bluuebunny/crossref_metadata_2025 huggingface dataset:
Evolution of the Longmen Shan Foreland Basin (Western Sichuan, China) during the Late Triassic Indosinian Orogeny
Authors: Yong L. , Allen P. A. , Densmore A. L. , Qiang X.
Published: March 2003

The Longmen Shan Foreland Basin developed as a flexural foredeep during the Late Triassic Indosinian orogeny, spanning the time period c. 227–206 Ma. The basin fill can be divided into three tectonostratigraphic units overlying a basal megasequence boundary, and is superimposed on the Palaeozoic–Middle Triassic (Anisian) carbonate‐dominated margin of the South China Block. The remains of the load system responsible for flexure of the South China foreland can be seen in the Songpan‐Ganzi Fold Belt and Longmen Shan Thrust Belt. Early in its history the Longmen Shan Foreland Basin extended well beyond its present northwestern boundary along the trace of the Pengguan Fault, to at least the palinspastically restored position of the Beichuan Fault.

The basal boundary of the foreland basin megasequence is a good candidate for a flexural forebulge unconformity, passing from conformity close to the present trace of the Beichuan Fault to a karstified surface towards the southeast. The overlying tectonostratigraphic unit shows establishment and drowning of a distal margin carbonate ramp and sponge build‐up, deepening into offshore marine muds, followed by progradation of marginal marine siliciclastics, collectively reminiscent of the Alpine underfilled trinity of Sinclair (1997). Tectonostratigraphic unit 2 is marked by the severing of the basin's oceanic connection, a major lake flooding and the gradual establishment of major deltaic‐paralic systems that prograded from the eroding Longmen Shan orogen. The third tectonostratigraphic unit is typified by coarse, proximal conglomerates, commonly truncating underlying rocks, which fine upwards into lacustrine shales.

The foreland basin stratigraphy has been further investigated using a simple analytical model based on the deflection by supracrustal loads of a continuous elastic plate overlying a fluid substratum. Load configurations have been partly informed by field geology and constrained by maximum elevations and topographic profiles of present‐day mountain belts. The closest match between model predictions and stratigraphic observations is for a relatively rigid plate with flexural rigidity on the order of 5 × 1023 to 5 × 1024 N m (equivalent elastic thickness of c. 43–54 km). The orogenic load system initially (c. 227–220 Ma) advanced rapidly (>15 mm yr−1) towards the South China Block in the Carnian, associated with the rapid closure of the Songpan‐Ganzi ocean, before slowing to < 5 mm yr−1 during the sedimentation of the upper two tectonostratigraphic units (c. 220–206 Ma).
Risk factors for mortality in users of ibopamine
Authors: Feenstra J. , In′t Veld B. A. , Van Der Linden P. D. , Grobbee D. E. , Stricker B. H. Ch.
Published: March 2003

Aims
 In September 1995, the indication for the oral dopamine agonist ibopamine was restricted in the Netherlands and in several other European countries to patients with NYHA‐class II heart failure as a result of an interim analysis of the PRIME‐II trial. This trial demonstrated an increased risk of mortality in patients with NYHA‐class III/IV heart failure on ibopamine. In September 1995, we initiated an assessment of the effects of ibopamine under everyday circumstances in a cohort of users of ibopamine in all NYHA‐classes.

Methods
 In a nationwide retrospective cohort study all 2147 community pharmacies and drug dispensing general practitioners received a request to list all patients to whom they had dispensed ibopamine in the preceding years. All responding drug dispensing outlets (DDO) received a questionnaire on cardiovascular risk factors and mortality for the general practitioner of a random sample of these patients. DDO were also requested to send an anonymised printout of the complete medication record. On the end‐date of follow‐up, February 15th 1996, mortality rates were compared across categories of ibopamine use, adjusted for potential confounders. To assess medication use, drug exposure was compared in a 3 months’ period before date of death in the deceased, and before a random date in those patients who were still alive.

Results
 In patients with NYHA‐class III/IV heart failure, multivariate analysis indicated that current use of ibopamine was significantly associated with mortality (RR 1.37;95% CI: 1.15–1.64). In patients with NYHA‐class I/II heart failure, however, multivariate analysis showed a 2.03 (95% CI: 1.10–3.72) risk of mortality in current users of ibopamine. Apart from current use of ibopamine, male gender and increased serum creatinine were also independent risk factors for mortality in all NYHA‐classes. No statistically significant association was found between mortality and current use of amiodarone or use of amiodarone at baseline.

Conclusions
 The increased risk of mortality in patients with NYHA‐class III and IV heart failure on ibopamine seems to confirm the main finding of the recently published PRIME‐II trial. However, our results indicate that also patients with NYHA‐class I/II heart failure may be at an increased risk of mortality when using ibopamine. Additional research on the effects of ibopamine in these patients is warranted and the use of ibopamine in NYHA‐class II heart failure patients may have to be reconsidered.
Radioreceptor assay analysis of tamsulosin and terazosin pharmacokinetics
Authors: Taguchi Katsunari , Schäfers Rafael F. , Michel Martin C.
Published: March 2003

Aims
 A radioreceptor assay has been developed for α1‐adrenoceptor subtypes and applied to a pharmacokinetic analysis of tamsulosin and terazosin.

Methods
 Young, male, healthy volunteers received 0.4 mg tamsulosin (as Omnic® modified release capsules) or 5 mg terazosin (as Flotrin® tablets) in a randomized, cross‐over design. Before and after 1, 3, 5, 7, 10 and 23.5 h plasma was analyzed by radioreceptor assay using cloned human α1A‐, α1B‐ and α1D‐adrenoceptors and specific h.p.l.c. analysis.

