bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetic‐pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis
Authors: Angus B. J. , Smith M. D. , Suputtamongkol Y. , Mattie H. , Walsh A. L. , Wuthiekanun V. , Chaowagul W. , White N. J.
Published: March 2003

Aims  Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta‐lactam antibiotics for serious Gram‐negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis.

Methods  Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg−1 8 hourly by bolus injection or 4 mg kg−1 h−1 by constant infusion following a 12 mg kg−1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters.

Results  Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l−1, giving a target concentration CT, of 8 mg l−1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half‐lives of ceftazidime were 0.468 (0.241–0.573) l kg−1, 0.058 (0.005–0.159) l kg−1 h−1 and 7.74 (1.95–44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0.71; P < 0.001) and there was no evidence of significant nonrenal clearance.

Conclusions  Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance =k* creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg−1 (1.9–4.6) and infusion rate I = 0.46 mg kg h−1 (0.04–1.3) (which equals 14.8 mg kg−1 day−1). A nomogram for adjustment in renal failure is given.
Pharmacokinetics and tolerability of intravenous infusion of adenosine (SUNY4001) in healthy volunteers
Authors: Uematsu Toshihiko , Kozawa Osamu , Matsuno Hiroyuki , Niwa Masayuki , Yoshikoshi Hirofumi , Oh‐uchi Mikio , Kohno Ken‐ichi , Nagashima Satoru , Kanamaru Mitsutaka
Published: March 2003

Aims
To examine the tolerability and disposition of i.v. adenosine (SUNY4001) in healthy male Japanese volunteers.

Methods
SUNY4001 was infused i.v. for 6 min at 0 (placebo), 60, 100, 120 and 140 µg kg−1 min−1 in a dose‐escalating manner in 30 healthy subjects. Adenosine and its metabolites were determined in the plasma and urine.

Results
Only plasma hypoxanthine was increased from 3 min during until 5–10 min after SUNY4001 infusion at the higher rates without any significant dose‐related changes in plasma adenosine, inosine, xanthine or uric acid, or in urinary adenosine and all metabolites compared with the placebo. There was a dose‐related increase in the incidence of subjective symptoms such as heat sensation, flushed face, dyspnoea, chest discomfort, etc. Transient and self‐subsiding episodes of second‐degree atrioventricular block were found in two subjects each at the higher doses.

Conclusions
Adenosine infusion at ≤ 140 µg kg−1 min−1 was concluded to be generally well tolerated.
Muscular and cardiorespiratory effects of pseudoephedrine in human athletes
Authors: Gill Nicholas D. , Shield Anthony , Blazevich Anthony J. , Zhou Shi , Weatherby Robert P.
Published: March 2003

Aims
Pseudoephedrine (PSE) is a readily available over‐the‐counter nasal decongestant which is structurally similar to amphetamine and is included on the International Olympic Committee's list of banned substances. However to date, little research has supported its putative ergogenic effect. This study investigated whether a 180 mg dose of PSE ingested 45 min prior to exercise enhanced short‐term maximal exercise performance and/or altered related physiological variables.

Methods
A randomised, double‐blind, crossover study in 22 healthy male athletes.

Results
Maximum torque (mean ± s.d., n = 22) produced in an isometric knee extension exercise was 321.1 ± 62.0 Nm (PSE) and 295.7 ± 72.4 Nm (placebo), and peak power obtained on the ‘all‐out’ 30 s cycle test was 1262.5 ± 48.5 W (PSE) and 1228.4 ± 47.1 W (placebo) (P < 0.01, P < 0.03, respectively). Subjects were estimated to be producing 96.9 ± 2.4% of their maximal possible isometric leg extension force after PSE ingestion, but only 95.3 ± 2.4% when PSE was not ingested. Bench press tasks and total work during the cycle test were not affected by the ingestion of PSE. Lung function was altered following ingestion of PSE (P < 0.05) with FEV1 and FVC significantly increased (P < 0.02, P < 0.01, respectively) although the FEV1/FVC ratio was not altered. Heart rate was significantly elevated by the ingestion of PSE immediately following the 30 s cycle sprint (P < 0.01) however, lactate concentration was not altered by the ingestion of PSE.

Conclusions
The administration of a 180 mg dose of PSE increased maximum torque, produced in an isometric knee extension and produced an improvement in peak power during maximal cycle performance, as well as improving lung function.
Identification of the cytochrome P450 enzymes involved in the N‐demethylation of sildenafil
Authors: Hyland R. , Roe E. G. H. , Jones B. C. , Smith D. A.
Published: March 2003

Aims  To characterize the cytochrome P450 (CYP) enzymes responsible for the N‐demethylation of sildenafil to its main metabolite, UK‐103 320, to investigate the potential inhibitory effects of sildenafil on CYP enzymes and to evaluate the potential of selected drugs to affect sildenafil metabolism.

Methods  The metabolic pathways of sildenafil N‐demethylation were studied using human liver microsomes, as well as microsomes expressing individual human CYP enzymes. Further studies to identify the individual enzymes were performed at 2.5 and 250 µm sildenafil, and employed a combination of chemical inhibition, correlation analysis, and metabolism by expressed recombinant CYP enzymes. In addition, the effect of sildenafil on the activity of the six major drug metabolizing enzymes was investigated.

