pain prior to the bleed, but of these only two (11%) admitted reduced compliance with NSAID therapy. In contrast, 10 (67%) of the 15 control patients who had suffered epigastric discomfort admitted reduced compliance, an odds ratio of 16.0 (95% CI 2.6–98.8, P<0.001). Our results suggest that patients who report not having been informed of adverse effects of NSAIDs are less likely to reduce intake in response to epigastric pain than patients who report having received such information. If the patients who bled had reduced their intake of NSAIDs to the same extent as apparently better informed control patients in response to epigastric pain, it is possible that some episodes of acute gastrointestinal bleeding would have been avoided.
In vitro adrenaline and collagen‐induced mobilization of platelet calcium and its inhibition by naftopidil, doxazosin and nifedipine
Authors: Alarayyed N. A. , Cooper M. B. , Prichard B. N. C. , Betteridge D. J. , Smith C. C. T.
Published: October 2003

Aims The aim of the study was to obtain further information regarding the modes of action of doxazosin, naftopidil and nifedipine on platelet function.

Methods We conducted an in vitro study of drug influences on adrenaline and collagen‐induced mobilization of platelet calcium.

‘fn2\Results In the presence of fibrinogen (300 μg ml−1 ) both collagen (5 μg ml−1 ) and adrenaline (16 μm ) stimulated the aggregation of washed platelets. Collagen induced a transient rise (+4.97±0.63 μm ) in platelet Ca2+ concentration, [
Ca2+]i, as measured using the photoprotein aequorin, which coincided with the onset of aggregation. Adrenaline induced a smaller rise (+3.6±0.96 μm ) which, however, occurred after the onset of aggregation. Naftopidil, an α1‐adrenoreceptor antagonist produced a concentration‐dependent inhibition of collagen‐induced Ca2+ mobilization, maximum inhibition (22.9±4%, P<0.05) occurring with 40 μm naftopidil. The inhibition of Ca2+ mobilization was not reflected by a concentration‐dependent inhibition of platelet aggregation, although 40 μm naftopidil produced statistically significant inhibition (23.3±11.7%, P<0.05). The adrenaline‐induced rise in [Ca2+]i was inhibited dose dependently by naftopidil (e.g. 40 μm naftopidil, 100±0%, P<0.05), as was aggregation (40 μm naftopidil, 100±0%, P<0.05). Doxazosin, another α1‐adrenoreceptor blocker, inhibited Ca2+ mobilization induced by collagen to similar extents as for naftopidil (30 μm doxazosin, 17.4±2.5%, P<0.05), but did not inhibit platelet aggregation. It also inhibited the adrenaline‐induced rise in [Ca2+]i in a concentration‐dependent manner (30 μm doxazosin, 37.6±13.7%, P<0.05), significant inhibitions of platelet aggregation also being produced (30 μm, 49.6±17.2%, P<0.05). As expected, the calcium channel blocker nifedipine produced concentration‐dependent inhibitions of both collagen‐induced Ca2+ mobilization (e.g. 28 μm nifedipine, 47.8±2.7%, P<0.05) and aggregation (28 μm, 55.1±9.2%, P<0.05).

Conclusions These data indicate that the α1‐adrenoreceptor blockers, naftopidil and doxazosin, inhibit Ca2+ mobilization, this mechanism being possibly the means whereby these drugs inhibit platelet aggregation.
The acute effects of inhaled salbutamol on the beat‐to‐beat variability of heart rate and blood pressure assessed by spectral analysis
Authors: Jartti Tuomas , Kaila Timo , Tahvanainen Kari , Kuusela Tom , Vanto Timo , Välimäki Ilkka
Published: October 2003

Aims We wanted to study the effects of a 600 μg inhaled salbutamol dose on the cardiovascular and respiratory autonomic nervous regulation in eight children suffering from bronchial asthma.

Methods In this randomized, double‐blind, placebo‐controlled, crossover study we continuously measured electrocardiogram, finger systolic arterial pressure (SAP) and flow‐volume spirometry at baseline as well as 20 min and 2 h after the drug inhalation. The R–R interval (the time between successive heart beats) and SAP variabilities were assessed by using spectral analysis. Baroreflex sensitivity was assessed by using cross‐spectral analysis.