Results
 Following ingestion of tamsulosin median peak plasma levels of 16 ng ml−1 were reached after 5 h and declined to 2 ng ml−1 at 23.5 h. The time course in the radioreceptor assay was similar, and at most time points binding to α1A‐adrenoceptors was significantly greater than to α1B‐ and α1D‐adrenoceptors. Following ingestion of terazosin median peak plasma levels of 91 ng ml−1 were reached after 1 h and declined to 11 ng ml−1 at 23.5 h. In the radioreceptor assay binding also peaked at 1 h and declined thereafter, but even after 23.5 h considerable binding activity remained detectable at all three subtypes. At most time points binding to the α1A‐ and α1D‐adrenoceptor was significantly greater than to the α1B‐adrenoceptor.

Conclusions
 We conclude that α1‐adrenoceptor antagonist pharmacokinetics can be monitored by radioreceptor assays in a subtype‐selective manner. Tamsulosin and terazosin exhibit subtype selective receptor binding ex vivo. The discordance between terazosin blood levels as determined by h.p.l.c. and radioreceptor assay at late time points indicates the possible involvement of metabolites in in vivo terazosin effects.
A limited sampling method for the estimation of AUC and Cmax of carbamazepine and carbamazepine epoxide following a single and multiple dose of a sustained‐release product
Authors: Mahmood Iftekhar , Chamberlin Nancy
Published: March 2003

Aims
 The objectives of this study are to develop a model to predict area under the curve (AUC) and maximum plasma concentration (Cmax ) of carbamazepine (CBZ) and its active metabolite carbamazepine epoxide (CBZE) following single and multiple dose of CBZ using one or two samples in volunteers.

Methods
 Limited sampling models (LSM) were developed for CBZ and CBZE following 200–800 mg single oral dose and 400–800 mg twice daily dose for 14 days of a sustained‐release product (CBZ‐SR) to estimate AUC and Cmax. The LSM was developed from a training data set of 15 subjects using one blood sample taken at 48 h following a single dose. The model was validated on 60 subjects who received different doses of CBZ. Following multiple dosing, the LSM was developed from a training data set of 10 subjects using the steady state Cmin (plasma concentration obtained 5 min before the last CBZ‐SR dose).

Results
 The model provided good estimates of AUC and Cmax for CBZ and CBZE. The bias and the precision of the predicted AUC and Cmax for CBZ and CBZE were less than 10% and 15%, respectively. Similar results were obtained when CBZ was given as multiple dose.

Conclusions
 The method described here may be used to estimate AUC and Cmax for CBZ and CBZE without detailed pharmacokinetic studies following single or multiple dose of CBZ.
Induction of CYP1A2 activity by carbamazepine in children using the caffeine breath test
Authors: Parker A. C. , Pritchard P. , Preston T. , Choonara I.
Published: March 2003

Aims
 Carbamazepine is a known enzyme inducer. The aim of this study was to determine whether carbamazepine induces the metabolism of caffeine in children.

Methods
 Children due to receive carbamazepine for epilepsy were recruited into the study. The caffeine breath test was carried out prior to the administration of carbamazepine and after a minimum of 2–3 weeks therapy. Five children were studied and they received 200–600 mg carbamazepine daily.

Results
 The mean values of the 2 h cumulative labelled carbon dioxide were 3.47% before and 7.65% during carbamazepine. There was a significant increase in the percentage labelled caffeine exhaled as carbon dioxide during the administration of carbamazepine (Student's paired t‐test, P<0.05).

Conclusions
 The results suggest that carbamazepine induces the metabolism of caffeine by the CYP1A2 pathway in the children studied.
Agreement between the pharmacy medication history and patient interview for cardiovascular drugs: the Rotterdam elderly study
Authors: Sjahid Suzy I. , Van Der Linden Paul D. , Stricker Bruno H. Ch.
Published: March 2003

Aims
 To study whether there is agreement between cardiovascular drugs presented at patient interview and pharmacy records in an elderly population.

Setting
 The Rotterdam Elderly Study, a prospective population based cohort study of people older than 55 years of age.

Methods
 We compared cardiovascular drug use as presented during patient interview with the computerized pharmacy medication history. Concordance of cardiovascular drug use in patient interview and pharmacy data was measured by merging the two data sets and assessed in two episodes: in a period of 6 months before patient interview and within the legend duration of each cardiovascular drug.

Results
 We found 2706 concordant pairs in a total of 3365 prescriptions (80.4%) in the merged data. There were 195 prescriptions presented at patient interview which had not been filled at the pharmacy, and 464 which had been filled but were not presented by the patient. The percentage of concordant pairs slightly increased to 80.6% (2275 of a total of 2824) for prescriptions of which the legend duration included the date of patient interview. The highest agreement was noted with β‐adrenoceptor blocking agents with Kappa statistics of 0.97 for atenolol and metoprolol. The lowest Kappa statistic was found for organo‐heparinoid, mainly as ointments against haemorrhoids (0.26).

Conclusion
 The agreement between patient interview and pharmacy records is good for prescription only drugs, and pharmacy records are a useful resource for pharmacoepidemiological studies on cardiovascular agents.
Determinants of the blood pressure response to the first dose of ACE inhibitor in mild to moderate congestive heart failure
Authors: Murray Lilian , Squire Iain B. , Reid John L. , Lees Kennedy R.
Published: March 2003

Aims
 To investigate the relationship in patients with heart failure between BP response to the first dose of ACE inhibitor and (1) plasma drug concentration and (2) baseline clinical and laboratory variables.