Results  Sildenafil conversion was found to be mediated by at least two CYP enzymes, for which the mean kinetic parameters were Km1 = 6(±3 µm), Km2 = 81(±45 µm), Vmax1 = 22(±9 pmol) and Vmax2 = 138(±77 pmol) UK‐103 320 formed min−1 mg−1. At 250 µm sildenafil, N‐demethylation was primarily mediated through the low‐affinity, high‐Km enzyme (approximately 83%), whilst at 2.5 µm there was a greater role for the high‐affinity, low‐Km enzyme (approximately 61%). Ketoconazole strongly inhibited metabolism at both sildenafil concentrations and was the only significant inhibitor at 250 µm sildenafil. At the lower sildenafil concentration, sulphaphenazole and quinidine also inhibited formation of UK‐103 320. Overall, 75% or more of the N‐demethylation of sildenafil at any concentration is probably attributable to CYP3A4. These results were supported by experiments using expressed human CYP enzymes, in which only CYP3A4 and CYP2C9 exhibited substantial sildenafil N‐demethylase activity (respective Km values of 221 µm and 27 µm). Sildenafil metabolism was inhibited by potent CYP3A4 inhibitors which are used clinically, but was found to be only a weak inhibitor of drug metabolizing enzymes itself, the strongest inhibition occurring against CYP2C9 (Ki = 80 µm).

Conclusions  Evidence is provided for CYP3A4 and to a lesser extent CYP2C9‐mediated metabolism of sildenafil. There is the possibility that elevated plasma concentrations of sildenafil could occur with coadministration of known inhibitors of CYP2C9 or CYP3A4. Since peak plasma concentrations of clinical doses of sildenafil are only 200 ng ml−1 (∼0.4 µm) it is very unlikely that sildenafil will significantly alter the plasma concentration of other compounds metabolized by cytochrome P450 enzymes.
Population pharmacokinetics of thioTEPA and its active metabolite TEPA in patients undergoing high‐dose chemotherapy
Authors: Huitema Alwin D. R. , Mathôt Ron A. A. , Tibben Matthijs M. , Schellens, Jan H. M. , Rodenhuis Sjoerd , Beijnen Jos H.
Published: March 2003

Aims  To study the population pharmacokinetics of thioTEPA and its main metabolite TEPA in patients receiving high‐dose chemotherapy consisting of thioTEPA (80–120 mg m−2 day−1), cyclophosphamide (1000–1500 mg m−2 day−1) and carboplatin (265–400 mg m−2 day−1) for 4 days.

Methods  ThioTEPA and TEPA kinetic data were processed with a two‐compartment model using the nonlinear mixed effect modelling program NONMEM. Interindividual variability (IIV), interoccasion variability (IOV) and residual variability in the pharmacokinetics were estimated. The influence of patient characteristics on the pharmacokinetics was also determined.

Results  A total number of 40 patients receiving 65 courses of chemotherapy was included. Clearance of thioTEPA (CL) was 34 l h−1 with an IIV and IOV of 18 and 11%, respectively. The volume of distribution of thioTEPA was 47 l (IIV = 7.5%; IOV = 19%). The fraction of thioTEPA converted to TEPA divided by the volume of distribution of TEPA was 0.030 l−1 (IIV = 39%; IOV = 32%) and the elimination rate constant of TEPA was 0.64 h−1 (IIV = 27%; IOV = 32%). CL of thioTEPA was correlated with alkaline phosphatase and serum albumin. The volume of distribution of thioTEPA and the elimination rate constant of TEPA were correlated with total protein levels and body weight, respectively.

Conclusions  A model for the description of the pharmacokinetics of thioTEPA and TEPA was developed. Factors involved in the interpatient variability of thioTEPA and TEPA pharmacokinetics were identified. Since, IOV of both thioTEPA and TEPA was equal to or smaller than IIV, therapeutic drug monitoring based on data of previous courses may be meaningful using this population model.
Pharmacokinetics and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, following chronic infusion in healthy subjects
Authors: Dingemanse Jasper , Clozel Martine , Van Giersbergen Paul L. M.
Published: March 2003

Aims  The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of tezosentan, an intravenous dual endothelin receptor antagonist, during chronic infusions in healthy male subjects.

Methods  Tezosentan was infused at a rate of 100 mg h−1 for 6 h (study A, six subjects) and at a rate of 5 mg h−1 for 72 h (study B, eight subjects). Both studies had a randomized, placebo‐controlled, double‐blind design. Tolerability and safety were monitored by the recording of vital signs, ECG, adverse events and clinical laboratory parameters. Blood samples were collected frequently for pharmacokinetic determinations and measurement of plasma endothelin‐1 concentrations.

Results  In both studies tezosentan was well tolerated with headache the most frequently reported adverse event (incidence of 75–100% for tezosentan and 50% for placebo). Plasma concentrations of tezosentan rapidly approached steady state (3000 and 125 ng ml−1 in study A and B, respectively) and did not change upon prolonged infusion. A two‐compartment model could describe its pharmacokinetic profile. The half‐lives of the two disposition phases were approximately 0.10 and 3.2 h. Endothelin‐1 concentrations increased rapidly 11‐ and 2‐fold compared with pre‐dose values in study A and B, respectively, during infusion of tezosentan and did not change during the 72 h infusion.

