bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of urine pH and urinary flow on the renal excretion of memantine
Authors: Freudenthaler  , Meineke  , Schreeb  , Boakye  , Gundert‐Remy  , Gleiter
Published: March 2003

Aims The present study assessed the influence of urinary flow rate and urine pH on the renal excretion of the NMDA‐receptor antagonist memantine.

Methods In a randomized, open, four‐period cross‐over trial, 12 healthy male volunteers received 10 mg memantine daily for 43 days. After reaching steady state conditions the volunteers were allocated to four different regimens to alter urine pH and urinary flow, which were each separated by a 1 week period while the study medication continued (A: acidification of urine pH, low urinary flow; B: acidification of urine pH, high urinary flow; C: alkalinization of urine pH, low urinary flow; D: alkalinization of urine pH, high urinary flow).

Results The renal clearance of memantine (CLR ) in regimen A and B was 7–10 fold higher in comparison with regimen C and D (P<0.05). There were small but statistically significant differences of CLR between the two regimens with acidic urine pH (A: median: 210.2 ml min−1vs B: median: 218.7 ml min−1 ) and between the two regimens with alkaline urine pH (C: median: 19.4 ml min−1vs D: median: 30.5 ml min−1 ). The amount of memantine excreted into the urine within one regimen (Ae0–24 h ) was 5.7–7.4 fold higher in regimens A and B than C and D (P<0.05). Differences of the AUC(0,24 h) and Cmax/AUC(0,24 h) were significant (P<0.05) between each of the regimens with acidic urine pH (A, B) and regimens (C, D) with alkaline urine pH (A vs C, A vs D, B vs C, B vs D) but not between regimens A vs B or C vs D.

Conclusions The present study demonstrated a considerable effect of urine pH, whereas no clinically relevant change of the renal excretion of memantine with urinary flow could be detected. As the renal excretion of memantine may have an impact on therapeutic efficacy changes of dietary habits that may alter urine pH should be avoided during treatment with memantine.
Substance P‐induced vasodilatation is mediated by the neurokinin type 1 receptor but does not contribute to basal vascular tone in man
Authors: Newby David E. , Sciberras David G. , Ferro Charles J. , Gertz Barry J. , Sommerville David , Majumdar Anup , Lowry Richard C. , Webb David J.
Published: March 2003

Aims Following intravenous administration of its prodrug, L‐758,298, we assessed the pharmacodynamics of L‐754,030, a novel and highly selective NK1 receptor antagonist, by examining systemic haemodynamics and the blood flow responses to intra‐arterial substance P infusion.

Methods Sixteen healthy male volunteers participated in a double‐blind, randomised, placebo controlled crossover trial of L‐758 298. Forearm blood flow was measured using venous occlusion plethysmography during intrabrachial substance P infusion (0.125–128 pmol min−1 ). In part 1, eight subjects received substance P infusions before and during placebo, 0.25 mg, 1 mg or 5 mg of L‐758 298. In part 2, eight subjects received substance P infusions 24 h after placebo or 1.43 mg of L‐758 298.

Results L‐758 298 caused dose dependent inhibition of substance P induced vasodilatation (P<0.001). Placebo adjusted differences (95% CI) in baseline forearm blood flow, mean arterial pressure and heart rate showed no relevant changes with 5 mg of L‐758 298 (>1400–fold shift in substance P response): 0.00 (−0.49 to +0.49) ml 100 ml−1 min−1, 1.0 (−3.2 to +5.2) mmHg and 1.9 (−5.9 to +9.7) beats min−1, respectively. Twenty‐four hours after 1.43 mg of L‐758,298, there was ~34–fold shift in response to substance P induced vasodilatation (P<0.008) at plasma L‐754 030 concentrations of 2–3 ng ml−1. L‐758 298 was generally well tolerated without serious adverse events.

Conclusions Substance P induced forearm vasodilatation is mediated by the endothelial cell NK1 receptor in man but endogenous substance P does not appear to contribute to the maintenance of peripheral vascular tone or systemic blood pressure.
Pharmacokinetics of bambuterol during oral administration to asthmatic children
Authors: Ahlström Hans , Alvero Josefino , Alvero Rita , Espos Roberto , Fajutrao Liberty , Herrera Jocelyn , Kjellman Bengt , Kubista Josef , Leviste Carolina , Meyer Peter , Oldæus Göran , Siricururat Areerat , Vichyanond Pakit , Wettrell Göran , Wong Ellick , Laxmyr Lena , Nyberg Lars , Olsson Håkan , Weibull Eva , Rosenborg Johan
Published: March 2003

Aims To investigate dose proportionality, dosing frequency, and ethnic aspects of the pharmacokinetics of bambuterol in asthmatic children, and to discuss the relationship with previous observations in adults.

Methods Forty‐eight children in four different studies completed two double‐blind bambuterol treatments each (daily doses of bambuterol hydrochloride): 12 preschool (5 mg×2 vs 10 mg) and 12 school (10 mg vs 20 mg) Caucasians, 12 preschool (2.5 mg vs 5 mg), and 12 school (10 mg vs 20 mg) Orientals. Peak plasma concentrations and dosing interval area under curve (AUC) of bambuterol and the active metabolite terbutaline were assessed at steady state. Treatment differences were analysed statistically within each study. Differences between the studies and the relation to steady‐state AUC in adults were described.