Methods
 We studied individual placebo‐corrected BP responses to initiation of treatment with one of a number ACE inhibitor preparations in 132 patients with mild to moderate CHF. Various pharmacokinetic/pharmacodynamic models were compared. We assessed the strength of association between baseline physiological and laboratory variables and the BP response as assessed directly from the AUC(0,10 h) and indirectly from the slope of the PK/PD relationship. Predictive models for response variables were developing using regression analysis.

Results
 BP response was primarily related to plasma drug concentration. The association between the fall in BP and baseline variables was weak. The strongest single predictor of BP response was baseline mean arterial pressure (r2=5.8%, P=0.02). The best combinations of predictor variables contained mean arterial pressure, plasma renin activity, creatinine concentration and age (r2=14.4%, P=0.37). When the choice of ACE inhibitor was added, the predictive power of the model increased (r2=23.6%, P<0.01) but left the majority of the variability in response unexplained.

Conclusions
 The first‐dose blood pressure response to ACE inhibition cannot be accurately predicted from baseline pathophysiological variables in patients with mild to moderate CHF. The choice of ACE inhibitor accounts for a small proportion of the variability in response but wide inter‐individual variability exists in the response to each treatment.
Relationship between proguanil metabolic ratio and CYP2C19 genotype in a Caucasian population
Authors: Hoskins Janelle M. , Shenfield Gillian M. , Gross Annette S.
Published: March 2003

Aims To investigate the relationship between proguanil metabolic ratio (MR, proguanil/cycloguanil) and CYP2C19 genotype in a Caucasian population.

Methods Ninety‐nine Caucasians (age range: 18–55 years, 54 female, 45 male) were genotyped for CYP2C19 and phenotyped for proguanil oxidation by collecting urine for 8 h after taking 100 mg proguanil hydrochloride. Proguanil and cycloguanil concentrations were measured by h.p.l.c. PCR was employed for CYP2C19 genotyping.

Results The three (3%) individuals who were homozygous for CYP2C19*2 (*2/*2 ) had the highest proguanil MRs (range: 8.0–134.6). Seventy‐three (74%) individuals were homozygous for the wild‐type allele (*1/*1 ) and 23 (23%) were heterozygous (*1/*2 ). The *1/*1 individuals had lower MRs (median=1.4, range: 0.23–5.9, P=0.003, Mann–Whitney U‐test) than the *1/*2 subjects (median=2.5, range: 0.88–7.3).

Conclusions A CYP2C19 gene‐dose effect for proguanil oxidation to cycloguanil was observed, confirming a role for CYP2C19 in cycloguanil formation in vivo. However, there was substantial overlap of proguanil MRs in subjects of different CYP2C19 genotypes, due possibly to variability in the activity of other enzymes contributing to the formation of cycloguanil.
Age and sex distribution of suspected adverse drug reactions to newly marketed drugs in general practice in England: analysis of 48 cohort studies
Authors: Martin Richard M. , Biswas Pipasha N. , Freemantle Shayne N. , Pearce Gillian L. , Mann Ronald D.
Published: March 2003

Aims Little is known about the frequency with which suspected adverse drug reactions are seen by general practitioners after the prescription of newly marketed drugs. We investigated age and sex specific incidence rates of suspected adverse drug reactions recorded by general practitioners in England after the prescription of selected newly marketed drugs.

Methods Information was collected from 48 national cohort studies of newly marketed drugs studied by prescription‐event monitoring. Questionnaires were sent to prescribers asking for details of events and suspected adverse drug reactions recorded in the patients’ notes occurring after the drugs were prescribed.

Results During the 48 cohort studies, a total of 513 608 patients were investigated, of which 221 781 (43.2%) were males and 285 862 (55.7%) were females. The overall incidence of suspected adverse drug reactions in males was 12.9 per 10 000 patient‐months of exposure (95% confidence limits 12.3 to 13.5), and in females was 20.6 per 10 000 patient‐months of exposure (95% confidence limits 19.9 to 21.3). The overall age‐standardised relative risk of an adverse drug reaction in females compared with males was 1.6 (1.5–1.7). This sex difference was significant in all age groups above 19 years of age, and was relatively consistent across all age groups (χ2 test for heterogeneity=9.2, P=0.3).The highest rate of recording in males was in the 50–59 year age group, and in females was in the 30–39 year age group.

Conclusions In general practice in England, suspected adverse drug reactions to newly marketed drugs are recorded more often in adults aged between 30 and 59 years of age and are 60% more common in women than in men. The sex difference occurs in all age groups over 19 years of age.
Concurrent administration of donepezil HCl and cimetidine: assessment of pharmacokinetic changes following single and multiple doses
Authors: Tiseo  , Perdomo  , Friedhoff
Published: March 2003

Aim The aim of this study was to examine the pharmacokinetics of donepezil HCl and cimetidine separately, and in combination, following administration of multiple oral doses.

Methods This was an open‐label, randomized, three‐period crossover study in healthy male volunteers (n=19). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg), cimetidine (800 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3‐week, drug‐free washout period.

Results On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil+cimetidine groups in terms of the Cmax and AUC(0–24) values for donepezil. The combination group had an 11–13% greater Cmax and a 10% greater AUC(0–24) than the donepezil‐only group. No significant difference was observed between the tmax of the two treatment groups on day 1, and no significant differences in tmax, t½ or the rate of drug accumulation (RA ) were observed between the groups on day 7.

Cimetidine pharmacokinetics were essentially unchanged by co‐administration of the two drugs. The donepezil+cimetidine treatment group had a 20% greater maximum cimetidine concentration (Cmax ) than the cimetidine‐only group (P=0.001) on day 1, but not on day 7, and no difference was observed in any of the other pharmacokinetic parameters examined.