Conclusions  On the basis of these results, dose finding studies with tezosentan in acute heart failure can be initiated in the dose range 5–100 mg h−1.
Pharmacokinetics of the antianginal agent perhexiline: relationship between metabolic ratio and steady‐state dose
Authors: Sallustio Benedetta C. , Westley Ian S. , Morris Raymond G.
Published: March 2003

Aims  1) To develop an estimate of oral clearance ( /F) for the antianginal agent perhexiline based on the ratio of cis‐OH‐perhexiline metabolite/parent perhexiline plasma concentrations at steady‐state

. 2) To determine whether the ratio measured in the first fortnight of treatment

may be used to guide patient dosing with perhexiline, a drug with a narrow therapeutic index, long half‐life and saturable metabolism via CYP2D6.

Methods  Two retrospective studies were conducted reviewing patient records and data obtained from routine monitoring of plasma perhexiline and cis‐OH‐perhexiline concentrations.

Results  Study 1 (n=70). At steady‐state, the frequency distributions of

/F and

/ were consistent with CYP2D6 metabolism. Putative poor metabolizers (approximately 8%) were identified by

/F≤50 ml min−1 or

/≤0.3. A group of patients with

/F≥950 ml min−1 may have been ultra‐rapid metabolizers. In this group, the high

/F values suggest extensive first‐pass metabolism and poor bioavailability. In patients with therapeutic plasma perhexiline concentrations (0.15–0.60 mg l−1), the variability in dose appeared directly proportional to

/F (r2=0.741, P<0.0001). Study 2 (n=23). Using

/ patients were tentatively identified as poor, extensive and ultra‐rapid metabolizers, with

/F of 23–72, 134–868 and 947–1462 ml min−1, respectively, requiring doses of 10–25, 100–250 and 300–500 mg day−1, respectively.

Conclusions  The cis‐OH‐perhexiline/perhexiline concentration ratio may be useful for optimizing individual patient treatment with the antianginal agent perhexiline.
Dose–response relationships between individual nonaspirin nonsteroidal anti‐inflammatory drugs (NANSAIDs) and serious upper gastrointestinal bleeding: a meta‐analysis based on individual patient data
Authors: Lewis S. C. , Langman M. J. S. , Laporte Joan‐Ramon , Matthews John N. S. , Rawlins Michael D. , Wiholm Bengt‐Erik
Published: March 2003

Aims
To define by amalgamation of data obtained in contemporaneous case‐control studies, the risks associated with individual nonaspirin nonsteroidal anti‐inflammatory drugs (NANSAIDs) according to doses used.

Methods
Meta‐analysis of individual patient data from three retrospective case‐control studies using similar data collection protocols was carried out in hospitals in Catalonia, England, Scotland and Sweden. 2472 cases of upper gastrointestinal bleeding and 5877 controls were studied. Main outcome measures were risks associated with individual NANSAIDs according to dose used and the period of time for which they were given.

Results
Ibuprofen showed the lowest odds ratio (OR = 1.7; 95% confidence interval 1.1, 2.5), followed by diclofenac (4.9; 3.3, 7.1), indomethacin (6.0; 3.6, 10.0), naproxen (9.1; 6.0–13.7), piroxicam (13.1; 7.9–21.8) and ketoprofen (34.9; 12.7, 96.5). Striking dose–response relationships were seen with four to eight‐fold increases in risk within conventionally used dose ranges for all except ketoprofen, where numbers were too few to allow dose analysis. Across the class, risk was highest during the first week of use (11.7; 6.5, 21.0), decreased thereafter with continuing use (5.6; 4.6, 7.0), and fell to 3.2 (2.1, 5.1) 1 week after discontinuing use. Concurrent use of more than one NANSAID substantially increased risk.

Conclusions
The risk of upper gastrointestinal bleeding with NANSAIDs varies twenty‐fold depending on the drug, and by three to seven‐fold depending on the dose chosen. Risk is maximal during the first week and decreases thereafter. Paracetamol (acetaminophen) is not associated with upper gastrointestinal bleeding at any dose and should be the first‐line analgesic wherever possible.
The pharmacological treatment of schizophrenia in Chinese patients: a comparison of prescription patterns between 1996 and 1999
Authors: Ungvari Gabor S , Chung Yiu Gar , Chee Yip Ka , Fung‐Shing Ng , Kwong Tang Wai , Chiu Helen F. K.
Published: March 2003

Aims
In 1996 a Hong Kong‐wide survey of pharmacological treatment for schizophrenic inpatients identified a few idiosyncratic prescription patterns that were not consistent with international standards. In the context of continuous quality assurance, the survey was repeated in 1999 to monitor trends in the pharmacotherapy of schizophrenia and to identify changes in prescribing practices. It was expected that the widespread introduction of novel antipsychotic drugs coupled with continuing medical education would favourably alter prescribing habits.

Methods
A representative random sample of 1202 schizophrenic patients from all inpatient settings in Hong Kong was surveyed. Basic socio‐demographic data and a list of all psychotropic medication taken on census day were collected.