Results Dose proportionality was seen for terbutaline but not for bambuterol. Twice‐daily dosing (2×AUC(0,12 h)) could not be shown to differ from once‐daily dosing (AUC(0,24 h)) in the preschool Caucasians. Mean AUC of terbutaline was 128 and 242 nmol l−1 h in the preschool Caucasians (5 mg/12 h; 10 mg/24 h), 213 and 406 nmol l−1 h in the Caucasian school children (10 mg; 20 mg), 87.4 and 202 nmol l−1 h in the Oriental preschool children (2.5 mg; 5 mg), and 356 and 640 nmol l−1 h in the Oriental school children (10 mg; 20 mg). Oriental school children had higher plasma concentrations of bambuterol and terbutaline than Caucasian school children. The strict ethnical implication of the difference could not be elucidated, because demographic data were not perfectly matched. Terbutaline AUC was only moderately increased in the Caucasian school children compared with Caucasian adults. The increase was more pronounced in Oriental children and in some preschool Caucasians. The highest concentration of terbutaline, 58 nmol l−1, was seen in an Oriental school child after a 20 mg dose.

Conclusions Caucasian school children can be given bambuterol hydrochloride very much as Caucasian adults, 10 or 20 mg once daily, but Oriental preschool and school children plus preschool Caucasians should be given lower doses.
Pharmacokinetics and pharmacodynamics of allopurinol in elderly and young subjects
Authors: Turnheim  , Krivanek  , Oberbauer
Published: March 2003

Aims The prevalence of hyperuricaemia and gout increases with age as does the incidence of adverse effects to allopurinol, the major uric acid lowering drug. The present study was performed to compare the disposition and effects of allopurinol and its active metabolite oxipurinol in elderly and young subjects without major health problems.

Methods Ten elderly (age range 71–93 years) and nine young subjects (24–35 years) received an oral dose of 200 mg allopurinol in an open, single dose, cross sectional design. Four of these individuals were additionally dosed with 200 mg allopurinol intravenously. Plasma and urine concentrations of allopurinol, oxipurinol, hypoxanthine, xanthine, and uric acid were measured by h.p.l.c.

Results Total clearance of allopurinol was not different in elderly (15.7±3.8 ml min−1 kg−1, mean±s.e. mean) and young subjects (15.7±2.1), whereas total clearance of oxipurinol was significantly reduced in the aged (0.24±0.03) compared with young controls (0.37±0.05) as was the distribution volume of oxipurinol (0.60±0.09 and 0.84±0.07 l kg−1, respectively). Oxipurinol was eliminated primarily by the kidneys, allopurinol by metabolism. Fractional peroral bioavailability of allopurinol was 0.81±0.16 (n=4, two elderly and two young subjects). Although maximal plasma concentrations of oxipurinol were significantly higher in elderly (5.63±0.83 μg ml−1 ) than in young persons (3.75±0.25) as was the area under the oxipurinol plasma concentration‐time curve, AUC (260±46 and 166±23 μg ml−1h, respectively), the pharmacodynamic effect of oxipurinol was smaller in elderly than young subjects (time‐dependent decrease of plasma uric acid 83±30 μg ml−1 h in elderly compared with 176±21 in young controls). Oxipurinol increased the renal clearance of xanthine, suggesting inhibition of tubular xanthine reabsorption by oxipurinol.

Conclusions Although allopurinol elimination is not reduced in the aged, that of its active metabolite oxipurinol is because of an age‐dependent decline in renal function. Xanthine oxidase inhibition by oxipurinol appears to be reduced in old age. In addition to its uricostatic action, oxipurinol has a xanthinuric effect which is also diminished in the elderly.
Rapid development of tolerance to dipyridamole‐associated headaches
Authors: Theis  , Deichsel  , Marshall
Published: March 2003

Aims In the Second European Stroke Prevention Study headaches associated with dipyridamole frequently (8% of patients taking dipyridamole or dipyridamole plus acetylsalicylic acid (ASA) vs2% of patients taking ASA or placebo) led to discontinuation of therapy. We have now used data from a recent trial comparing the bioequivalence of two formulations of the fixed combination of 200 mg dipyridamole in an extended release formulation and 25 mg ASA to explore predicting factors for headaches associated with this drug combination.

Methods The bioequivalence trial employed a two‐way crossover, randomised, open design. Trial medication was given for two periods of five days separated by a 72 h washout period. Statistical methods were employed to explore the prevalence, the time course, and the relation to individual pharmacokinetic parameters of treatment associated headaches.

Results Headache episodes, being mostly mild and transient, rapidly declined from 67% of the volunteers on the first day of treatment to 3% on the final days of treatment (days 4–5 of the second period). During the first days the prevalence of the headaches peaked 2–3 h after the morning administration, which coincided with the peak of the plasma concentrations of dipyridamole. The occurrence of headaches was not related to interindividual differences of the pharmacokinetic parameters.

Conclusions The rapid decrease in the incidence of headaches over time implies that most patients quickly develop tolerance to dipyridamole‐associated headaches. Appropriate information given to the patient when prescribing and dispensing dipyridamole/ASA may reduce early withdrawals from treatment and increase compliance.
Changes in systolic time intervals—a non‐invasive marker for the haemodynamic effects of sumatriptan
Authors: Hood Stuart , Birnie David , Murray Lilian S. , MacIntyre Paul D. , Hillis W. Stewart
Published: March 2003

Aims This study assessed the use of systolic time intervals (STI) as a potential non‐invasive marker of the haemodynamic effects of sumatriptan, a 5HT1 receptor agonist.

Methods Twenty‐six patients undergoing diagnostic cardiac catheterization participated. STIs were derived from haemodynamic pressure tracings at baseline, following placebo injection and following either subcutaneous (n=18) or intravenous injection (n=8) of sumatriptan.