Conclusions Co‐administration of donepezil HCl (5 mg) and cimetidine (800 mg) did not produce clinically significant changes in the pharmacokinetic profiles of either drug.
Concurrent administration of donepezil HCl and ketoconazole: assessment of pharmacokinetic changes following single and multiple doses
Authors: Tiseo  , Perdomo  , Friedhoff
Published: March 2003

The aim of this study was to examine the pharmacokinetics of donepezil HCl and ketoconazole separately, and in combination, following administration of single and multiple oral doses.

 This was an open‐label, randomized, three‐period crossover study in healthy volunteers (n=21). During each treatment period, subjects received single daily doses of either donepezil HCl (5 mg), ketoconazole (200 mg), or a combination of both drugs for 7 consecutive days. Pharmacokinetic comparisons were made between treatment groups for the day 1 and day 7 profiles. Each treatment period was followed by a 3‐week, drug‐free washout period.

 On both day 1 and day 7, a statistically significant difference was observed between the donepezil and the donepezil+ketoconazole treatment groups in terms of Cmax and AUC(0–24) of donepezil. The concurrent administration of both drugs resulted in a 12% greater Cmax (9.5 ng ml−1 versus 8.4 ng ml−1; P=0.01) and a 12% greater AUC(0–24) (135.2 ng h ml−1 versus 118.7 ng h ml−1; P=0.001) than donepezil alone on day 1, and a 26.8% greater Cmax (37.7 ng ml−1 versus 27.6 ng ml−1; P<0.0001) and a 26.4% greater AUC(0–24) (680.9 ng h ml−1 versus 501.0 ng h ml−1; P<0.0001) than donepezil alone on day 7.

In contrast, ketoconazole plasma concentrations were unaffected by the concurrent administration of donepezil, and there were no statistically significant differences in ketoconazole pharmacokinetics when ketoconazole administered alone was compared with ketoconazole administered with donepezil.

 The concurrent administration of ketoconazole and donepezil produces no change in ketoconazole plasma concentrations, but a statistically significant change in donepezil plasma concentrations. These observed changes, which are smaller than those produced by ketoconazole for other agents sharing the CYP‐3A4 pathway, are most likely the result of donepezil also being metabolized by CYP‐2D6, as well as its slow rate of clearance from plasma.
Fosinopril/hydrochlorothiazide: single dose and steady‐state pharmacokinetics and pharmacodynamics
Authors: O’Grady Padraig , Yee Kan‐Fat , Lins Robert , Mangold Bernhard
Published: March 2003

Aims Fosinoprilat, the active product of fosinopril, is eliminated by an hepatic pathway in addition to the renal pathway shared by other angiotensin converting enzyme inhibitors (ACEIs). This study aimed to determine whether impaired renal function affects the pharmacokinetics and pharmacodynamics of a combination of fosinopril and hydrochlorothiazide (HCTZ).

Methods The study had a parallel‐group design comparing patients with renal impairment and body‐mass‐index‐matched normal controls. The study was done in a University clinic in 13 patients with renal impairment (mean creatinine clearance 55.7±15.6 ml min−1 1.73 m−2 ) and 13 age‐, sex‐, and body‐mass‐index‐matched normal controls (mean creatinine clearance 102.4±8.9 ml min−1 1.73 m−2 ). All patients and normal controls received fosinopril sodium 20 mg and HCTZ 12.5 mg as a daily oral administration on days 1–5. Non‐compartmental pharmacokinetic parameters of fosinoprilat and HCTZ were determined from blood and urine samples obtained over 48 h starting on Day 1 (single dose) and Day 5 (steady state): maximum serum concentration (Cmax ), time to maximum serum concentration (tmax ), area under the serum concentration‐time curve during the dosing interval (AUC), cumulative urinary excretion (CUE) and the accumulation index (AI; ratio of AUC‐day 5/AUC‐day 1). Pharmacodynamic parameters were also measured over 24 h on day 1 and over 48 h on day 5: serum ACE activity and arterial blood pressure.

Results Fosinoprilat pharmacokinetic parameters on day 1 in renally impaired vs normal patients: Cmax=387±0.19 vs 324±0.25 ng ml−1 (P=0.07); tmax=3.5 vs 3.0 h (P=0.58); AUC=3510±0.29 vs 2701±0.35 ng ml−1 h (P=0.072); CUE=5.08±2.70 vs 7.40±2.56% (P=0.009). Fosinoprilat parameters on day 5: Cmax=517±0.40 vs 357±0.19 ng ml−1 (P=0.007); tmax=3.0 vs 3.0 h (P >0.99); AUC=4098±0.43 vs 2872±0.30 ng ml−1 h (P=0.027); CUE=6.81±3.53 vs 8.10±2.80% (P=0.068). AI=1.17±0.33 vs 1.06±0.23 (P=0.29). In both groups ACE inhibition and blood pressure response were similar over 24 h and slightly greater 48 h after last dosing.

Conclusions In renally impaired subjects fosinopril and HCTZ can be coadministered without undue increases in fosinoprilat concentrations or any clinically significant pharmacodynamic effects. This is probably due to the dual excretory pathways for fosinoprilat.
Comparison of the effects of venlafaxine, desipramine, and paroxetine on noradrenaline‐ and methoxamine‐evoked constriction of the dorsal hand vein
Authors: Abdelmawla  , Langley  , Szabadi  , Bradshaw
Published: March 2003

Aims To examine whether the antidepressant venlafaxine, a novel serotonin‐noradrenaline re‐uptake inhibitor (SNRI), can modify α‐adrenoceptor‐mediated venoconstriction in man. The effects of venlafaxine were compared with those of desipramine, a tricyclic antidepressant with noradrenaline uptake inhibiting properties, and paroxetine, a selective serotonin re‐uptake inhibitor (SSRI), on noradrenaline‐and methoxamine‐evoked venoconstriction using the dorsal hand vein compliance technique.