Results  
Significant  improvement  was  noted  in  several  aspects  of  pharmacotherapy in   1999   as   compared   with   1996.   The   total   daily   dosage   of   antipsychotic   drugs decreased from 716 ± 627 to 561 ± 482 mg day−1 chlorpromazine equivalent (CPZeq) (Mann–Whitney U‐test; Z = −3.906, P = 0.000; 95% confidence interval [CI] = 70.0, 240.2 mg day−1 CPZeq), for acute patients and from 923 ± 809 to 675 ± 545 mg day−1 CPZeq (Mann–Whitney U‐test; Z=−5.036, P = 0.000; 95% CI = 175.57, 321.63 mg day−1 CPZeq) for chronic patients. The percentage of patients coprescribed antipsychotics and an antiparkinson drug significantly decreased from 67.8% to 61.8% (χ2 = 5.558, P = 0.018) in the chronic schizophrenia group. The percentage of patients taking atypical antipsychotic medication increased significantly from 5.5% to 19.2% (χ2 = 27.14, P = 0.000) in the acute and 3.4% to 12.3% (χ2 = 27.76, P = 0.000) in the chronic group.

Conclusions
Repeated surveys of prescribing practices proved to be a useful tool to demonstrate trends in the pharmacological treatment of schizophrenia. Our findings suggest that the widespread use of atypical antipsychotic drugs contributed to a more rational pharmacotherapy for schizophrenia.
St John's wort (Hypericum perforatum): drug interactions and clinical outcomes
Authors: Henderson L. , Yue Q. Y. , Bergquist C. , Gerden B. , Arlett P.
Published: March 2003

Aims
The aim of this work is to identify the medicines which interact with the herbal remedy St John's wort (SJW), and the mechanisms responsible.

Methods
A systematic review of all the available evidence, including worldwide published literature and spontaneous case reports provided by healthcare professionals and regulatory authorities within Europe has been undertaken.

Results
A number of clinically significant interactions have been identified with prescribed medicines including warfarin, phenprocoumon, cyclosporin, HIV protease inhibitors, theophylline, digoxin and oral contraceptives resulting in a decrease in concentration or effect of the medicines. These interactions are probably due to the induction of cytochrome P450 isoenzymes CYP3A4, CYP2C9, CYP1A2 and the transport protein P‐glycoprotein by constituent(s) in SJW. The degree of induction is unpredictable due to factors such as the variable quality and quantity of constituent(s) in SJW preparations. In addition, possible pharmacodynamic interactions with selective serotonin re‐uptake inhibitors and serotonin (5‐HT1d) receptor‐agonists such as triptans used to treat migraine were identified. These interactions are associated with an increased risk of adverse reactions.

Conclusions
In Sweden and the UK the potential risks to patients were judged to be significant and therefore information about the interactions was provided to health care professionals and patients. The product information of the licensed medicines involved has been amended to reflect these newly identified interactions and SJW preparations have been voluntarily labelled with appropriate warnings.
Pharmacokinetic modelling of morphine, morphine‐3‐glucuronide and morphine‐6‐glucuronide in plasma and cerebrospinal fluid of neurosurgical patients after short‐term infusion of morphine
Authors: Meineke Ingolf , Freudenthaler Stefan , Hofmann Ute , Schaeffeler Elke , Mikus Gerd , Schwab Matthias , Prange Hilmar W. , Gleiter Christoph H. , Brockmöller J.
Published: March 2003

Aims Concentrations in the cerebrospinal fluid (CSF) are a useful approximation to the effect site for drugs like morphine. However, CSF samples, are available only in rare circumstances. If they can be obtained they may provide important insights into the pharmacokinetics/pharmacodynamics of opioids.

Methods Nine neurological and neurosurgical patients (age 19–69 years) received 0.5 mg kg−1 morphine sulphate pentahydrate as an intravenous infusion over 30 min. Plasma and CSF were collected for up to 48 h. Concentration time‐course and interindividual variability of morphine (M), morphine‐3‐glucuronide (M3G) and morphine‐6 glucuronide (M6G) were analysed using population pharmacokinetic modelling.

Results While morphine was rapidly cleared from plasma (total clearance = 1838 ml min−1 (95% CI 1668, 2001 ml min−1)) the glucuronide metabolites were eliminated more slowly (clearance M3G = 44.5 ml min−1 (35.1, 53.9 ml min−1), clearance M6G = 42.1 ml min−1 (36.4, 47.7 ml min−1)) and their clearance could be described as a function of creatinine clearance. The central volumes of distribution were estimated to be 12.7 l (11.1, 14.3 l) for morphine. Transfer from the central compartment into the CSF was also rapid for M and considerably slower for both glucuronide metabolites. Maximum concentrations were achieved after 102 min (M), 417 min (M3G) and 443 min (M6G). A P‐glycoprotein exon 26 polymorphism previously found to be linked with transport activity could be involved in CSF accessibility, since the homozygous mutant genotype was associated (P < 0.001) with high maximum CSF concentrations of M but not M3G or M6G.

Conclusions From the population pharmacokinetic model presented, CSF concentration profiles can be derived for M, M3G and M6G on the basis of dosing information and creatinine clearance without collecting CSF samples. Such profiles may then serve as the link between dose regimen and effect measurements in future clinical effect studies.
Quantification of heparin‐induced TFPI release: a maximum release at low heparin dose
Authors: Kemme Michiel J. B. , Burggraaf Jacobus , Schoemaker Rik C. , Kluft Cornelis , Cohen Adam F.
Published: March 2003

Aims Heparin releases tissue factor pathway inhibitor (TFPI) from the endothelium and this release may decrease after repeated high dose heparin administration. The primary aim was to investigate and quantify this phenomenon during a short low dose heparin infusion. Also, the effects of heparin on tissue plasminogen activator (t‐PA) were studied.

