bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of lipoproteins in the plasma binding of SDZ PSC 833, a novel multidrug resistance‐reversing cyclosporin
Authors: Simon Nicolas , Dailly Eric , Combes Olivier , Malaurie Emmanuelle , Lemaire Michel , Tillement Jean‐Paul , Urien Saïk 
Published: March 2003

Aims
The plasma binding of the cyclosporin D analogue SDZ PSC 833 was investigated in vitro.
Methods
The plasma total binding constant (corresponding to the bound‐to‐free concentration or binding ratio) was determined at 37° C by the erythrocyte partitioning technique on plasma samples from three healthy volunteers and three cancer patients. Lipoproteins were also removed from plasma samples from three healthy volunteers by a standard ultracentrifugal technique.
Results
SDZ PSC 833 plasma binding was 97.8±1.1% and 97.3±0.2% in samples from three healthy volunteers and three cancer patients respectively. More than 95% of blood SDZ PSC 833 was distributed in plasma. When the original plasma samples of three individuals were delipidated, SDZ PSC 833 binding was strongly decreased (58% bound to plasma proteins) and when lipoproteins were resuspended in the delipidated plasma samples to produce varying lipoprotein plasma concentrations, the binding increased continuously with the fraction of added lipoproteins. When lipoproteins were resuspended to restore the original lipoprotein plasma content, the % plasma‐bound SDZ PSC 833 increased to 98.2%, close to the value observed with the original plasma (98.7%).
Conclusions
These results clearly indicate that SDZ PSC 833 plasma binding is mainly determined by lipoproteins and that in blood, most of SDZ PSC 833 is distributed in plasma.
Non‐linear fluvoxamine disposition
Authors: Spigset Olav , Granberg Kerstin , Hägg Staffan , Söderström Emma , Dahlqvist Rune 
Published: March 2003

Aims
To study the pharmacokinetics of fluvoxamine when given in increasing doses to healthy volunteers.
Methods
Ten healthy, non‐smoking men were given maintenance treatment with fluvoxamine for 4 weeks. Eight subjects were CYP2D6 extensive metabolisers (EMs) and two were CYP2D6 poor metabolisers (PMs). As a measure of the CYP1A2 phenotype, the paraxanthine/caffeine ratio in saliva after intake of caffeine was studied. The fluvoxamine doses given were 25 mg day−1 the first week, 50 mg day−1 the second week, 100 mg day−1 the third week and 200 mg day−1 the fourth week, divided in two daily doses. On the seventh day every week, serum concentrations of fluvoxamine were followed for a dose interval of 12 h. After discontinuation of treatment, fluvoxamine concentrations were followed for 1 week.
Results
For each of the three two‐fold increases in given dose, the mean AUC increased 3.25‐fold, 3.17‐fold and 3.14‐fold, respectively (P<0.0001), indicating a decrease in oral clearance with increasing dose. The elimination half‐life based upon the serum concentrations 12–48 h after discontinuation of fluvoxamine was 32.1±11.0 h whereas the half‐life based upon the concentrations 3–7 days after discontinuation was significantly shorter, 15.8±4.2 h (means±s.d.; P<0.001). There were no significant correlations between the CYP1A2 phenotype and fluvoxamine AUCs at different doses (r=−0.56; P=0.095 for the correlation between the paraxanthine/caffeine ratio in saliva and fluvoxamine AUC at a dose of 50 mg day−1 ). The two CYP2D6 PMs had AUC values in the same range as the EMs.
Conclusions
The present study conclusively demonstrates that fluvoxamine exhibits non‐linear kinetics within the therapeutic dose interval. The reason for non‐linearity is not Michaelis‐Menten saturation kinetics of a single metabolic pathway, but rather a complex involvement of multiple parallel pathways.
Nitric oxide: an important role in the maintenance of systemic and pulmonary vascular tone in man
Authors: Kiely David G. , Lee Alison F. C. , Struthers Allan D. , Lipworth Brian J. 
Published: March 2003