Results Salbutamol significantly decreased the total and low frequency (LF) variability of R–R intervals as well as the high frequency (HF) variability of R–R intervals and of SAP. Salbutamol significantly increased the LF/HF ratio of R–R intervals and of SAP, minute ventilation, heart rate and forced pulmonary function in comparison with placebo. The weight of the subjects significantly correlated positively with baroreflex sensitivity and negatively with heart rate after the salbutamol inhalation.

Conclusions We conclude that the acute salbutamol inhalation decreases cardiovagal nervous responsiveness, increases sympathetic dominance in the cardiovascular autonomic balance, and has a tendency to decrease baroreflex sensitivity in addition to improved pulmonary function.
Pharmacokinetics of thiopentone enantiomers following intravenous injection or prolonged infusion of rac‐thiopentone
Authors: Cordato D. J. , Gross A. S. , Herkes G. K. , Mather L. E.
Published: October 2003

Aims Thiopentone is administered as a racemate (rac‐thiopentone) for induction of anaesthesia as well as for neurological and neurosurgical emergencies. The pharmacokinetics and pharmacodynamics of rac‐thiopentone have been extensively studied but the component R‐(+)‐ and S‐(−)‐ enantiomers, until very recently, have been largely ignored.

Methods The present study analyses the pharmacokinetics of R‐(+)‐ and S‐(−)‐thiopentone in 12 patients given rac‐thiopentone intravenously for induction of anaesthesia and five patients given a prolonged infusion of rac‐thiopentone used for treatment of intracranial hypertension.

Results The mean total body clearance (CLT ) and apparent volume of distribution at steady‐state (V 
ss ) showed trends towards higher values for R‐(+)‐ than for S‐(−)‐thiopentone in both patient groups; CLT and V
ss of unbound fractions of R‐(+)‐ and S‐(−)‐thiopentone, however, did not show these trends. The time courses of R‐(+)‐ and S‐(−)‐ thiopentone serum concentrations were so similar that EEG effect could not be attributed to one or other enantiomer. Serum protein binding for S‐(−)‐thiopentone was greater than for R‐(+)‐thiopentone (P=0.02) and 24 h urinary excretion of R‐(+)‐thiopentone was greater than for S‐(−)thiopentone (P=0.03). In one patient, concomitant measurement of CSF and serum thiopentone concentrations found that serum: CSF equilibration of unbound fractions of both enantiomers was essentially complete.

Conclusions The study was unable to determine any pharmacokinetic difference of clinical significance between the R‐(+)‐ and S‐(−)‐thiopentone enantiomers and concludes that minor differences in CLT and V
ss could be explained by enantioselective difference found in serum protein binding.
Increase in force of contraction by activation of the Na+‘ox/Ca2+‘ox‐exchangerin human myocardium
Authors: Müller‐Ehmsen Jochen , Frank Konrad , Brixius Klara , Schwinger Robert H. G.
Published: October 2003

Aims The aim of the present study was to investigate whether agents which enhance force of contraction via increasing intracellular Na+, i.e. cAMP‐independently, remain effective in failing human myocardium.

Methods Cumulative concentration‐response curves with (±)BDF 9148 (0.01–10 μmol l−1 ), a Na+‐channel activator, and ouabain (0.01–0.1 μmol l−1 ), a Na+/K+‐ATPase inhibitor, were performed on electrically driven left ventricular human papillary muscle strips (1 Hz, 37° C; dilative cardiomyopathy, NYHA IV, heart transplantation, n=16; nonfailing, donor hearts, n=5). The β‐adrenoceptor agonist isoprenaline (0.001–1 μmol l−1 ) and Ca2+ (1.8–15 mmol l−1 ) were studied for control. In addition, Ca2+ response curves were obtained on skinned fibre preparations from left ventricular myocardium (NYHA IV, n=7) in the presence of BDF 9148 (1 μmol l−1 ) or a high Na+ concentration (50 mmol l−1 ) to investigate a possible direct or indirect interaction of (±)BDF 9148 with the myofilaments.