Methods Nine healthy, nonsmoking, male volunteers (range 19–23 years) received a continuous heparin infusion (2000 IU) over 40 min. The endothelial TFPI release rate was estimated from the total TFPI concentration profile using a pharmacokinetic model.

Results   Mean  ± s.d.  total  and  free  TFPI  increased  from  62.9 ± 9.4/8.3 ± 2.1 ng ml−1 at baseline to 237.2 ± 40.9/111.0 ± 19.9 ng ml−1 after 40 min infusion. The relationship between heparin concentration (anti‐IIa activity) and TFPI concentration followed a maximum effect model and a clockwise loop (proteresis) was observed. The TFPI release rate rapidly increased to maximum of 200 ± 45 µg min−1 after 17.5 min heparin infusion but did not increase further although heparin concentrations further doubled. In contrast to TFPI, t‐PA antigen decreased from 5.6 ± 1.0 at baseline to 4.5 ± 1.0 ng ml−1 at the end of infusion (t = 40 min) (difference of 1.1 ng ml−1 (95% confidence interval; 0.9, 1.3).

Conclusions Our application of concentration‐effect models and pharmacokinetic principles to these haemostatic variables showed that endothelial TFPI release has a maximum that is already reached at low heparin dose, corresponding with an anti‐IIa activity of 0.08 IU ml−1. The relationship between anti‐IIa activity and TFPI release rate showed signs of acute tolerance (clockwise loop) indicating exhaustion of endothelial TFPI pools. These findings may be of importance for the heparin dose used in conditions such as unstable angina, in which the favourable effects of heparin have been ascribed to its ability to release TFPI.
Lack of effect of ketoconazole on the pharmacokinetics of rosuvastatin in healthy subjects
Authors: Cooper Kelvin J. , Martin Paul D. , Dane Aaron L. , Warwick Mike J. , Raza Ali , Schneck Dennis W.
Published: March 2003

Aims  To examine in vivo the effect of ketoconazole on the pharmacokinetics of rosuvastatin, a 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor.

Methods  This was a randomized, double‐blind, two‐way crossover, placebo‐controlled trial. Healthy male volunteers (n = 14) received ketoconazole 200 mg or placebo twice daily for 7 days, and rosuvastatin 80 mg was coadministered on day 4 of dosing. Plasma concentrations of rosuvastatin, and active and total HMG‐CoA reductase inhibitors were measured up to 96 h postdose.

Results  Following coadministration with ketoconazole, rosuvastatin geometric least square mean AUC(0,t) and Cmax were unchanged compared with placebo (treatment ratios (90% confidence intervals): 1.016 (0.839, 1.230), 0.954 (0.722, 1.260), respectively). Rosuvastatin accounted for essentially all of the circulating active HMG‐CoA reductase inhibitors and most (> 85%) of the total inhibitors. Ketoconazole did not affect the proportion of circulating active or total inhibitors accounted for by circulating rosuvastatin.

Conclusions  Ketoconazole did not produce any change in rosuvastatin pharmacokinetics in healthy subjects. The data suggest that neither cytochrome P450 3A4 nor P‐gp‐mediated transport contributes to the elimination of rosuvastatin.
Pharmacokinetic interaction between amprenavir and delavirdine after multiple‐dose administration in healthy volunteers
Authors: Justesen Ulrik S. , Klitgaard Niels A. , Brosen Kim , Pedersen Court
Published: March 2003

Aims  To evaluate the safety and the pharmacokinetic interaction between amprenavir and delavirdine after multiple dose administration in healthy volunteers.

Methods  This was a prospective, open‐label, randomized, controlled, two‐sequence, two‐period multiple dose study with 18 healthy subjects. Volunteers were randomly assigned to amprenavir, 600 mg twice a day, or delavirdine, 600 mg twice a day, for 10 days, followed by both drugs for another 10 days with pharmacokinetic evaluation on day 10 and day 20. Adverse events were recorded throughout the study.

Results  Amprenavir decreased all the delavirdine pharmacokinetic parameters apart from tmax. Delavirdine C12h dropped from 7916 to 933 ng ml−1 (median decrease 5930 ng ml−1, 95% CI 3013, 8955 ng ml−1). A decrease in amprenavir t½ was also seen leading to almost identical median amprenavir C24h values. No serious clinical adverse events were observed during the study. The most frequently reported effects were gastrointestinal symptoms, headache, fatigue and rash.

Conclusions  Amprenavir is an effective inducer of delavirdine metabolism, probably through its effect on hepatic CYP3A4. This could have consequences in other drug‐drug interaction situations. Delavirdine is an inhibitor of amprenavir metabolism. The regimen of amprenavir 600 mg and delavirdine 600 mg twice a day is not recommended when an antiretroviral effect from delavirdine is required.
Pharmacokinetics, food intake requirements and tolerability of once‐daily combinations of nelfinavir and low‐dose ritonavir in healthy volunteers
Authors: Aarnoutse R. E. , Droste J. A. H. , Van Oosterhout J. J. G. , Koopmans P. P. , Popescu M. , Reiss P. , Hekster Y. A. , Burger D. M.
Published: March 2003

Aims This study was performed to evaluate the steady‐state pharmacokinetics, food intake requirements and short‐term tolerability of once‐daily combinations of nelfinavir and low‐dose ritonavir.