Methods Fifteen healthy male volunteers participated in five weekly experimental sessions. Each session was associated with a clinically effective dose of an antidepressant or placebo. The following oral dosages were used: venlafaxine 75 mg, venlafaxine 150 mg, desipramine 100 mg, paroxetine 20 mg, or placebo. A double‐blind, cross‐over, balanced design was used. In each session, dose–response curves to both locally infused noradrenaline acid tartrate (0.1–33.33 ng min−1 ) and methoxamine hydrochloride (0.5–121.5 μg min−1 ) were constructed. Systolic and diastolic blood pressure and pulse rate were measured in the supine and erect positions. Salivation was measured by the dental roll technique.

Results Venlafaxine 150 mg and desipramine 100 mg potentiated the venoconstrictor response to noradrenaline (anova of log ED50s: P<0.01; individual comparisons: venlafaxine 150 mg vs placebo: P<0.005; mean difference, 95% CI: −0.49 (−0.81, −0.17); desipramine 100 mg vs placebo: P<0.005; mean difference, 95% CI: −0.34 (−0.60, −0.09) without affecting the response to methoxamine. Neither paroxetine nor placebo had any effects on the venoconstrictor responses. Both doses of venlafaxine increased systolic blood pressure (supine and erect) and venlafaxine 150 mg increased diastolic blood pressure (supine) (anova, P<0.05). Desipramine increased heart rate (P<0.05). Desipramine and both doses of venlafaxine reduced salivation (P<0.025).

Conclusions These results show that, similarly to desipramine 100 mg, venlafaxine 150 mg can potentiate venoconstrictor responses to noradrenaline, consistent with venlafaxine’s ability to block noradrenaline uptake in man. The importance of noradrenaline uptake blockade in these observations is confirmed by the lack of effect of the antidepressants on methoxamine‐evoked venoconstriction and the failure of paroxetine to modify noradrenaline‐evoked venoconstriction.
The vasodilator action of nebivolol in forearm vasculature of subjects with essential hypertension
Authors: Dawes  , Brett  , Chowienczyk  , Mant  , Ritter
Published: March 2003

Aims Brachial artery administration of nebivolol increases forearm blood flow in normotensive subjects through activation of the l‐arginine/NO pathway. The aim of the present study was to investigate the effect of brachial artery administration of nebivolol in subjects with essential hypertension.

Methods We studied eight patients with uncomplicated essential hypertension and serum cholesterol less than 6.9 mmol l−1. Antihypertensive medication was discontinued 2 weeks before the study in previously treated patients. Following cannulation of the left brachial artery, saline was infused to establish baseline blood flow, followed by increasing doses of nebivolol (88.5, 177 and 354 μg min−1, each dose for 6 min), followed by saline for 12 min, followed by a 30 min infusion of ‐NMMA (2 mg min−1 ). During the final 18 min of the l‐NMMA infusion, nebivolol was coinfused using the same doses as before. Forearm blood flow was measured in both arms using venous occlusion plethysmography.

Results Blood flow in the noninfused arm did not change significantly throughout the study. In the infused arm blood flow increased significantly in a dose‐related manner during the first series of nebivolol infusions from 2.76±0.39 ml min−1–1 100 ml forearm−1 during the baseline period to 4.40±0.60 ml min−1–1 100 ml forearm−1 (mean±s.e. mean, n=8, P=0.0003 by anova ). ‐NMMA antagonized the vasodilator effect of nebivolol: baseline blood flow in the infused arm was 2.41±0.53 ml min−1 100 ml forearm−1 and 2.94±0.42 ml min−1 100 ml forearm−1 during coinfusion of the top dose of nebivolol with ‐NMMA (P=0.0006 for an effect of ‐NMMA on nebivolol response). There were no serious adverse events.

Conclusions Nebivolol causes vasodilation in the forearm vascular bed in subjects with essential hypertension. Since this response is antagonized by ‐NMMA, the vasodilatation is probably caused by activation of the l‐arg/NO pathway.
Pharmacokinetics of flutamide in patients with renal insufficiency
Authors: Anjum  , Swan  , Lambrecht  , Radwanski  , Cutler  , Affrime  , Halstenson
Published: March 2003

Aims The aim of this study was to determine the pharmacokinetic parameters of flutamide, a nonsteroidal antiandrogenic compound, and its pharmacologically active metabolite, hydroxyflutamide, in renal insufficiency. Haemodialysis (HD) clearance of flutamide and hydroxyflutamide was also determined.

Methods Pharmacokinetic parameters were assessed for flutamide and hydroxyflutamide in 26 male subjects with normal renal function (creatinine clearance by 24 h urine collection, CLcr , greater than 80 ml min−1 1.73 m−2; n=6) or reduced renal function; CLcr=50–80 (n=7), 30–49 (n=3), 5–29 (n=4), and <5 ml min−1 1.73 m−2‐HD (n=6), following a single, oral 250 mg flutamide dose. Subjects undergoing HD received a second 250 mg dose of flutamide 4 h prior to HD; blood and dialysate were collected during HD to determine dialysability of flutamide and hydroxyflutamide.

Results Cmax , tmax , AUC, t1/2 , and renal clearance of flutamide and hydroxyflutamide did not differ between groups. Less than 1% of the dose appeared in dialysate as hydroxyflutamide. No serious adverse events were observed.