Results While isoprenaline was significantly less effective in increasing force of contraction in failing human myocardium than in nonfailing myocardium (P<0.01), in NYHA IV, (±)BDF 9148 and ouabain were as effective as in nonfailing human tissue. In failing and nonfailing myocardium, (±)BDF 9148 and ouabain exerted positive inotropic effects similar to those of Ca2+. However, the potency for (±)BDF 9148 to increase force of contraction was higher in NYHA IV than in nonfailing human myocardium (P<0.05). Neither (±)BDF 9148 (1 μmol l−1 ) nor an increased concentration of Na+ (50 mmol l−1 ) altered the Ca2+ sensitivity or maximal developed tension of the contractile apparatus in experiments on chemically skinned left ventricular fibres.

Conclusions The enhanced sensitivity of the failing human myocardium towards Na+‐channel modulation is not due to a direct or indirect interaction of (±)BDF 9148 with cardiac myofilaments but may be due to an altered Na+‐homeostasis in human heart failure.
Lack of inhibitory effect of cimetidine on caffeine metabolism in children using the caffeine breath test
Authors: Parker A.C. , Pritchard P. , Preston T. , Dalzell A.M. , Choonara I.
Published: October 2003

Aims To study the potential drug interaction between cimetidine and caffeine in a group of children who received cimetidine for gastritis.

Methods The caffeine breath test was carried out prior to the administration of cimetidine and after 2–3 weeks therapy. The children (n=1) received 300–800 mg cimetidine daily (11–36 mg kg−1 day−1 ).

Results There was no significant change in the 2 h cumulative labelled CO2 following the administration of cimetidine (mean values 5.61% before and 4.87% during cimetidine; Student’s t‐test P >0.2).

Conclusions Cimetidine did not have an inhibitory effect on the metabolism of caffeine in this group of children studied.
Venlafaxine: in vitro inhibition of CYP2D6 dependent imipramine and desipramine metabolism; comparative studies with selected SSRIs, and effects on human hepatic CYP3A4, CYP2C9 and CYP1A2
Authors: Ball Simon E. , Ahern Dennis , Scatina Joann , Kao John
Published: October 2003

Aims In order to anticipate drug‐interactions of potential clinical significance the ability of the novel antidepressant, venlafaxine, to inhibit CYP2D6 dependent imipramine and desipramine 2‐hydroxylation was investigated in human liver microsomes. The data obtained were compared with the selective serotonin re‐uptake inhibitors, fluoxetine, sertraline, fluvoxamine and paroxetine. Venlafaxine’s potential to inhibit several other major P450s was also studied (CYP3A4, CYP2D6, CYP1A2).

Methods Ki values for venlafaxine, paroxetine, fluoxetine, fluvoxamine and sertraline as inhibitors of imipramine and desipramine 2‐hydroxylation were determined from Dixon plots of control and inhibited rate data in human hepatic microsomal incubations. The inhibitory effect of imipramine and desipramine on liver microsomal CYP2D6 dependent venlafaxine O‐demethylation was determined similarly. Venlafaxine’s IC50 values for CYP3A4, CYP1A2 CYP2C9 were determined based on inhibition of probe substrate activities (testosterone 6β‐hydroxylation, ethoxyresorufin O‐dealkylase and tolbutamide 4‐hydroxylation, respectively).

Results Fluoxetine, paroxetine, and fluvoxamine were potent inhibitors of imipramine 2‐hydroxylase activity (Ki values of 1.6±0.8, 3.2±0.8 and 8.0±4.3 μm, respectively; mean±s.d., n=3), while sertraline was less inhibitory (Ki of 24.7±8.9 μm ). Fluoxetine also markedly inhibited desipramine 2‐hydroxylation with a Ki of 1.3±0.5 μm. Venlafaxine was less potent an inhibitor of imipramine 2‐hydroxylation (Ki of 41.0±9.5 μm ) than the SSRIs that were studied. Imipramine and desipramine gave marked inhibition of CYP2D6 dependent venlafaxine O‐demethylase activity (Ki values of 3.9±1.7 and 1.7±0.9 μm, respectively). Venlafaxine did not inhibit ethoxyresorufin O‐dealkylase (CYP1A2), tolbutamide 4‐hydroxylase (CYP2C9) or testosterone 6β‐hydroxylase (CYP3A4) activities at concentrations of up to 1 mm.