Methods Twenty‐seven healthy volunteers were randomized over three groups to receive a once‐daily regimen of nelfinavir/ritonavir 2000/200 mg (group 1), 2000/400 mg (group 2) or 2500/200 mg (group 3) with food for 14 days. Pharmacokinetic parameters for nelfinavir and its active metabolite M8 were assessed on study days 15 and 16, after administration of the regimens with a full (610 kcal) or light (271 kcal) breakfast, respectively.

Results Pharmacokinetic data were evaluable for eight volunteers in group 1, eight in group 2 and four in group 3. Administration of nelfinavir/ritonavir with a full breakfast resulted in geometric mean (GM) nelfinavir AUC24h values of 76.8, 51.3, and 61.9 h*mg/l in group 1, 2 and 3, respectively. GM 24‐h Cmin concentrations of nelfinavir were 0.76 mg l−1, 0.43 mg l−1 and 0.47 mg l−1, respectively. Co‐administration of ritonavir increased M8 concentrations more than nelfinavir concentrations, resulting in GM AUC24h and Cmin values for nelfinavir plus M8 that were higher than or comparable to reference values for the approved regimen of nelfinavir (1250 mg BID without ritonavir). In the 2000/200 mg group, seven out of eight subjects had a Cmin value of nelfinavir plus M8 above a threshold of 1.0 mg l−1. Administration of the combinations with a light breakfast resulted in significant decreases in the AUC24h and Cmin of nelfinavir and nelfinavir plus M8, compared with intake with a full breakfast. For the Cmin of nelfinavir plus M8, the GM ratio (light/full breakfast) was 0.76 (90% confidence interval 0.67–0.86, participants from all groups combined). Short‐term tolerability was satisfactory, apart from a higher than expected incidence of mild rash (12%).

Conclusions Administration of nelfinavir in a once‐daily regimen appears feasible. A nelfinavir/ritonavir 2000/200 mg combination appears appropriate for further evaluation. Once‐daily nelfinavir/ritonavir should be taken with a meal containing at least 600 kcal.
Apocrine acrosyringeal keratosis in association with syringocystoadenoma papilliferum
Authors: Kishimoto S. , Wakabayashi S. , Yamamoto M. , Noda Y. , Takenaka H. , Yasuno H.
Published: March 2003

We report the clinical and histopathological features of a keratosis that developed in association with syringocystadenoma papilliferum. This tumour shows a pinkish, pedunculated, spherical nodule with a cerebriform surface and visible keratinous plugs. In addition to the typical features of syringocystadenoma papilliferum, the tumour shows many hyperkeratotic columns surrounded by acanthotic epidermis with the characteristics of trichilemmal keratinization and keratohyalin granules. This keratosis seems to be derived from the middle to lower portion of the apocrine acrosyringium, based on the distribution of keratohyalin granules and the direct connection with the apocrine acrosyringium in an early lesion. Accordingly, we propose to identify this rare keratosis as apocrine acrosyringeal keratosis.
Megakaryocyte progenitors derived from bone marrow or G‐CSF‐mobilized peripheral blood CD34+ cells show a distinct phenotype and responsiveness to interleukin‐3 (IL‐3) and PEG‐recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF)
Authors: Catani Lucia , Gugliotta Luigi , Campanini Elena , Mangianti Serena , Gibellini Davide , Baravelli Stefano , Vianelli Nicola , Lemoli Roberto Massimo , Tura Sante
Published: March 2003

In the present study we investigated the proliferative response of megakaryocyte progenitor cells (CFU‐MK) derived from peripheral blood stem cell (PBSC) collections of patients with haematological malignancies and normal donors. Highly purified CD34+ cells and mononuclear cell fractions were assayed in the presence of recombinant interleukin‐3 (IL‐3) and pegylated‐recombinant human megakaryocyte growth and development factor (PEG‐rHuMGDF), alone or in combination, and megakaryocyte colony formation was evaluated in the plasma clot. In comparison, steady‐state bone marrow samples from normal donors were highly enriched in CD34+ cells and tested with the cytokines studied. Our results showed that IL‐3 was able to stimulate CFU‐MK colony formation from bone marrow and peripheral blood CD34+ cells. Similarly, PEG‐rHuMGDF stimulated, in a dose–response manner, CD34+ cells from the bone marrow. However, normal mobilized peripheral blood CD34+ cells were not induced to generate CFU‐MK colonies by PEG‐rHuMGDF. The same lack of response was observed when patients peripheral blood CD34+ cells primed with chemotherapy plus G‐CSF or with G‐CSF alone were assessed. In contrast, PEG‐rHuMGDF stimulated CFU‐MK growth when mononuclear cells, either from the bone marrow or from mobilized peripheral blood, were grown in plasma clot. Moreover, we analysed by flow cytometry the expression of Mpl receptor on the cell membrane of normal mobilized peripheral blood and normal steady‐state bone marrow CD34+ cells. Our results showed a reduced expression of Mpl receptor on mobilized peripheral blood progenitor cells in comparison with bone marrow cells.
A1,2BO1,2 genotyping by multiplexed allele‐specific PCR
Authors: Pearson Steven L. , Hessner Martin J.
Published: March 2003

The ABO blood group is the most clinically important human alloantigen system in transfusion medicine. The system involves three antigens A, B and H. H antigen is converted to either A or B by the activity of α1 → 3‐ n‐acetyl‐galactosaminyl transferase (A transferase) or α1 → 3 galactosyl transferase (B transferase). The O phenotype is the result of an inactive glycosyltransferase, which is unable to glycosylate the H antigen.