Aims
The aim of this study was to examine whether nitric oxide (NO) has an important role in maintaining basal vascular tone in normal man by examining the effects of nitric oxide inhibition using NG‐monomethyl‐l‐arginine (l‐NMMA) on systemic and pulmonary haemodynamics.
Methods
Ten normal male volunteers 26±1.6 years were studied on two separate occasions in a double‐blind, placebo controlled crossover study. They were randomised to receive either a continuous infusion of l‐NMMA (4 mg kg−1 h−1 ) with a front loaded bolus (4 mg kg−1 ) or volume matched placebo. Pulsed wave Doppler echocardiography was used to measure cardiac output (CO), mean pulmonary artery pressure (MPAP) and hence systemic vascular resistance (SVR) and total pulmonary vascular resistance (TPR). Measurements were made prior to infusion (t0 ) and after 4, 8, and 12 min (t1, t2 and t3 ).
Results
Infusion of l‐NMMA significantly increased mean arterial blood pressure (MAP), SVR and TPR and significantly reduced heart rate (HR), stroke volume (SV) and CO compared to placebo. These effects were observed at t1 and persisted during the entire infusion period.
Conclusions
These results are consistent with a role for basal nitric oxide generation in the maintenance of basal systemic and pulmonary vascular tone in normal man.
Effect of age and gender on the pharmacokinetics of eprosartan
Authors: Tenero David M. , Martin David E. , Miller Ann K. , Ilson Bernard , Boike Steven C. , Zariffa Névine , Jorkasky Diane K. 
Published: March 2003

Aims
To compare the pharmacokinetics of eprosartan between young (18–45 years) and elderly (65 years) men and between young men and young, premenopausal women (18–45 years).
Methods
Twenty‐four subjects (eight subjects/group) received a single 200 mg eprosartan oral dose followed by serial blood sampling over 24 h.
Results
Eprosartan was safe and well tolerated. There were no apparent differences in the pharmacokinetics of eprosartan between young females and young males or in the plasma protein binding of eprosartan (≈98%) for the three groups. On average, AUC (0,∞) and Cmax values were ≈2‐fold higher in elderly men than young men [AUC (0,∞) 95% CI: 1.22, 4.34; Cmax 95% CI: 0.98, 4.00]. Similarly, unbound AUC (0,∞) and Cmax values were, on average, ≈2‐fold higher in elderly men than young men [unbound AUC (0,∞) 95% CI: 1.29, 4.44; unbound Cmax 95% CI: 1.02, 4.12]. tmax was delayed in the elderly men compared with young men, with a median difference of 2.5 h (95% CI: 1.00, 3.01 h).
Conclusions
No gender differences were observed in the pharmacokinetics of eprosartan. There were ≈ two fold higher AUC and Cmax values for eprosartan observed in elderly men as compared with young men, most likely due to increased bioavailability of eprosartan in the elderly. Based on the excellent safety profile in the elderly in Phase III clinical trials (doses up to 1200 mg eprosartan) eprosartan can be safely administered to elderly hypertensive patients without an initial dose adjustment. Subsequently, the dose of eprosartan, as for other antihypertensive agents, may be individualized based on tolerability/response.
Withdrawal of peripheral vasodilators in primary care
Authors: Stewart Derek , Krska Janet , Kendle Keith , Wintour David , McGregor Campbell 
Published: March 2003

Aims
To investigate the use of peripheral vasodilators in selected practices in primary care and to observe the effect of withdrawing therapy in a sample of patients.
Methods
Patients receiving repeat prescriptions for peripheral vasodilators, identified from two practices in Grampian, were interviewed prior to and following withdrawal of therapy.
Results
Of the 35 patients, review of the continued need for therapy was documented in the medical notes of only one patient. Treatment was successfully withdrawn from 17 patients, generating considerable savings.
Conclusions
Review of peripheral vasodilators merits further attention in larger numbers of patients.
The pharmacokinetics of lamivudine in healthy Chinese subjects
Authors: Jiang J. , Hu P. , Xie H. , Chen H. , Fan F. , Harker A. , Johnson M. A. 
Published: March 2003

Aims
The purpose of this study was to investigate the pharmacokinetics of daily oral doses of lamivudine administered to healthy Chinese subjects for 1 week.
Methods
Twenty‐four subjects were enrolled, 12 males and 12 females, all between the ages of 18 and 40 years. After an overnight fast, all subjects received a single oral dose of 100 mg lamivudine. Blood was obtained before lamivudine administration and at regular intervals to 24 h post dose. Subsequent doses were given once daily for a total of 7 days. On the last day another full pharmacokinetic profile was obtained to 24 h postdose. Timed urine collections were performed for all subjects on day 1 only. Pharmacokinetic parameters were calculated by using standard non compartmental techniques.
Results
Lamivudine was well absorbed in all subjects (tmax 1 h). On day 1 and day 7 the overall geometric mean Cmax was 1304 and 1385 ng ml−1, and AUC(0,24h) was 4357 and 4353 ng ml−1 h, respectively. On average 78% of the lamivudine dose was recovered in urine as parent compound. Pharmacokinetic parameters were very similar between male and female subjects, between day 1 and day 7 and in comparison with data obtained in many other pharmacokinetic studies.
Conclusions
This study demonstrated that the pharmacokinetics of lamivudine are essentially identical between Chinese and Caucasian subjects, and between males and females. It confirms 100 mg lamivudine is an appropriate dose for use in Chinese patients, providing adequate exposure for optimal antiviral effect.
Inhibition of vasoconstriction by the thromboxane A2 antagonist GR32191B in the human radial artery
Authors: He Guo‐Wei , Yang Cheng‐Qin 
Published: March 2003