Conclusions It is concluded that venlafaxine has a low potential to inhibit the metabolism of substrates for CYP2D6 such as imipramine and desipramine compared with several of the most widely used SSRIs, as well as the metabolism of substrates for several of the other major human hepatic P450s.
Natriuretic efficiency of frusemide as a consequence of drug input rate
Authors: Wakelkamp Monique , Alván Gunnar , Paintaud Gilles
Published: October 2003

Aims  The aim of the present study was to investigate the influence of the rate of delivery of frusemide to its site of action on the effect and efficiency of the drug.

Methods  Frusemide 30 mg was administered as a bolus dose, a slow‐rate infusion and a bolus dose in combination with 2 g of probenecid in a three way cross‐over design to seven healthy volunteers. Urinary volume and contents of frusemide and sodium were measured in samples collected over 10 h.

Results
 Total natriuretic response was 40% higher (P<0.001) after the infusion and 20% higher (P<0.05) after the combined treatment with probenecid, as compared with the bolus dose. Total natriuretic efficiency did not differ between the infusion (0.013 mmol μg−1 ) and the combined treatment with probenecid (0.015 mmol μg−1 ), but was significantly higher as compared with the bolus dose (0.009 mmol μg−1 ). Natriuretic effect data were modeled according to the sigmoid Emax model and the frusemide excretion rate with maximum efficiency (EReffmax) was calculated from the estimated parameters. For both the frusemide infusion and the combined treatment with probenecid, the time course of delivery of frusemide into the urine consistently approached EReffmax more closely than was the case for the bolus dose. The natriuretic effect vs frusemide excretion rate curves were shifted to the right, and the estimated values of the sigmoid Emax model were higher for EC50 and lower for the slope factor after the bolus dose, which may indicate tolerance development for this treatment.

Conclusions  Slowing the delivery of frusemide to the site of action increased the efficiency of the drug, leading to an increased natriuretic response.
The peptide endothelin receptor antagonist, TAK‐044, produces sustained inhibition of endothelin‐1 mediated arteriolar vasoconstriction
Authors: Ferro C. J. , Haynes W. G. , Johnston N. R. , Lomax C. C. , Newby D. E. , Webb D. J.
Published: October 2003

Aims Endothelin‐1 (ET‐1) has been implicated in the pathophysiology of a number of cardiovascular diseases for which endothelin receptor antagonists are currently under clinical development. We have previously reported that systemic administration of the combined endothelin A/B receptor antagonist, TAK‐044, abolishes the forearm vasoconstriction caused by intrabrachial ET‐1 infusion for at least 3 h. In this study we investigated whether TAK‐044 can inhibit ET‐1 mediated forearm vasoconstriction for longer periods.

Methods Eighteen subjects were recruited to a randomized, placebo‐controlled, single‐blind, three‐way, crossover study. Subjects were divided into three groups of six. Groups received 25 mg, 50 mg or 100 mg TAK‐044 on two separate occasions, 6 and 10 h before the start of a 2 h intrabrachial infusion of ET‐1 (5 pmol min−1 ). On a third occasion subjects received only placebo before intra‐arterial ET‐1 infusion. Forearm vasoconstriction to ET‐1 was measured by venous occlusion plethysmography.

Results In the placebo phase, ET‐1 caused significant, slowly‐progressive local forearm vasoconstriction of ∼30% (P<0.01) in all three groups. All three doses of TAK‐044, administered at both timepoints, tended to blunt the vasoconstriction caused by ET‐1. When the responses from all three groups were combined, TAK‐044 significantly reduced ET‐1 mediated vasoconstriction compared with placebo −9% (95% CI −15 to −3; P=0.01) at 8 h and by −9% (95% CI −17 to −2; P=0.01) 12 h after dosing.