Conclusions Renal function did not affect flutamide nor hydroxyflutamide disposition. HD did not alter hydroxyflutamide pharmacokinetics. Dosing adjustments for renal impairment or HD are not indicated for flutamide.
A study of the relative bioavailability of cysteamine hydrochloride, cysteamine bitartrate and phosphocysteamine in healthy adult male volunteers
Authors: Tennezé Laurent , Daurat Véronique , Tibi Annick , Chaumet‐Riffaud Philippe , Funck‐Brentano Christian
Published: March 2003

Aims Cysteamine, the only drug available for the treatment of cystinosis in paediatric patients, is available as the hydrochloride, the bitartrate and as sodium phosphocysteamine salts. It has been suggested that cysteamine bitartrate and phosphocysteamine are better tolerated and may have a better bioavailability than cysteamine hydrochloride. This has, however, never been demonstrated.

Methods We compared the pharmacokinetics and tolerance of these three formulations of cysteamine in 18 healthy adult male volunteers in a double‐blind, latin‐square, three‐period, single oral dose cross‐over relative bioavailability study.

Results No statistical difference was found between relative bioavailabilities, AUC (0, ∞) (geometric mean and s.d. in μmol l−1h: 169±51, 158±46, 173±49 with cysteamine hydrochloride, phosphocysteamine and cysteamine bitartrate respectively), Cmax (geometric mean and s.d. in μmol l−1: 66±25.5, 59±12, 63±20) and tmax (median and range in h: 0.88 (0.25–2), 1.25 (0.25–2), 0.88 (0.25–2)) with each of the three forms of cysteamine tested. Bioequivalence statistics (90% confidence intervals) showed non equivalence of Cmax of cysteamine base as the only non equivalence of pharmacokinetics between the three formulations: 90% CI for Cmax relative ratios to cysteamine hydrochloride were [75.6–105.8] for phosphocysteamine and [74.2–124.2] for cysteamine bitartrate. The only significant adverse event was vomiting whose frequency was inversely correlated with body weight (Spearman’s r=−0.76, P<0.001). The nature of the salt tested did not influence vomiting.

Conclusions While none of the three forms of cysteamine tested has a clear advantage over the others in terms of pharmacokinetics and tolerance profile, this should now however be addressed in patients treated for cystinosis during repeat administrations.
The effects of age on human venous responsiveness to neuropeptide Y
Authors: Lambert Michelle L. , Callow Ian D. , Feng QingPing , Arnold J. Malcolm O.
Published: March 2003

Aims Neuropeptide Y (NPY) is a sympathetic neurotransmitter released with noradrenaline during sympathetic stimulation. Ageing has been shown to be associated with a reduction in α2 and ß‐adrenoceptor mediated responses in veins, but it is not known whether NPY responsiveness is also altered with increasing age.

Methods Using a dorsal hand vein technique, we examined NPY receptor responsiveness in 24 normal, healthy subjects (20–72 years; 10 males, 14 females). Graded infusions of NPY (25–2000 pmol min−1 ) were administered (5 min at each dose) into a dorsal hand vein. Venous distension at 45 mmHg was measured at 3–5 min of each infusion. Dose‐response curves to NPY were constructed and the peak venoconstriction was calculated.

Results Dose‐dependent venoconstriction was seen in all but one subject. The peak venoconstriction observed with NPY was significantly and negatively correlated with the age of the normal subjects (r=−0.63, P<0.01). When subjects were ranked from youngest to oldest and divided into tertiles, (20–40 years, n=8; 41–55 years, n=8; 56–72 years, n=8), mean dose‐response curves were different with the oldest tertile being significantly less responsive (P<0.05). The peak venoconstriction observed (% of control) was 65.1±7.0, 46.5±9.4, and 24.4±4.8%, respectively. The oldest tertile had a significantly decreased peak venoconstriction compared with the youngest tertile (P<0.01). Infusion of NPY into a dorsal hand vein had no systemic effects on heart rate or blood pressure in any of the subjects studied.

Conclusions Hand vein responsiveness to exogenously infused NPY in normal subjects is decreased as age increases. The reduction of NPY‐receptor‐mediated responses with age may influence sympathetic nervous system control of the venous system with advancing age.
Ketotifen and cardiovascular effects of xamoterol following single and chronic dosing in healthy volunteers
Authors: Schäfers Rafael F. , Karl Ingeborg , Mennicke Kirsten , Daul Anton Erich , Philipp Thomas , Brodde Otto‐Erich
Published: March 2003

Aims To study whether desensitization occurs after long‐term administration of the β1‐adrenoceptor partial agonist xamoterol and, if so, whether this can be influenced by ketotifen.

Methods In a double‐blind, randomized design 10 young, healthy males received ketotifen (2×1 mg day−1 p.o.) or placebo for 3 weeks with xamoterol (2×200 mg day−1 p.o.) administered concomitantly during the last 2 weeks. β1‐adrenoceptor mediated responses were assessed as exercise‐induced tachycardia and isoprenaline‐induced shortening of heart rate corrected electromechanical systole (QS2c); isoprenaline‐induced tachycardia was measured as a mixed β1‐/β2‐adrenoceptor‐mediated effect.

Results The first dose of xamoterol significantly increased resting heart rate and systolic blood pressure and significantly shortened QS2c. The last dose of xamoterol after 2 weeks of treatment still produced the same responses. Ketotifen did not influence these effects of xamoterol on resting haemodynamics. The first dose of xamoterol caused a rightward shift of the exercise‐ and isoprenaline‐induced tachycardia (mean dose ratios±s.e.mean: 1.20±0.05 and 2.46±0.23) and the isoprenaline‐evoked shortening of QS2c (dose ratio 3.59±0.68). This rightward shift was even more pronounced after 2 weeks xamoterol treatment. This additional rightward shift after 2 weeks of xamoterol was not affected by ketotifen (mean difference (95% CI) of log transformed dose ratios between placebo and ketotifen: exercise tachycardia 0.001 (−0.03; 0.04); isoprenaline tachycardia 0.03 (−0.15; 0.21); isoprenaline induced shortening of QS2c 0.13 (−0.22; 0.48)).