The immunological properties of the ABO system were identified at the turn of the century; however, the genetic basis of the ABO system has only recently been characterized. This has enabled the development of a number of molecular ABO typing methods. Described here is a two‐reaction multiplex allele‐specific PCR (ASPCR) genotyping assay for the A1, A2, B, O1 and O2 subtypes. 11 different allele‐specific oligonucleotide primers were selected to detect the presence or absence of the O1 associated G →  (−) deletion at base 261, the O2 associated G → A substitution at base 802, the B associated G → A substitution at base 803, and finally the A2 associated C → (−) deletion at base 1059.

A total of 122 peripheral blood samples were genotyped and serologically forward and reverse typed. A concordance rate of 98.4% (120/122 samples) was observed between the actual genotype and the serologically‐based predicted genotype. These results indicate that this assay provides a rapid, accurate, and simple method for A1,2BO1,2 genotyping that serves as a useful supplement to standard serological ABO typing.
Protein A immunoadsorption in chronic refractory ITP reverses increased platelet activation but fails to achieve sustained clinical benefit
Authors: Cahill  , Macey  , Cavenagh  , Newland
Published: March 2003

Adults with chronic relapsing ITP present a difficult therapeutic challenge. The ongoing antibody‐ mediated platelet destruction in this group might be expected to be associated with increased expression of platelet surface membrane activation antigens.

We have studied a group of 10 patients with refractory ITP and 35 healthy controls. Using an immediate, sensitive, unfixed, whole blood, flow cytometric method to detect platelet surface P‐selectin and GP53, we have detected markedly increased platelet activation in the ITP group compared with the controls (P‐selectin; patient median 24.5% v control median 2.0%, GP53 median 6.5% v 2.1%, P < 0.01 for both).

Five patients underwent protein A immunoadsorption therapy. The effect of protein A immunoadsorption on platelet activation before, during and after 18 treatments in these patients was studied and patients were followed‐up to assess clinical outcome. Platelet‐associated immunoglobulin measurements were made before and at the end of six treatments.

Platelet activation decreased after immunoadsorption. P‐selectin expression fell significantly; pre‐ and post‐treatment median values differed by 15.5%, P < 0.01, for GP53 the difference was 2.5.%, P = NS. A reduction in both platelet‐associated IgG (median reduction of 11.8 ng/106 platelets, P = 0.08) and IgM (7.6 ng/106 platelets, P = 0.06) was recorded.
Effective mobilization of Philadelphia‐chromosome‐negative cells in chronic myelogenous leukaemia patients using a less intensive regimen
Authors: Carella Angelo M. , Lerma Enrica , Celesti Lidia , Dejana Anna , Panagiotis Zikos , Corsetti Maria Teresa , Frassoni Francesco
Published: March 2003

To determine if reducing the intensity of the mobilizing chemotherapy protocol used would alter the number and/or quality of the progenitors mobilized in patients with chronic myelogenous leukaemia (CML), we undertook a pilot study. 36 consecutive CML patients previously treated only with hydroxyurea were given mobilization therapy within 12 months of diagnosis. 17 patients were treated by the ICE protocol and 19 patients received the mini‐ICE protocol. The leukapheresis product collected from 22/36 patients (62%) was entirely Ph‐negative. The cytogenetic results between ICE and mini‐ICE‐treated protocols were not significant, although the reduction in median days of hospitalization required for the mini‐ICE versus the ICE protocol was highly significant (P < 0.0001). There was no significant difference in the yield of CD34+ cells and CFU‐GM collected. No patient in the mini‐ICE protocol experienced high‐grade oral mucositis and GI toxicity whereas three such cases occurred with the ICE protocol. No patient died of the mobilization procedure in either group.
Deleted HTLV provirus in peripheral blood cells of a patient with T‐cell prolymphocytic leukaemia
Authors: Kojima Kensuke , Sawada Takashi , Yasukawa Masaki , Matsuo Yoshinubu , Yakushijin Yoshihiro , Narumi Hiroshi , Azuma Taichi , Takimoto Hidetaka , Hara Masamichi
Published: March 2003

We describe the first case of T‐cell prolymphocytic leukaemia (T‐PLL) in which the peripheral blood cells contained a human T‐lymphotropic virus (HTLV) related tax sequence. Serum screening tests for anti‐HTLV‐I/II antibodies were negative. Polymerase chain reaction disclosed the presence of an HTLV‐I tax sequence in the peripheral blood. Other sets of oligonucleotide primers for HTLV‐I gag, pol, env and the long terminal repeat regions and for the HTLV‐II pol region were negative in the DNA of the cells. Although patients with T‐PLL have been reported to be seronegative for HTLV‐I, our findings point to the possibility that HTLV‐I infection might be involved in the aetiology of at least some cases of T‐PLL and that there may be alternative mechanisms involved in HTLV‐associated leukaemogenesis.
Platelet activation in patients with sickle cell disease
Authors: Wun Ted , Paglieroni Teresa , Rangaswami Arun , Hill Franklin Patricia , Welborn Jeanna , Cheung Anthony , Tablin Fern
Published: March 2003