Results Sumatriptan (i.v. or s.c.) was associated with significant increases in mean arterial pressure (95% C.I. 9,14mmHg, P=0.0001), total electromechanical systole (95% C.I.8,36ms, P<0.0001), pre‐ejection period (95%C.I. 8,21ms, P=0.0001) and left ventricular ejection time (95% C.I. 2,12ms, P=0.004).

Conclusion STI responses were consistent with sumatriptan‐induced changes in afterload. In summary, the measurement of STIs is a potential non‐invasive method of investigating the influence of serotonergic compounds on the cardiovascular system.
Differential vascular α1‐adrenoceptor antagonism by tamsulosin and terazosin
Authors: Schäfers Rafael F. , Fokuhl Bernd , Wasmuth Andrea , Schumacher Helmut , Taguchi Katsunari , De Mey Christian , Philipp Thomas , Michel Martin C.
Published: March 2003

Aims In patients with lower urinary tract symptoms suggestive of benign prostatic obstruction the α1‐adrenoceptor antagonist terazosin lowers blood pressure whereas only very small if any alterations were reported with the α1‐adrenoceptor antagonist tamsulosin. Therefore, we have compared the vascular α1‐adrenoceptor antagonism of tamsulosin and terazosin directly.

Methods Ten healthy subjects were investigated in a randomized, single‐blind, three‐way cross‐over design and received a single dose of 0.4 mg tamsulosin, 5 mg terazosin or placebo on 3 study days at least 1 week apart. Before and 1, 3, 5, 7, 10 and 23.5 h after drug intake, alterations of diastolic blood pressure and other haemodynamic parameters in response to a graded infusion of the α1‐adrenoceptor agonist phenylephrine were determined non‐invasively.

Results At most time points tamsulosin inhibited phenylephrine‐induced diastolic blood pressure elevations significantly less than terazosin (5 h time point: median difference in inhibition 35%, 95% CI: 18.7–50.3%). On the other hand, phenylephrine‐induced changes of cardiac output, heart rate and stroke volume were similar during both active treatments.

Conclusions In doses equi‐effective for treatment of lower urinary tract symptoms tamsulosin causes less inhibition of vasoconstriction than terazosin.
Effect of electrostatic charge in plastic spacers on the lung delivery of HFA‐salbutamol in children
Authors: Anhøj Jacob , Bisgaard Hans , Lipworth Brian J.
Published: March 2003

Aims The effect of the electrostatic charge in plastic spacers in vivo on drug delivery to the lung of hydrofluoroalkane (HFA) salbutamol spray was studied in children.

Methods Five children, aged 7–12 years, were included in a 3‐way crossover randomised single‐blind trial. Salbutamol HFA spray was delivered on 3 different study days from plastic spacers with mouthpiece. Pre‐treatment of the spacers differed between study days: (a) Non‐electrostatic 350 ml Babyhaler (coated with benzalkonium chloride) (b) New 350 ml Babyhaler (rinsed in water), and (c) New 145 ml AeroChamber (rinsed in water). Plasma salbutamol was measured before and 5, 10, 15 and 20 min after inhalation of four single puffs of 100 μg salbutamol. Cmax and Cav (5–20min) were calculated as a reflection of lung dose.

Results For Cmax: (A) Non‐electrostatic Babyhaler 4.3 ng ml−1 (B) New Babyhaler 1.9 ng ml−1 (C) New AeroChamber 1.6 ng ml−1: AvsB (95% CI for difference 0.5–4.5 ng ml−1 ), A vs C (95% CI for difference 0.7–4.8 ng ml−1 ). The geometric mean ratio for A:B was 2.4 fold, and for A:C was 2.9 fold. The values for Cav were similar with ratios for A:B of 2.4 fold, and A:C of 4.1 fold. The nonelectrostatic Babyhaler delivered a significantly (P<0.05) higher lung dose (for both Cmax and Cav ) than either of the other two spacers.

Conclusions The electrostatic charge in plastic spacers reduces lung dose in children by more than two‐fold. This is clinically significant and the use of potentially electrostatically charged spacers should be avoided.
Pharmacokinetic profile of alniditan nasal spray during and outside migraine attacks
Authors: Roon  , Soons  , Uitendaal  , De Beukelaar  , Ferrari
Published: March 2003

Aims To compare the pharmacokinetic profile of intranasal alniditan during and outside migraine attacks, and to investigate the relationship between initial rise of alniditan plasma concentration, and headache improvement.

Methods Twenty‐seven migraine patients (age: 18–65 years) were randomized to receive alniditan 2 mg or 4 mg, and investigated both during and outside a migraine attack. Maximal plasma concentrations (Cmax ), time to Cmax (tmax ), and the area under the curve over 2 h (AUC(0,2 h)), were calculated from the individual plasma concentration‐time profile, obtained from 10 blood samples in each patient, during each of the two administrations.

Results Alniditan was rapidly absorbed into the systemic circulation (tmax=11min). All investigated pharmacokinetic parameters (Cmax, tmax, AUC(0,2 h)) were similar during and outside migraine attacks, both in the 2 mg (n=13) and the 4 mg group (n=14). In the 4 mg group, during attacks, mean plasma alniditan concentration at 5 min after administration (Ct=5 ) in responders (21±16 ng ml−1; n=10) was significantly higher than the Ct=5 in nonresponders (3±3 ng ml−1; P=0.01; n=4). However, the Cmax and AUC(0,2 h) in responders (33±18 ng ml−1 and 12±6 ng ml−1 h) were also significantly higher than the Cmax and AUC(0,2 h) in nonresponders (13±9 ng ml−1; P=0.048 and 5±3 ng ml−1 h; P=0.03).