Conclusions TAK‐044 attenuated, but did not abolish, local ET‐1 mediated vasoconstriction, for up to 12 h after administration. Vasoconstriction to local intra‐arterial administration of ET‐1 appears to represent a safe and reproducible pharmacodynamic index of systemic endothelin receptor antagonism in humans.
Compliance with a 2 day course of artemether‐mefloquine in an area of highly multi‐drug resistant Plasmodium falciparum malaria
Authors: Na‐Bangchang K. , Congpuong K. , Sirichaisinthop J. , Suprakorb K. , Karbwang J.
Published: October 2003

Aims Multi‐drug resistant Plasmodium falciparum malaria is a rapidly increasing problem in the world, particularly Thailand. Practical antimalarial regimens which are highly effective against multi‐drug resistant parasites with short‐term course of administration are needed. In this study, we assessed the patient compliance of a short course regimen using artemether‐mefloquine.

Methods Clinical effectiveness (efficacy, tolerability and patient compliance) of a 2‐day regimen of artemether‐mefloquine was evaluated in 126 patients with acute uncomplicated falciparum malaria who were attending the two malaria clinics in an area of highly multi‐drug resistant P. falciparum malaria (Thai‐Myanmar border). Patients were treated with a single oral dose of 300 mg artemether on the day of attendance. Two additional doses of mefloquine were given for home treatment on the following day (750 and 500 mg after breakfast and lunch, respectively).

Results The combination regimen was effective, with a cure rate of 92.6%. Based upon the concentrations of whole blood mefloquine on day‐2, compliance for this 2 day regimen of artemether‐mefloquine was 98.1% (full compliance 86.8%, partial compliance 11.3%, non‐compliance 1.9%).

Conclusions We conclude that the 2 day regimen of artemether‐mefloquine is, at present, a good alternative regimen for the treatment of uncomplicated multi‐drug resistant falciparum malaria.
Lack of effect of eprosartan on the single dose pharmacokinetics of orally administered digoxin in healthy male volunteers
Authors: Martin D. E. , Tompson D. , Boike S. C. , Tenero D. , Ilson B. , Citerone D. , Jorkasky D. K.
Published: October 2003

Aims To study the effect of eprosartan, a nonbiphenyl tetrazole angiotensin II receptor antagonist, on digoxin pharmacokinetics in a randomized, open‐label, two period, period balanced crossover study in 12 healthy men.

Methods Each subject received a single 0.6 mg oral dose of digoxin (Lanoxicaps® 0.2 mg/capsule, Glaxo Wellcome) alone or following 4 days of dosing with eprosartan 200 mg orally every 12 h. Each study period was separated by a 14 day washout interval. Serial blood samples were obtained for up to 96 h after each digoxin dose for determination of digoxin pharmacokinetics. The effect of eprosartan on digoxin pharmacokinetics was assessed through an equivalence‐type approach using AUC(0, t′) as the primary endpoint.

Results For AUC(0, t′), the ratio of digoxin+eprosartan:digoxin alone was 0.99 with a 90% confidence interval (CI) of [
0.90, 1.09]. For Cmax, the ratio was 1.00 with a 90% CI of [0.86, 1.17]. tmax was similar for both regimens. Both regimens were safe and well tolerated.

Conclusions Based on AUC and Cmax data, it can be concluded that eprosartan has no effect on the pharmacokinetics of a single oral dose of digoxin.
Haemodynamic effects of adrenomedullin in human resistance and capacitance vessels
Authors: Cockcroft John R. , Noon Joseph P. , Gardner‐Medwin Janet , Bennett Terry
Published: October 2003

Aims The haemodynamic effects of adrenomedullin and calcitonin gene‐related peptide (CGRP) were studied in resistance and capacitance vessels of healthy volunteers.