Aims
The newly revived coronary bypass graft, the radial artery (RA), is more spastic than the internal mammary artery. Thromboxane A2 is a potent vasoconstrictor for arterial grafts. This study was therefore designed to determine whether the specific thromboxane A2 (TP) receptor antagonist, GR32191B, is effective in inhibition of prostanoid or nonprostanoid receptors in the RA.
Methods
The effect of GR32191B was studied in human RA segments, taken from coronary bypass patients, in organ chambers. Two effects of GR32191B were tested: (1) the relaxation induced by GR32191B in the RA precontracted with the TP receptor agonists U46619 and PGF2α or nonprostanoid vasoconstrictors (noradrenaline [NA], angiotensin II [AII], and K+ ) and (2) the inhibitory effect of GR32191B on TP receptor agonists and nonprostanoid vasoconstrictors.
Results
In U46619 (10 nm, n=7) and PGF2α (1 μm, n=7) precontracted RA, GR32191B induced 100% relaxation (10–100 μm ) but not after precontraction with nonprostanoid stimuli (5.8% for K+, 25 mm, n=6, 24.4% for NA, 3 μm, n=8, and 53.2% for AII, 3 nm, n=5) (P<0.001). Treatment with GR32191B (30 nm ) significantly depressed the contraction with U46619 (from 160.1±11.0% to 116.8±13.1%, P<0.05) or PGF2α (from 91.3±12.3% to 42.2±9.2%, P<0.01). The contraction was further abolished by 3 μm GR32191B. However, GR32191B at 3 μm did not significantly inhibit the contraction induced by either NA, AII, or K+.
Conclusions
GR32191B is a highly potent and specific TP receptor antagonist for the human RA. It may be particularly useful in inhibiting TXA2‐mediated vasoconstriction and therefore in reducing the complications related to vasospasm in this graft.
Pharmacodynamics of milnacipran in young and elderly volunteers
Authors: Hindmarch I. , Rigney U. , Stanley N. , Briley M. 
Published: March 2003

Aims To investigate the pharmacodynamics of milnacipran in healthy young and elderly volunteers. Methods Randomized double‐blind crossover designs were employed and a standardized psychometric battery was administered pre and post dose for both studies. In the first study 10 healthy young volunteers received milnacipran 12.5 mg, 25 mg, 50 mg, 100 mg as a single dose or matched placebo. The test battery was administered at baseline and at 1, 2, 4 and 6 h post dose. The second study compared the effects of milnacipran 75 mg (50 mg+25 mg) per day, amitriptyline 50 mg (25 mg+25 mg) per day and placebo for 3 days’ dosing in healthy volunteers aged over 65 years. The test battery was administered at baseline and at 2, 10 and 24 h post dose. The psychometric battery included critical flicker fusion (CFF), choice reaction time (CRT), compensatory tracking (CTT) and tests of short‐term memory (STM), subjective sedation (LARS) and subjective sleep (LSEQ). Results Milnacipran produced no significant dose related effects in the young volunteers. For the elderly, milnacipran significantly (P<0.05) raised CFF scores compared with placebo but had no significant effects on any of the other measures used. Amitriptyline, in contrast, significantly (P<0.05) lowered CFF threshold, lengthened CRT and increased error on the CTT. On the subjective variables, LARS and LSEQ, amitriptyline increased ratings both of sedation and of difficulty in waking from sleep. Conclusions The results showed that milnacipran at single doses of up to 100 mg in healthy young volunteers is free from disruptive effects on cognitive function and psychomotor performance. In addition, milnacipran 75 mg (50+25 mg) appears to be free of negative effects on cognitive function in elderly volunteers, where it seemingly improves performance on CFF. In contrast, the tricyclic antidepressant amitriptyline, used here as a positive internal control, significantly impaired performance in the elderly on the majority of psychometric measures used in this study. This finding not only validated the sensitivity of this current test battery but also indicates the potential behavioural toxicity of amitriptyline in clinical use in the elderly.
Identification of the major human liver cytochrome P450 isoform(s) responsible for the formation of the primary metabolites of ziprasidone and prediction of possible drug interactions
Authors: Prakash C. , Kamel A. , Cui D. , Whalen R. D. , Miceli J. J. , Tweedie D. 
Published: March 2003