Conclusions Absorption of alniditan nasal spray was not affected by migraine attacks, although 95% confidence intervals were wide. Early rise of plasma concentrations and the amount of drug in the circulation were related to headache improvement in the higher dose group.
Phenotypic polymorphism and gender‐related differences of CYP1A2 activity in a Chinese population
Authors: Ou‐Yang Dong‐Shen , Huang Song‐Lin , Wang Wei , Xie Hong‐Guang , Xu Zhen‐Hua , Shu Yan , Zhou Hong‐Hao
Published: March 2003

Aims To investigate the distribution characteristics of CYP1A2 in a Chinese population, and to examine gender‐related differences in CYP1A2 activity.

Methods Two hundred and twenty‐nine healthy subjects, 120 men and 109 women, were enrolled in this study. CYP1A2 activity was measured by plasma paraxanthine/caffeine (1,7X/1,3,7X) ratio 6 h after administration of 300 mg caffeine. The concentrations of paraxanthine and caffeine in plasma were detected by h.p.l.c.

Results A 16‐fold variation of CYP1A2 activity (range 0.09 to 1.46) was shown in this study. The coefficient of variation (CV %) of CYP1A2 activity was 62.9%. Non‐normal distribution of CYP1A2 activity was indicated by the Shapiro‐Wilk test (P<0.001). Probit plots of CYP1A2 activity revealed a bimodal distribution with breakpoint of 1,7X/1,3,7X ratio of 0.12. The percentage of poor metabolizers (PMs) was 5.24% (95% CI: 2.35%~8.13%) in this Chinese population. Residual analysis of the data also supported bimodality (P<0.01). The CYP1A2 activity of men was higher than that of women (median: 0.33 vs 0.23, P<0.001). A probit plot of CYP1A2 activity in men was shifted to the left compared with that in women. Based on phenotype, the gender‐related difference was observed in extensive metabolizers (EMs) (P<0.001), but not in PMs (P >0.1). In addition, there was no sex‐related difference in the incidence of PMs (P >0.1).

Conclusions There is a phenotypic polymorphism in CYP1A2 activity in this Chinese population, and CYP1A2 activity is higher in men than that in women.
Pharmacokinetic analysis of felodipine–grapefruit juice interaction based on an irreversible enzyme inhibition model
Authors: Takanaga Hitomi , Ohnishi Ayako , Matsuo Hirotami , Murakami Hideyasu , Sata Hiroko , Kuroda Ken , Urae Akinori , Higuchi Shun , Sawada Yasufumi
Published: March 2003

Aims Ingestion of grapefruit juice (GFJ) alters the pharmacokinetics of various orally administered drugs. Quantitative evaluation of this GFJ–drug interaction is required for the proper clinical management of patients.

Methods Using felodipine as a model drug, we constructed a pharmacokinetic model based on irreversible inhibition of intestinal cytochrome P450 3A4 (CYP3A4) by GFJ. We fitted previously publised data [5, 6] for felodipine ER (extended release formulation) to the ratio of CLGI,int before and after grapefruit juice ingestion by nonlinear least‐squares regression analysis to estimate the reaction rate constant between GFJ and CYP3A4 (K) and the elimination rate constant of CYP3A4 (k ).

Results The model gave a turnover rate of CYP3A4 of 0.0849 h−1, corresponding to a half‐life of 8.16 h, in agreement with reported values. The AUC‐time profiles of felodipine ER in the case of different amounts and schedules of GFJ ingestion were simulated using the parameter values estimated from the model.

Conclusions The modelling leads to the important conclusion that GFJ–felodipine interaction increases with increasing frequency and amount of GFJ ingestion, and that an interval of 2–3 days between GFJ intake and felodipine administration is necessary if GFJ–felodipine interaction is to be avoided.
Single‐ and multiple‐dose pharmacokinetics of ziprasidone under non‐fasting conditions in healthy male volunteers
Authors: Miceli J. J. , Wilner K. D. , Hansen R. A. , Johnson A. C. , Apseloff G. , Gerber N.
Published: March 2003

Aims  To evaluate the pharmacokinetics and tolerability of single and multiple oral doses of ziprasidone in healthy male volunteers, and to determine the influence of ziprasidone on serum prolactin levels.

Methods  Single and multiple doses of ziprasidone were given orally (as two divided daily doses), at fixed dosages of 10 and 40 mg day− 1, and using titrated regimens of 40–80 and 40–120 mg day− 1, for 14 days. All dosages were taken immediately after food. The study adopted a randomized, double‐blind, placebo‐controlled design. Prolactin response, sedative properties, tolerability, and extrapyramidal symptoms were also investigated.

Results  Steady‐state exposure to ziprasidone was attained after 1 day of dosing. Mean Cmax and AUC(0,12 h) increased with increasing dose, with apparent dose‐proportionality between the 20 and 60 mg dose levels. Trough‐to‐peak ratios at steady state ranged from 2 to 5. Accumulation ratios for the fixed‐dose regimens were 1.49 and 1.48 at the 5 and 20 mg dose levels, respectively. Ziprasidone was associated with transient prolactin elevation but levels of prolactin returned to baseline within the dosing interval at steady state. There was a marginal, transient increase in serum prolactin levels which was not dose‐related at the 80 and 120 mg day− 1 doses, and which was noted to attenuate with chronic dosing. Ziprasidone was generally well tolerated. The most frequent side‐effect was mild or moderate headache. A minority of patients suffered first‐dose postural hypotension. Ziprasidone was also associated with a mild sedative effect that became less pronounced as treatment continued. There were no drug‐related changes in electrocardiogram or clinical laboratory variables that were of clinical importance.