Methods Adrenomedullin and CGRP were infused into the brachial artery of eight healthy subjects on two separate occasions at doses between 0.3–30 pmol min−1. Forearm blood flow was measured using venous occlusion plethysmography. Venodilatation to adrenomedullin and CGRP was assessed in a further eight subjects by infusing the peptides at doses between 0.3–10 pmol min−1 into a dorsal hand vein preconstricted with noradrenaline. Venodilator responses were measured as percentage reduction in noradrenaline preconstriction.

Results Adrenomedullin and CGRP at a dose of 30 pmol min−1, produced an increase in forearm blood flow of 288±42% and 252±30% respectively (mean±s.e. mean, P<0.001). At doses between 3 and 10 pmol min−1 adrenomedullin was significantly more potent than CGRP. The vasodilatation to both peptides was of similar duration with a biological half‐life of approximately 18 min. Adrenomedullin reversed constriction in dorsal hand veins by 84±2% (P<0.001) at a dose of 10 pmol min−1. CGRP produced a similar effect reversing constriction by 72±12% at the same dose (P<0.01). In veins, adrenomedullin was also more potent than CGRP at doses between 0.3 and 3 pmol min−1.

Conclusions The lowest dose of adrenomedullin producing significant arteriolar dilatation was calculated to produce plasma levels similar to those found in heart failure. These findings suggest that in pathophysiological conditions such as heart failure circulating levels of adrenomedullin may be within a range capable of influencing vascular resistance directly.
Differential inhibition of cytochrome P450 isoforms by the protease inhibitors, ritonavir, saquinavir and indinavir
Authors: Eagling V. A. , Back D. J. , Barry M. G.
Published: October 2003

Aims To compare the inhibitory potential of the HIV protease inhibitors saquinavir, ritonavir and indinavir against CYP1A2, CYP2C9, CYP2E1 and CYP3A4 catalysed metabolic reactions in human liver microsomes in vitro.

Methods Microsomes from six human livers were utilized in this study. The probe substrates were phenacetin (CYP1A2), tolbutamide (CYP2C9), chlorzoxazone (CYP2E1) and testosterone (CYP3A4). Metabolites were analysed by high performance liquid chromatography. IC50 (concentration of inhibitor giving 50% decrease in enzyme activity) and, where appropriate, Ki values were calculated.

Results Ritonavir was a very potent inhibitor of CYP3A4 mediated testosterone 6β‐hydroxylation (mean Ki=0.019±0.004 μm, mean±s.d.; n=6) and also inhibited tolbutamide hydroxylation (IC50=4.2±1.3 μm, mean±s.d.; n=6). Inhibition of phenacetin O‐deethylation and chlorzoxazone 6‐hydroxylation was negligible. Indinavir was an order‐of‐magnitude less potent in inhibiting CYP3A4 (Ki=0.17±0.01 μm ) and did not produce appreciable inhibition of the CYP1A2, CYP2C9 or CYP2E1 catalysed reactions. Saquinavir was the least potent CYP3A4 inhibitor (Ki=2.99±0.87 μm ) and produced some inhibition of CYP2C9 (approximately 50% at 50 μm ).

Conclusions The HIV protease inhibitors have differential effects on CYP isozymes. There is obviouspotential for clinically significant drug interactions particularly with ritonavir. Pharmacokinetic drug interaction studies are crucial to gain an overall understanding of the beneficial and potentially harmful effects of this important group of drugs.
Effect of melatonin and metabolites on copper‐mediated oxidation of low density lipoprotein
Authors: Seeger Harald , Mueck Alfred O. , Lippert Theodor H.
Published: October 2003

Aims A prophylactic use of melatonin as an anti‐ageing drug has recently gained public interest due to its radical scavenging property in vitro. The present study was designed to investigate a possible antiatherogenic effect of melatonin and its physiological metabolites by examining their action on the radical‐initiated formation of oxidized LDL, which is known to possess a high atherogenic potency. The metabolites investigated were the precursors serotonin and N‐acetyl‐serotonin and the main breakdown product 6‐hydroxymelatonin.

Methods The effect of the test substances on the in vitro oxidation of LDL (increase in conjugated diene formation) was investigated at concentrations of 1, 5, and 10 μm.