Aims  To identify the cytochrome P450 (CYP) isoform(s) responsible for the formation of the primary metabolite of ziprasidone (ziprasidone sulphoxide), to determine the kinetics of its formation and to predict possible drug interactions by investigating CYP isoform inhibition in an in vitro study.Methods  In vitro metabolism of [14C]‐ziprasidone was studied using human liver microsomes. The metabolites were identified using mass spectrometry. The kinetics of metabolite formation were determined using [14C]‐ziprasidone (10–200 μm) over 5 min, and Km and Vmax were estimated from Lineweaver‐Burk plots. IC50 values for the inhibition of specific probe substrates for CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4, by ziprasidone, risperidone and 9‐hydroxyrisperidone were also determined using human liver microsomes from three subjects. Mean Ki values were calculated.Results  Three CYP‐mediated metabolites – ziprasidone sulphoxide, ziprasidone sulphone and oxindole acetic acid – were identified. The apparent Km and Vmax values for the formation of the major metabolite, ziprasidone sulphoxide (measured as the sum of sulphoxide and sulphone) were 235 μm and 1.14 nmol mg− 1 protein min− 1, respectively. Isoform‐selective inhibitors and recombinant enzymes indicated that CYP3A4 is responsible for the formation of ziprasidone metabolites. Ziprasidone was not a substrate for the other isoforms studied. Similar in vitro inhibition of CYP2D6 (Ki 6.9–16 μm) and CYP3A4 (Ki 64–80 μm) was obtained with ziprasidone, risperidone and 9‐hydroxyrisperidone. The in vivo free drug concentrations associated with clinically effective doses of ziprasidone are at least 1500‐fold lower than the mean Ki for either CYP2D6 inhibition or CYP3A4 inhibition.Conclusions  Ziprasidone is predominantly metabolized by CYP3A4 in human liver microsomes and is not expected to mediate drug interactions with coadministered CYP substrates, at clinically effective doses.
Ziprasidone and the activity of cytochrome P450 2D6 in healthy extensive metabolizers
Authors: Wilner K. D. , Demattos S. B. , Anziano R. J. , Apseloff G. ,   &, Gerber N. 
Published: March 2003

Aims  To determine whether ziprasidone alters the metabolizing activity of the 2D6 isoenzyme of cytochrome P450 (CYP2D6).Methods  Twenty‐four healthy young subjects aged 18–45 years were screened for CYP2D6 metabolizing activity and shown to be extensive metabolizers of dextromethorphan. These subjects were then randomized to receive a single dose of ziprasidone 80 mg, paroxetine 20 mg or placebo, 2 h before receiving a dose of dextromethorphan. Urine samples for the determination of dextromethorphan concentrations were collected over the 8 h period following dextromethorphan dosing, and used for the determination of dextromethorphan/dextrorphan ratios. Blood samples were collected immediately before and up to 10 h after the administration of ziprasidone or paroxetine, and used to derive pharmacokinetic parameters of ziprasidone and paroxetine.Results  There were no statistically significant changes in the urinary dextromethorphan/dextrorphan ratio in the ziprasidone group or the placebo group. By contrast, there was a 10‐fold increase in the urinary dextromethorphan/dextrorphan ratio in the paroxetine group and this differed significantly from those in the ziprasidone and placebo groups (P= 0.0001).Conclusions  The findings of this study suggest that ziprasidone does not inhibit the clearance of drugs metabolized by CYP2D6.
Dose loading with delayed‐release mesalazine: a study of tissue drug concentrations and standard pharmacokinetic parameters
Authors: Hussain F. N. , Ajjan R. A. , Riley S. A. 
Published: March 2003