Conclusions  Ziprasidone is characterized by a predictable pharmacokinetic profile resulting in symptoms that reflect its pharmacological action.
Ion channels and the control of blood pressure
Authors: Baker Emma H.
Published: March 2003

Ion channels exist in all cells and are enormously varied in structure, function and regulation. Some progress has been made in understanding the role that ion channels play in the control of blood pressure, but the discipline is still in its infancy. Ion channels provide many different targets for intervention in disorders of blood pressure and exciting advances have been made in this field. It is possible that new drugs, as well as antisense nucleotide technology or gene therapy directed towards ion channels, may form a new class of treatments for high and low blood pressure in the future.
The single dose pharmacokinetics of ribavirin in subjects with chronic liver disease
Authors: Glue Paul , Schenker Steven , Gupta Samir , Clement Robert P. , Zambas Demetris , Salfi Margaret
Published: March 2003

Aims  The primary objective of this study was to describe the single dose pharmacokinetics of ribavirin in subjects with normal liver function and those with various degrees of stable chronic liver disease. Additionally this study assessed the safety and tolerability of ribavirin in this population.

Methods  Single oral 600 mg doses of ribavirin were administered to healthy male and female volunteers (n = 6) and patients with stable chronic liver disease (n = 17), in a parallel group study. Pharmacokinetic sampling and tolerability assessments were performed up to 168 h post dose.

Results  Single oral doses of 600 mg ribavirin were well tolerated by healthy volunteers and patients with varying degrees of hepatic dysfunction. Although mean Cmax increased with the severity of hepatic dysfunction, there was no change in extent of absorption or renal clearance of ribavirin.

Conclusions  There are no pharmacokinetic reasons for initial dose adjustment of ribavirin in patients with hepatic dysfunction.
The completeness of medication histories in hospital medical records of patients admitted to general internal medicine wards
Authors: Lau Hong Sang , Florax Christa , Porsius Arijan J. , De Boer Anthonius
Published: March 2003

Aims
Accurate recording of medication histories in hospital medical records (HMR) is important when patients are admitted to the hospital. Lack of registration of drugs can lead to unintended discontinuation of drugs and failure to detect drug related problems. We investigated the comprehensiveness of medication histories in HMR with regard to prescription drugs by comparing the registration of drugs in HMR with computerized pharmacy records obtained from the community pharmacy.

Methods
Patients admitted to the general ward of two acute care hospitals were included in the study after obtaining informed consent. We conducted an interview on drugs used just prior to hospitalization and extracted the medication history from the HMR. Pharmacy records were collected from the community pharmacists over a 1 year period before the admission. Drugs in the pharmacy records were defined as possibly used (PU‐drugs) when they were dispensed before the admission date and had a theoretical enddate of 7 days before the admission date or later. If any PU‐drug was not recorded in the HMR, we asked the patient whether they were using that drug or not.

Results
Data were obtained from 304 patients who had an average age of 71 (range 40–92) years. The total number of drugs according to the HMR was 1239, 43 of which were not used. When compared with the pharmacy records we found an extra 518 drugs that were not recorded in the HMR but were possibly in use. After verification with the patients, 410 of these were indeed in use bringing the total number of drugs in use to 1606. The type of drugs in use but not recorded in the HMR covered a broad spectrum and included many drugs considered to be important such as cardiovascular drugs (n = 67) and NSAIDs (n = 31). The percentages of patients with 0, 1, 2, 3, 4, 5–11 drugs not recorded in the HMR were 39, 28, 16, 8, 3.6 and 5.5, respectively. Of the 1606 drugs in use according to information from all sources, only 38 (2.4%) were not retrievable in the pharmacy records when the complete year prior to hospitalization was evaluated.

Conclusions
The medication history in the hospital medical record is often incomplete, as 25% of the prescription drugs in use is not recorded and 61% of all patients has one of more drugs not registered. Pharmacy records from the community pharmacist can be used to obtain more complete information on the medication history of patients admitted to the hospital.
Intracranial haemorrhage and use of selective serotonin reuptake inhibitors
Authors: De Abajo Francisco J. , Jick Hershel , Derby Laura , Jick Susan , Schmitz Stephen
Published: March 2003

Aims
In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs.

Methods
We carried out a case‐control study nested in a cohort of antidepressants users with the UK‐based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first‐time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed‐up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression.

Results
We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10.8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0.8 (0.3,2.3). The estimate for ‘other antidepressants’ was 0.7 (0.3,1.6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid).

Conclusions
Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other antidepressants at large. However, smaller but still relevant increased risks cannot be ruled out.
A double‐blind placebo‐controlled study of the effectiveness and tolerability of oral stevioside in human hypertension
Authors: Chan Paul , Tomlinson Brian , Chen Yi‐Jen , Liu Ju‐Chi , Hsieh Ming‐Hsiung , Cheng Juei‐Tang
Published: March 2003

AimsStevioside is a natural plant glycoside isolated from the plantStevia rebaudianawhich has been commercialized as a sweetener in Japan for more than 20 years. Previous animal studies have shown that stevioside has an antihypertensive effect. This study was to designed to evaluate the effect of stevioside in human hypertension.