Conclusions In humans xamoterol is a partial β1‐adrenoceptor agonist with positive chrono‐ and inotropic effects at rest and antagonistic properties under conditions of β‐adrenoceptor stimulation. These effects were well maintained after chronic dosing with no signs of β1‐adrenoceptor desensitization. Ketotifen does not change the β‐adrenoceptor mediated responses of xamoterol after chronic dosing.
Binding of propofol to blood components: implications for pharmacokinetics and for pharmacodynamics
Authors: Mazoit Jean Xavier , Samii Kamran
Published: March 2003

Aims Propofol is a widely used i.v. anaesthetic agent. However, its binding properties to blood components have not been fully studied.

Methods We studied the binding of propofol to erythrocytes, to human serum and to isolated serum proteins. Because propofol bound to ultrafiltration and equilibrium dialysis membranes, we used a co‐binding technique with dextran coated charcoal and with erythrocytes.

Results Propofol free fraction in blood was 1.2–1.7% at total concentrations ranging from 2.80 to 179 μm (0.5 to 32 μg ml−1 ). Fifty percent was bound to erythrocytes and 48% to serum proteins, almost exclusively to human serum albumin. In the clinical range of concentrations (0.5–16 μg ml−1 ) 40% of the molecules bound to erythrocytes are on the red blood cells membranes. No binding to lipoproteins occurred and binding to α1‐acid glycoprotein was less than 1.5%

Conclusions We conclude that hypoalbuminaemia may increase propofol free fraction particularly during prolonged administration. Since propofol is non‐restrictively cleared, no change in clearance is expected to occur, and the increase in free fraction will not be compensated by a parallel increase in clearance. It is also noted that many in vitro studies used concentrations 50 to 500 times the concentration expected to be encountered in the immediate cellular environment.
The absorption profile and availability of a physiological subcutaneously administered dose of recombinant human growth hormone (GH) in adults with GH deficiency
Authors: Janssen  , Frölich  , Roelfsema
Published: March 2003

Aims To investigate the absorption profile and estimate the bioavailability of three doses of recombinant human growth hormone (rhGH) smaller than 2 IU in females with GH deficiency (GHD). A second aim of the study was to compare the mean 24 h GH concentrations after s.c. injection of rhGH with the physiological mean 24 h GH concentration of healthy females of comparable age, height, and BMI.

Methods Fourteen female patients with substituted GHD, and 14 healthy females of comparable age, height, and BMI were studied. All GHD patients underwent 24 h GH sampling after s.c. injection of rhGH in doses of 0.6, 1.2, or 1.8 IU. In addition, these patients underwent a 4 h GH sampling after i.v. injection of rhGH (1 IU). In healthy subjects, blood was withdrawn every 10 min for 24 h to determine the physiological GH profile.

Results A s.c. dose of 0.6 IU resulted in a mean and maximum GH concentration of 0.95±0.04 mU l−1 and 2.62±0.09 mU l−1. A doubling (or tripling) of the rhGH dose resulted in a doubling (or tripling) of the mean and maximum GH concentration. The time of maximum GH concentration was reached on average after 261±27 min. Mean GH concentration in healthy females was comparable with the mean GH concentration after a s.c. dose of 1.2 IU. Mean availability of the s.c. injected dose was 63%±4%.

Conclusions A dose of 1.2 IU resulted in a mean GH concentration comparable with the mean physiological GH concentration in healthy females of comparable age, height, and BMI.
A comparative analysis of the particle size output of beclomethasone diproprionate, salmeterol xinafoate and fluticasone propionate metered dose inhalers used with the Babyhaler, Volumatic and Aerochamber spacer devices
Authors: Barry  , O’Callaghan
Published: March 2003

Aims To determine in vitro the effect of delay, inspiratory flow, and spacer washing on the drug output of metered dose inhalers (MDIs) used with different spacer devices.

Methods The amount of drug in particles <5 μm diameter from MDI+spacer, sampling after a delay of up to 20 s, was measured using a Multistage Liquid Impinger. Drug output was also measured at different flow rates, and after washing the Babyhaler in household detergent.

Results More fluticasone in small particles was recovered from the Babyhaler than the Volumatic or the Aerochamber spacers, and more beclomethasone and salmeterol was recovered from the Babyhaler and Volumatic spacers than from the Aerochamber. Washing the Babyhaler reduced the recovery of salmeterol, and did not alter the recovery of the other drugs tested.

Conclusions Spacer devices need to be fully evaluated for each drug prescribed for them.
Pharmacokinetics and tolerability of oral rizatriptan in healthy male and female volunteers
Authors: Lee  , Conroy  , Stepanavage  , Mendel  , Somers  , McLoughlin  , Olah  , De Smet  , Keymeulen  , Rogers
Published: March 2003

Aims The pharmacokinetics and dose proportionality of rizatriptan single oral doses from 2.5 to 15 mg administered as solutions to healthy volunteers were studied.

Methods In a randomized, crossover study with four periods, twenty‐four healthy volunteers (12 males and 12 females) took single oral doses of 2.5, 5, 10, and 15 mg rizatriptan in Periods 1–4. In a fifth period, subjects received 4 mg intravenous (i.v.) rizatriptan as a reference. Plasma and urine rizatriptan concentrations were determined at several timepoints/intervals for 12 and 24 h, respectively.