Aims  Tissue concentrations of 5‐aminosalicylic acid (5ASA) and its metabolites may influence the clinical course of inflammatory bowel disease. Since the factors that determine tissue drug concentrations are unknown we have studied the relationships between the oral dose of delayed‐release mesalazine, rectal tissue drug concentrations and standard pharmacokinetic parameters.Methods  Twelve healthy volunteers were studied following 7 days treatment with 1.2, 2.4 and 4.8 g of delayed‐release mesalazine daily. 5‐aminosalicylic acid and N‐acetyl 5‐aminosalicylic acid concentrations were measured in serum, urine, stool and rectal tissue biopsies.Results  Serum concentrations and 24 h urinary excretion of 5ASA and N‐acetyl 5ASA increased as the oral dose of mesalazine was increased from 1.2 g through 2.4 g to 4.8 g daily (serum area under curve (AUC):5ASA = 3.9, 15.4 and 46.8 µg ml−1 h, P < 0.0001; N‐acetyl 5ASA = 17.2, 30.9 and 57.8 µg ml−1 h, P < 0.0001: urinary excretion: 5ASA = 1.8, 85.5 and 445 mg, P < 0.0001; N‐acetyl 5ASA = 250, 524 and 1468 mg, P < 0.0001, respectively). Faecal 5ASA excretion increased as the oral dose increased from 1.2 g to 2.4 g but did not increase further with 4.8 g daily dosing whereas faecal N‐acetyl 5ASA excretion was similar at all three doses. Rectal tissue concentrations of 5ASA increased markedly, and N‐acetyl 5ASA increased modestly, as the dose of oral mesalazine increased from 1.2 g to 2.4 g daily but neither increased further with 4.8 g daily dosing.Conclusions  The relationship between the ingested dose of delayed‐release mesalazine and rectal tissue drug concentrations is complex. Factors other than dose are likely to be important determinants of rectal tissue drug concentrations.
Dutch Hospital Drug Formularies: pharmacotherapeutic variation and conservatism, but concurrence with national pharmacotherapeutic guidelines
Authors: Fijn R. , Engels S. A. G. , Brouwers, J. R. B. J. , Knaap R. J. , De Jong L. T. W. , Van den Berg ‐ 
Published: March 2003

Aims
This research examines current hospital drug formularies (HDFs) of all Dutch general hospitals. It assesses the extent to which they recommend the same drugs, the breadth of their coverage in terms of therapeutic areas, drug groups incorporated and individuals drugs included, and their extent of conservatism by considering the year of introduction of the drugs included within groups. Furthermore, it considers the extent to which their recommendations concur and comply with those of national pharmacotherapeutic guidelines and the WHO Essential Drugs List (EDL).
Methods
Seventy‐eight (81%) out of all 96 current Dutch HDFs were received of which 62 were suitable for study. Differences between HDFs and eventual associations with hospital characteristics were researched by statistical testing and case‐control studies. To evaluate HDFs’ concurrence with national guidelines and compliance with the WHO EDL, nine drug groups were studied in detail: benzodiazepines, calcium channel blockers, β‐adrenoceptor blocking agents, ACE‐inhibitors, angiotensin‐II inhibitors, NSAIDs, H2‐receptor antagonists, 5HT3‐antagonists, and H+‐pump inhibitors. Concurrence and compliance with national guidelines and the WHO EDL was defined as inclusion of recommended drugs. Non‐concurrence was defined as inclusion of nonrecommended drugs.
Results
The total number of indications addressed and drug groups incorporated within HDFs varied from 28 to 72 (median 56) and from 30 to 123 (median 97), respectively. The total number of individual drug entities (pharmacological substances) included ranged from 239 to 658 (median 430) and the total number of drug products, including all different dosage forms, from 412 to 1121 (median 655). Within drug groups, drug entities first marketed were most frequently included. Teaching hospitals were most likely to include recently marketed drugs. Depending on the drug group, HDFs’ concurrence and compliance with national guidelines and the WHO EDL ranged from 35% to 100%.
Conclusions
Findings indicate that Dutch HDFs are rather uniform in the indications addressed and the drug groups incorporated. However, the number of individual drug entities and drug products included within groups varies considerably. Furthermore, Dutch HDFs are considered rather conservative, as older drugs are favoured over more recent drugs. Generally, with some drug exceptions, Dutch HDFs concur and comply with recommendations in national pharmacotherapeutic guidelines and with the WHO EDL over 90%.
Antidepressants in the elderly: challenges for study design and their interpretation
Authors: Parikh C. 
Published: March 2003

Drug treatment of depressive illness in the elderly differs from that in younger patients and there is no clear consensus as to first line treatment in the former. Nor is it possible to extrapolate directly from studies in younger patients to the elderly with these agents. Whilst there are over two dozen antidepressants currently marketed in the U.K., most studies have been on younger adults and have excluded very old and frail patients. Design short‐comings of the few trials conducted in elderly patients do not allow accurate interpretation of differences in efficacy or safety between drugs.This paper identifies key deficiencies in the evidence currently available in support of both older and newer antidepressant agents and makes the proposal that specific studies are required in the elderly to determine the efficacy and safety of antidepressants in the treatment of depressive illness. It outlines a Phase II and III clinical trial programme which could be used to provide adequate evidence of efficacy and safety of new agents and which conforms to current European guidelines. Dose finding studies, short‐term efficacy, prevention of relapse (continuation therapy) and prevention of recurrence (maintenance therapy) studies are discussed as are key issues to be addressed in the trial protocol.