MethodsA multicentre, randomized, double‐blind, placebo‐controlled study was undertaken. This study group consisted of 106 Chinese hypertensive subjects with diastolic blood pressure between 95 and 110 mmHg and ages ranging from 28 to 75 years with 60 subjects (men 34, women 26; mean ± s.d., 54.1 ± 3.8 years) allocated to active treatment and 46 (men 19, women 27; mean ± s.d., 53.7 ± 4.1 years) to placebo treatment. Each subject was given capsules containing stevioside (250 mg) or placebo thrice daily and followed‐up at monthly intervals for 1 year.

ResultsAfter 3 months, the systolic and diastolic blood pressure of the stevioside group decreased significantly (systolic: 166.0 ± 9.4–152.6 ± 6.8 mmHg; diastolic: 104.7 ± 5.2–90.3 ± 3.6 mmHg,P < 0.05), and the effect persisted during the whole year. Blood biochemistry parameters including lipid and glucose showed no significant changes. No significant adverse effect was observed and quality of life assessment showed no deterioration.

ConclusionsThis study shows that oral stevioside is a well tolerated and effective modality that may be considered as an alternative or supplementary therapy for patients with hypertension.
Effect of an oral contraceptive preparation containing ethinylestradiol and gestodene on CYP3A4 activity as measured by midazolam 1′‐hydroxylation
Authors: Palovaara Sanna , Kivistö Kari T. , Tapanainen Pasi , Manninen Pekka , Neuvonen Pertti J. , Laine Kari
Published: March 2003

Aims
 To characterize the effect of an oral contraceptive (OC) containing ethinylestradiol and gestodene on the activity of CYP3A4 in vivo as measured by the 1′‐hydroxylation of midazolam.

Methods
 In this randomised, double‐blind, cross‐over trial nine healthy female subjects received either a combined OC (30 µg ethinylestradiol and 75 µg gestodene) or placebo once daily for 10 days. On day 10, a single 7.5 mg dose of midazolam was given orally. Plasma concentrations of midazolam and 1′‐hydroxymidazolam were determined up to 24 h and the effects of midazolam were measured with three psychomotor tests up to 8 h.

Results
 The combined OC increased the mean AUC of midazolam by 21% (95% CI 2% to 40%; P = 0.03) and decreased that of 1′‐hydroxymidazolam by 25% (95% CI 10% to 41%; P = 0.01), compared with placebo. The metabolic ratio (AUC of 1′‐hydroxymidazolam/AUC of midazolam) was 36% smaller (95% CI 19% to 53%; P = 0.01) in the OC phase than in the placebo phase. There were no significant differences in the Cmax, tmax, t½ or effects of midazolam between the phases.

Conclusions
 A combined OC preparation caused a modest reduction in the activity of CYP3A4, as measured by the 1′‐hydroxylation of midazolam, and slightly increased the AUC of oral midazolam. This study suggests that, at the doses used, ethinylestradiol and gestodene have a relatively small effect on CYP3A4 activity in vivo.
Pharmacokinetics of propionyl‐ l‐carnitine in humans: evidence for saturable tubular reabsorption
Authors: Pace S. , Longo A. , Toon S. , Rolan P. , Evans A. M.
Published: March 2003

Aims  Propionyl‐
l‐carnitine (PLC) is an endogenous compound which, along with
l‐carnitine (LC) and acetyl‐
l‐carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl‐
l‐carnitine hydrochloride.

Methods  This was a placebo‐controlled, double‐blind, parallel group, dose‐escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl‐
l‐carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p.l.c.

Results  All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl‐
l‐carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (± s.d.) half‐life of 1.09 ± 0.15 h, a clearance of 11.6 ± 0.24 l h−1 and a volume of distribution of 18.3 ± 2.4 l. None of these parameters changed with dose. In placebo‐treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal‐excretory clearance of PLC, which was 0.33 ± 0.38 l h−1 under baseline condition, increased (P < 0.001) from 1.98 ± 0.59 l h−1 at a dose of 1 g to 5.55 ± 1.50 l h−1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 ± 5.5% (1 g) to 50.3 ± 13.3% (8 g). The renal‐excretory clearance of LC and ALC also increased substantially after PLC administration and there was evidence for renal metabolism of PLC to LC and ALC.

Conclusions  Intravenous administration of propionyl‐
l‐carnitine hydrochloride caused significant increases in the renal excretory clearances of PLC, LC and ALC, due to saturation of the renal tubular reabsorption process – as a consequence there was a substantial increase with dose in the fraction excreted unchanged in urine. Despite the marked increase in the renal clearance of PLC, total clearance remained unchanged, suggesting a compensatory reduction in the clearance of the compound by non excretory routes.
Population PK and PK/PD modelling of microencapsulated octreotide acetate in healthy subjects
Authors: Zhou Honghui , Chen Tian‐Ling , Marino Mark , Lau Henry , Miller Thomas , Kalafsky Gaetana , McLeod James F.
Published: March 2003

Aims 
To develop a population model that can describe the pharmacokinetic profile of microencapsulated octreotide acetate in healthy cholecystectomized subjects. To investigate the correlation between serum IGF‐1 and octreotide concentration.

Methods  A population pharmacokinetic analysis was performed on octreotide data obtained following a single dose of 30 mg microencapsulated octreotide acetate intramuscularly. The relationship between serum IGF‐1 concentration and octreotide concentration was effectively described by a population pharmacokinetic/pharmacodynamic model.