Results The arithmetic mean AUC values following single oral doses of 2.5, 5, 10, and 15‐mg rizatriptan were 16, 33, 72, and 127 ng ml−1 h, respectively, in males; and 19, 42, 97, and 161 ng ml−1 h, respectively, in females. The overall bioavailability (F ) of rizatriptan was ∼40% in males. Following the 4 mg reference i.v. dose, the apparent plasma clearance (CL) and renal clearance (CLr ) were 1042 and 225 ml min−1, respectively, in males; and 821 and 174 ml min−1, respectively, in females.

Conclusions The disposition kinetics of oral rizatriptan were linear for doses of 2.5–10 mg in males, and for doses of 2.5–5 mg in females. However, the degree of nonlinearity for higher doses was minor for both genders. The plasma concentrations of rizatriptan were slightly greater in women compared to men but the difference was not considered to be clinically meaningful. Also, the clearance of rizatriptan appeared to be mainly nonrenal.
Pharmacokinetics, induction of anaesthesia and safety characteristics of Propofol 6% SAZN vs Propofol 1% SAZN and Diprivan®‐10 after bolus injection
Authors: Knibbe Catherijne A. J. , Voortman Henk‐Jan , Aarts Leon P. H. J. , Kuks Paul F. M. , Lange Rogier , Langemeijer Han J. M. , Danhof Meindert
Published: March 2003

Aims In order to avoid the potential for elevated serum lipid levels as a consequence of long term sedation with propofol, a formulation of propofol 6% in Lipofundin® MCT/LCT 10% (Propofol 6% SAZN) has been developed. The pharmacokinetics, induction of anaesthesia and safety characteristics of this new formulation were investigated after bolus injection and were compared with the commercially available product (propofol 1% in Intralipid® 10%, Diprivan®‐10) and propofol 1% in Lipofundin® MCT/LCT 10% (Propofol 1% SAZN).

Methods In a randomised double‐blind study, 24 unpremedicated female patients received an induction dose of propofol of 2.5 mg kg−1 over 60 s which was followed by standardized balanced anaesthesia. The patients were randomized to receive propofol as Propofol 6% SAZN, Propofol 1% SAZN or Diprivan®‐10.

Results For all formulations the pharmacokinetics were adequately described by a tri‐exponential equation, as the propofol concentrations collected early after the injection suggested an additional initial more rapid phase. The average values for clearance (CL), volume of distribution at steady‐state (Vd,ss ), elimination half‐life (t1/2,z ) and distribution half‐life (t1/2,λ2) observed in the three groups were 32±1.5 ml kg−1 min−1, 2.0±0.18 l kg−1, 95±5.6 min and 3.4±0.20 min, respectively (mean±s.e.mean, n=24) and no significant differences were noted between the three formulations (P >0.05). The half‐life of the additional initial distribution phase (t1/2,λ1 ) in all subjects ranged from 0.1 to 0.6 min. Anaesthesia was induced successfully and uneventfully in all cases, and the quality of induction was adequate in all 24 patients. The induction time did not vary between the three formulations and the average induction time observed in the three groups was 51±1.3 s which corresponded to an induction dose of propofol of 2.1±0.06 mg kg−1 (mean±s.e.mean, n=24). The percentage of patients reporting any pain on injection did not vary between the formulations and was 17% for the three groups. No postoperative phlebitis or other venous sequelae of the vein used for injection occurred in any of the patients at recovery of anaesthesia nor after 24 h.

Conclusions From the above results, we conclude that the alteration of the type of emulsion and the higher concentration of propofol in the new parenteral formulation of propofol does not affect the pharmacokinetics and induction characteristics of propofol, compared with the currently available product. Propofol 6% SAZN can be administered safely and has the advantage of a reduction of the load of fat and emulsifier which may be preferable when long term administration of propofol is required.
Netilmicin pharmacokinetics in Hong Kong Chinese cancer patients
Authors: Chang Sophie , Li Ronald C. , Chan Lesley S. Y. , Wong  , Zhu Min , Chan Anthony T. C. , Raymond Kenneth
Published: March 2003

Objectives To study the pharmacokinetics of netilmicin in Chinese haematology‐oncology patients and to determine the pharmacokinetic differences, if any, between this patient subpopulation of Chinese and Caucasians.

Methods A prospective study was carried out in the adult oncology unit of a major hospital in Hong Kong. During a 6 week period in 1997, all patients commencing on netilmicin therapy were monitored; the patients’ demographics, clinical status, netilmicin dose and regimen, and drug administration/blood sampling time were collected. Pharmacokinetic parameters were generated using the USC*PACK package based on specifics of the patients themselves and Caucasians matched for the same patients’ parameters using the Bayesian alogrithms.

Results A total of 22 patients were enrolled into the study. Twenty‐nine sets of levels were drawn, but only 25 sets from 18 patients (86%) were interpretable. The predicted peak (7.47±1.46 μg ml−1 ) and trough levels (1.39±0.96 μg ml−1 ) generated by USC*PACK were found to be significantly higher than the levels observed (6.01±1.14 μg ml−1 and 0.93±0.71 μg ml−1, respectively). Netilmicin clearance, volume of distribution and rate of elimination were all significantly higher in this Chinese subpopulation than those predicted for matched Caucasians.

Conclusion Alterations in the netilmicin pharmacokinetics observed in our study population might be related to the disease state and/or ethics of the study patient population. Direct application of Caucasian based population pharmacokinetic parameters to this subgroup of Chinese patients may not be appropriate and may result in underdose.