Results Melatonin increased the lag time of formation of oxidized LDL only at a concentration of 10 μm. In contrast, 6‐hydroxymelatonin, serotonin and N‐acetyl‐serotonin as well as vitamin E showed inhibitory effects starting at 1 μm. Thus the antioxidative action of melatonin was negligible compared with the effect of its main metabolite, its precursors and of vitamin E.

Conclusions The present results indicate that the pineal hormone melatonin appears to have little antiatherogenic property as regards the oxidation of LDL. Its main breakdown product 6‐hydroxymelatonin, however, inhibits LDL‐oxidation comparable to vitamin E. The precursors of melatonin, N‐acetyl‐serotonin and serotonin may also play a role in the inhibition of LDL oxidation in vivo.
Effect of troleandomycin on the pharmacokinetics of imipramine in Chinese: the role of CYP3A
Authors: Wang Jun‐Sheng , Wang Wei , Xie Hong‐Guang , Huang Song‐Lin , Zhou Hong‐Hao
Published: October 2003

Aims In vitro data indicate that imipramine (IMI), a widely used tricyclic antidepressant drug, is N‐demethylated by several isoforms of cytochrome P450, which include CYP3A4. The aim of this study was to investigate the role of CYP3A in the in vivo N‐demethylation of IMI.

Methods Healthy subjects were given troleandomycin (TAO), a selective inhibitor of CYP3A, 250 mg daily for 2 days before a single oral dose of 100 mg IMI was administered.

Results Pretreatment with TAO significantly increased the AUC of IMI by 59% (1971±938 vs 3134±2000 μg l−1 h, 95% confidence interval for difference between means: 218 to 2108 μg l−1 h, P<0.05) and decreased its oral clearance by 30% (60.9±27.4 vs 42.5±22.7 l h−1, 95% confidence internal for difference between means: 7.2 to 31.7 l h−1, P<0.05).

Conclusions We conclude that CYP3A may play an important role in the in vivo N‐demethylation of IMI.
The effect of age on plasma MEGX concentrations
Authors: Orlando R. , Palatini P.
Published: October 2003

Aims The study was designed to assess the effect age on the monoethylglycinexylidide (MEGX) liver function test.

Methods Plasma MEGX concentration was measured in 16 young and 17 elderly healthy volunteers 10, 15, 30, 45 and 60 min after intravenous injection of 1 mg kg−1 lignocaine.

Results Lower MEGX concentrations were noted in elderly subjects. The difference between young and old individuals became increasingly significant as the sampling time was increased, mainly because of a progressive decrease in intersubject variability within each of the two study groups. Linear regression analysis consistently showed that the strength of the relationships between MEGX concentration and age increased with increased sampling time and was maximal at 60 min (r=−0.70; P<0.0001; reduction in MEGX formation (95% CI) 0.51 (0.33–0.69) ng ml−1 per year).

Conclusions These data indicate that the rate of MEGX production declines significantly with age. Therefore, when the results of the MEGX test are to be compared in different study groups, subjects should be strictly matched for age.
Tamoxifen metabolic patterns within a glioma patient population treated with high‐dose tamoxifen
Authors: Ducharme Julie , Fried Karen , Shenouda George , Leyland‐Jones Brian , Wainer Irving W.
Published: October 2003

Aims The study was designed to evaluate tamoxifen metabolic profiles in 25 patients (13 M, 12 F) suffering from recurrent high‐grade cerebral astrocytomas who were treated with high oral doses of tamoxifen (120 mg/m2 twice daily).

Methods Tamoxifen was administered for at least 8 weeks; after 4 weeks blood samples were collected 7 h post dose. Tamoxifen and metabolites were analysed by h.p.l.c.