Results  The pharmacokinetic profile of octreotide was characterized by an initial peak of octreotide followed by a sustained‐release of drug. Plateau concentration were sustained up to day 70, and gradually declined to below the detection limit by day 112. A one‐compartment linear model was constructed which consisted of two absorption processes, characterized by KIR and KSR, rate constants for immediate‐release and sustained‐release, respectively, with first‐order elimination (Ke; 1.05 h−1). The surface, unencapsulated drug was immediately absorbed into the central compartment with first‐order absorption (KIR; 0.0312 h−1), while the microencapsulated drug was first released in a zero‐order fashion into a depot before being absorbed into the central compartment with first‐order absorption (KSR; 0.00469 h−1) during a period of τ (1680 h). Body weight and gender were important covariates for the apparent volume of distribution. The type of formulation was an important covariate for KIR but had no effect on KSR. An inhibitory Emax population pharmacokinetic/pharmacodynamic model could adequately describe the relationship between IGF‐1 (expressed as percent baseline) and octreotide concentration. Baseline IGF‐1 concentration was found to be a significant covariate for the baseline effect (E0). A relationship between GH concentration and octreotide concentration was not established.

Conclusions  The pharmacokinetic profile of microencapsulated octreotide acetate was effectively described by the derived population model. The relationship between IGF‐1 and drug concentration could be used to guide optimization of therapeutic octreotide dosage regimens.
Responsiveness of human varicose saphenous veins to vasoactive agents
Authors: Brunner Friedrich , Hoffmann Christine , Schuller‐Petrovic Sanja
Published: March 2003

Aims  To test in vitro the constrictor and relaxation responsiveness of variously diseased segments of human saphenous vein from patients with varicose vein disease.

Methods  The vein segments were derived (i) from the inguinal saphenous vein (valvularly incompetent and slightly dilated; tissue A); (ii) from the distal end of the lower leg just above the medial ankle (competent; tissue B); (iii) from a tributary to the long saphenous vein just below the knee (dilated, incompetent and overtly varicose; tissue C). The contractile responses were tested with phenylephrine (an α‐adrenergic receptor agonist) and aescin, a clinically used phlebotonic drug derived from horse chestnut extract. Relaxant responses were tested with acetylcholine and sodium nitroprusside.

Results  Both contractile agents contracted vein segments from the inguinal and ankle area with similar potency and efficacy, but were virtually without effect in the overtly varicose segments from the calf. EC50 values (molar concentration of the agonist that produces 50% of the maximum effect) in tissues A and B were 2.9 ± 0.3 and 2.5 ± 0.5 µmol l−1 (phenylephrine) and 9.4 ± 1.0 and 15.9 ± 2.5 µmol l−1 (aescin); the corresponding maximum effects (maximum effect, percent of KCl‐induced contraction) were 76 ± 3 and 70 ± 4% (phenylephrine) and 70 ± 2 and 71 ± 3% (aescin) (P = NS in both cases for A vs B). In tissue C, the maximum effects were 5 ± 5% (phenylephrine) and 10 ± 7% (aescin) of KCl‐induced contraction (not significantly different from zero). Acetylcholine‐induced relaxation was similar for vein segments from locations A and B, whereas sodium nitroprusside was more effective in tissue B than A.

Conclusions  These findings support the notion that abnormalities within the venous wall affect venous smooth muscle contractility. Since competent and incompetent clinically normal vessels show normal contractile responses, whereas varicose vessels are not responsive to vasoactive drugs, it is likely that pharmacological treatment regimens are effective in early, but not in late stages of the disease.
The genetics of essential hypertension
Authors: O'Shaughnessy Kevin M.
Published: March 2003

Essential hypertension is an escalating problem for industrialized populations. It is currently seen as a ‘complex’ genetic trait caused by multiple susceptibility genes the effects of which are modulated by gene‐environment and gene–gene interactions. Nevertheless, the success to date in identifying these susceptibility genes has been very limited. A number of candidates has been proposed, but demonstrating consistently the linkage or association with hypertension has been problematic. The data for angiotensinogen is undoubtedly the most extensive and meta‐analysis has confirmed a significant association overall, although the risk contributed by this gene appears to be modest (odds ratio of 1.2). Identifying further genes – probably conferring even smaller attributable risks – represents a major challenge for future developments in this area. This contrasts markedly with the success that has been achieved in the past 5 years in solving the molecular genetics of a number of rare familial hypertension syndromes. The true incidences of some of these disorders may be higher than first appreciated, but it is still unclear if the genes for these syndromes also play a part in essential hypertension. A more complete understanding of the genetic basis of essential hypertension should be possible in the coming years using new strategies that take advantage of the information provided by the human genome project. This knowledge will irrevocably change the way we approach this disease in terms of its diagnosis, risk assessment for end‐points such as stroke and heart disease, and the customised treatment that might be offered in the future.
Effect of α1‐acid glycoprotein on the intracellular accumulation of the HIV protease inhibitors saquinavir, ritonavir and indinavir in vitro
Authors: Jones K. , Hoggard P. G. , Khoo S. , Maher B. , Back D. J.
Published: March 2003

Aims  Since α1‐acid glycoprotein (AGP) levels may be raised during HIV infection, we have examined in vitro the effect of increasing the concentration of AGP on the intracellular accumulation of the HIV protease inhibitors saquinavir (SQV), ritonavir (RTV) and indinavir (IDV).

Methods  U937 cells (5 × 106 cells in 5 ml RPMI growth medium) were incubated at 37 °C for 18 h with [14C]‐SQV (0.1 µCi), [3H]‐RTV and [3H]‐IDV (0.135 µCi) to a final concentration of 1 µm in the presence of 0, 0.5 and 2.0 mg ml−1 AGP. Following extraction in 60% methanol the intracellular drug concentration was determined by liquid scintillation counting.

Results  Binding to AGP (2.0 mg ml−1) reduced the mean intracellular concentration of SQV from 31.5 µm to 7.4 µm (P < 0.0001; 95% CI 19.4–28.8). RTV concentration was also reduced (8.8 µm to 1.6 µm; P < 0.0001; 95% CI 5.4–9.0) as was the concentration of IDV (3.0 µm to 1.5 µm; P < 0.0001; 95% CI 1.1–1.9).

Conclusions  Reduced intracellular protease inhibitor concentrations in the presence of increasing concentrations of AGP will certainly impact on the antiviral activity in vitro. However, since protease inhibitors are high clearance drugs, free drug concentration will likely remain unaffected in the presence of elevated AGP during chronic oral dosing although there will be an increase in total plasma drug concentration.
Systemic bioavailability of fluticasone propionate administered as nasal drops and aqueous nasal spray formulations
Authors: Daley‐Yates Peter T. , Baker Richard C.
Published: March 2003

Aims  To measure and compare the systemic bioavailability of fluticasone propionate aqueous nasal spray and a new nasal drop formulation, using a sensitive analytical method and high dose regimen.

Methods  Volunteers received four 800 µg doses of fluticasone propionate as a nasal spray or drops over 2 days, separated by an 8 h dose interval. On day 2, blood samples were collected for assay of fluticasone propionate plasma concentrations.

Results  The mean systemic exposure, for both formulations was 8.5 pg ml−1 h (drops) and 67.5 pg ml−1 h (spray). Mean absolute bioavailabilities were estimated to be 0.06% (drops) and 0.51% (spray), by reference to historical intravenous data.

Conclusions  Both formulations exhibited low systemic bioavailability, even at 12 times the normal daily dose. The bioavailability from the nasal drops was approximately eight times lower than from the nasal spray.
Concentration‐effect relationships of two infusion rates of the imidazoline antihypertensive agent rilmenidine for blood pressure and development of side‐effects in healthy subjects
Authors: De Visser S. J. , Van Gerven J. M. A. , Schoemaker R. C. , Cohen A. F.
Published: March 2003

Aims  The aim of this study was to compare the effect profiles of i.v. administered rilmenidine aimed at the same target plasma concentration, but attained with different rates.

Methods  The study was placebo‐controlled, randomized, double‐blind, double‐dummy, three‐way, cross‐over in nine healthy volunteers. All subjects randomly received either a fast infusion, a slow infusion or a placebo infusion. The target concentration was set at 8 ng ml−1 with a fivefold difference in the time to reach the maximum concentration. Saccadic eye movements, electroencephalography (EEG), blood pressure and heart rate were measured every half hour. Drug plasma concentrations, adverse events, salivary flow and visual analogue scales were obtained every hour.

Results  Changes in systolic/diastolic blood pressure at the end of the infusion were (mean ± s.d.) 13.3 ± 16.4/7.9 ± 7.5 mmHg with the fast infusion and 16.3 ± 12.7/10.2 ± 7.9 mmHg during the slow infusion, compared with 0.0 ± 13.2/1.3 ± 8.3 mmHg for the placebo occasion. Decrease of saccadic peak velocity (SPV) at the end of the infusion was 18.0 ± 5.2% during the fast infusion, 23.0 ± 7.0% with the slow infusion, and 6.1 ± 5.2% with placebo. PK/PD analysis showed similar concentration‐dependent linear reduction in SPV and blood pressure up to the maximum observed rilmenidine plasma level for both the fast and the slow infusion.

Conclusions  The rate of infusion of rilmenidine in healthy volunteers does not influence the PK/PD relationship of saccadic eye movements and blood pressure up to the maximum observed rilmenidine plasma concentrations. Rilmenidine causes clear concentration‐dependent blood pressure reductions in healthy volunteers.
Metformin does not enhance ovulation induction in clomiphene resistant polycystic ovary syndrome in clinical practice
Authors: Sturrock N. D. C. , Lannon B. , Fay T. N.
Published: March 2003

Aims To determine whether metformin pretreatment has beneficial effects in clomiphene resistant infertile women with polycystic ovary syndrome (PCOS) in an infertility clinic.

Methods This was a randomized placebo controlled double‐blind crossover study of 3 months metformin (1500 mg day−1)/placebo, followed by 3 months metformin/placebo together with clomiphene (50–100 mg for 5 days) for three cycles in clomiphene resistant women with PCOS. The primary outcomes were restoration of spontaneous menses, ovulation induction (spontaneous or clomiphene induced) and pregnancy. Secondary endpoints were changes in biochemical parameters related to androgens and insulin.

Results Twelve women completed the metformin arm and 14 the placebo arm. Spontaneous menstruation resumed in five metformin treated patients and in six placebo treated women, P=0.63. No women given metformin spontaneously ovulated, although one patient given placebo did, P=0.30. There was no difference in the efficacy of clomiphene between the two groups with ovulation being induced in five (out of 12) metformin treated women and four (out of 14) placebo treated women, P=0.63. Pregnancy occurred in three (out of 12) women given metformin and two (out of 14) women given placebo, P=0.59.

Conclusions Metformin is not always beneficial when given to clomiphene resistant infertile women with PCOS in clinical practice.