Results Steady‐state plasma concentrations (mean μm±s.d.) were determined for tamoxifen (2.94±3.44), N‐desmethyltamoxifen (4.37±2.13), N‐desdimethyltamoxifen (1.49±0.54), 4‐hydroxytamoxifen (0.13±0.05) and tamoxifen primary alcohol (1.07±0.46). Male and female patients had comparable metabolic profiles, both qualitatively and quantitatively. The mean plasma tamoxifen concentrations were higher in dexamethasone‐treated patients than untreated patients: 3.94±4.35 μm (95% C.I.: 1.43–6.46) vs 1.67±0.84 μm (95% C.I.: 1.11–2.24), with vs without; while phenytoin‐treated patients had lower concentrations: 1.85±0.87 μm (95% C.I.: 1.37–2.34) vs 4.58±5.05 μm (95% C.I.: 0.97–8.19), with vs without. The differences approached but did not reach statistical significance (P=0.065 and 0.078 respectively).

Conclusions There was marked interpatient variability. The observed effect of dexamethasone on tamoxifen concentrations is consistent with the involvement of CYP3A in metabolism.
The effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in human plasma, saliva and gastric juice
Authors: Jessa M. J. , Goddard A. F. , Barrett D. A. , Shaw P. N. , Spiller R. C.
Published: October 2003

Aims To evaluate the effect of omeprazole on the pharmacokinetics of metronidazole and hydroxymetronidazole in plasma, gastric juice and saliva following intravenous infusion or oral dosing of metronidazole.

Methods Eight volunteers received single doses of metronidazole (400 mg) intravenously and orally, whilst taking placebo or omeprazole (40 mg, twice daily for 5 days) in a randomized 4‐way crossover study. Metronidazole and hydroxymetronidazole concentrations in plasma, saliva and gastric juice samples were determined by h.p.l.c. Pharmacokinetic parameters for metronidazole and hydroxymetronidazole were calculated, and the significance of the mean differences in parameters between omeprazole and placebo co‐administration was assessed using a two‐tailed, paired t‐test.

Results There were no significant differences (P<0.05) in any of the plasma or saliva pharmacokinetic parameter values for metronidazole between volunteers receiving omeprazole or placebo when metronidazole was administered either as an intravenous infusion or orally. Following intravenous administration of metronidazole to the placebo group and omeprazole treated group respectively, the gastric transfer of metronidazole was significantly reduced from 15.5±10.4% to 2.6±1.0% of the dose (P=0.007; 95% CI of difference 4.8 to 21.0) with concomitant changes in the metronidazole AUC (from 77.5±18.0 μmol l−1 h to 352.6±182.1 μmol l−1 h; P=0.0003; 95% CI of difference 127.6 to 422.7), Cmax (from 61.4±26.5 μmol l−1 to 271.8±104.3 μmol l−1; P=0.0001; 95% CI of difference 118.6 to 302.1). Similarly, the gastric juice AUC of hydroxymetronidazole was significantly reduced from 3.2±1.9 μmol l−1 h to 1.5±0.8 μmol l−1 h of the dose (P=0.0043; 95% CI of difference 0.4 to 3.0) with a concomitant change in Cmax (from 5.0±2.5 μmol l−1 to 3.0±1.2 μmol l−1; P=0.0007; 95% CI of difference 0.7 to 3.4).

Conclusions Omeprazole had little effect on the plasma and salivary pharmacokinetics of metronidazole (or its hydroxymetabolite) after intravenous or oral administration, but it did have a substantial effect on the pharmacokinetics of metronidazole and hydroxymetronidazole in gastric juice.
A study of the effects of long‐term use on individual sensitivity to temazepam and lorazepam in a clinical population
Authors: Van Steveninck Alfred L. , Wallnöfer Andreas E. , Schoemaker Rik C. , Pieters Monique S. M. , Danhof Meindert , Van Gerven Joop M. A. , Cohen Adam F.
Published: October 2003

Aims The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long‐term users of temazepam and lorazepam in a clinical population.

Methods The sensitivity to benzodiazepine effects in chronic users (1–20 years) of lorazepam (n=14) or temazepam (n=13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales.

Results Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1–2.5 mg of lorazepam. In addition, there was a two‐ to four fold reduction in the slopes of concentration‐effect plots for measures of saccadic eye movements and body sway (all; P≤0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half‐life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam.

Conclusions Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.