Vascular occlusion and vasculopathy underlie much of the morbidity in patients with sickle cell anaemia. Platelets may play a role in this vasculopathy. Samples from 43 patients with sickle cell disease (SCD) were examined for evidence of platelet activation using fluorescent‐labelled monoclonal antibodies and flow cytometry. There was increased expression of activation‐dependent antigens on the platelets from patients with SCD compared to those from both Caucasian and African‐American controls. In addition, SCD patients had increased levels of platelet microparticles. Platelets are activated in patients with sickle cell disease. The contribution of platelet activation to sickle cell pathophysiology is under active investigation in our laboratories.
Sustained decrease of peripheral lymphocytes after allogeneic blood stem cell aphereses
Authors: Novotny Jürgen , Kadar Janos , Hertenstein Bernd , Schröder Detlev , Petersen Detlev , Arseniev Lubomir , Stangel Walter , Ganser Arnold
Published: March 2003

48 healthy donors underwent peripheral blood stem cell (PBSC) apheresis for allogeneic transplantation beginning on day 4 of G‐CSF (2 × 5 μg/kg) mobilization. In one to four (median two) large‐volume mononuclear cell aphereses, a median of 55.9 × 109 of lymphocytes (range 21.0–109.2 × 109) were collected, an amount comparable to lymphocyte numbers removed by therapeutic lymphaphereses in autoimmune diseases. Mean peripheral lymphocyte counts decreased from premobilization values of 2.31 × 109/l to 1.31 × 109/l at a median of 34 d (1 month) and 1.53 × 109/l at a median of 327 d (11 months). The decrease in peripheral lymphocyte counts was significantly correlated with the number of lymphocytes removed and the number of aphereses. Neutrophil and platelet counts returned to normal values after 1 month whereas monocyte counts and haemoglobin concentrations were significantly decreased at 1 month but not at 11 months.
VH gene expression in hairy cell leukaemia
Authors: Maloum  , Magnac  , Azgui  , Cau  , Charlotte  , Binet  , Merle‐Béral  , Dighiero
Published: March 2003

Hairy cells are characterized by their typical morphology and expression of specific surface antigens. Although their B‐cell origin is now confirmed, their exact position in B‐cell development remains unclear. To better define the origin of hairy cells, we analysed the immunophenotype and the Ig VH nucleotide sequence of seven cases of hairy cell leukaemia (HCL). Six of them were typical HCL and the remaining case corresponded to a variant HCL. Analysis of sequenced VH genes revealed that the VH1 family was used in one case, VH2 in one, VH3 in two, VH4 in two and VH5 in one. No preferential usage of VH genes was observed in this small series. In five cases high rates of somatic mutations were observed, with a predominance of mutations and replacements in CDR regions for three, indicating that these cells originate from cells that have been exposed to the hypermutation mechanism. The distribution of mutations in our small series provides some evidence of a selective mutational process.
Serum thrombopoietin level is mainly regulated by megakaryocyte mass rather than platelet mass in human subjects
Authors: Nagasawa Toshiro , Hasegawa Yuichi , Shimizu Seiichi , Kawashima Yasuko , Nishimura Shigeko , Suzukawa Kazumi , Mukai Harumi , Hori Mitsuo , Komeno Takuya , Kojima Hiroshi , Ninomiya Haruhiko , Tahara Tomoyuki , Abe Tsukasa
Published: March 2003

A patient with idiopathic thrombocytopenic purpura (ITP) developed T‐cell lymphoma while undergoing steroid therapy. We examined the relationship between the patient's serum thrombopoietin (Tpo) level, platelet count, megakaryocyte number and CFU‐Meg number during the second 5 d course of chemotherapy for lymphoma in which megakaryopoiesis switched from ITP phase to amegakaryocytic phase. The patient's platelet count was temporarily elevated but CFU‐Meg numbers were markedly suppressed, and megakaryocyte numbers were decreased in this period, whereas serum Tpo level was not suppressed despite an increased platelet count, indicating that serum Tpo level is mainly regulated by megakaryocyte mass.
Regression of extramedullary haemopoiesis and augmentation of fetal haemoglobin concentration during hydroxyurea therapy in β thalassaemia
Authors: Saxon Ben R. , Rees David , Olivieri Nancy F.
Published: March 2003

Hydroxyurea increases fetal haemoglobin in many patients with sickle cell anaemia, but its effectiveness in thalassaemia appears to be less consistent. We describe the response to hydroxyurea in an adult male with homozygous β thalassaemia, symptomatic paraspinal extramedullary haemopoiesis, bone pain, and progressive tissue iron loading. Prior to therapy with hydroxyurea the circulating haemoglobin (Hb) concentration was 7.0 g/dl and absolute fetal haemoglobin concentration was 5.0 g/dl. Administration of sodium phenylbutyrate had induced no increase in either parameter. Subsequent therapy with hydroxyurea was associated with increases in total haemoglobin to 9.0 g/dl, and in fetal haemoglobin to 7.6 g/dl. Ineffective erythropoiesis was reduced and extramedullary haemopoiesis regressed during therapy.
Butyrate‐stable monosaccharide derivatives induce maturation and apoptosis in human acute myeloid leukaemia cells
Authors: Santini  , Scappini  , Gozzini  , Grossi  , Villa  , Ronco  , Douillet  , Pouillart  , Bernabei  , Rossi Ferrini
Published: March 2003

The rapid degradation and subsequent lack of efficacy of n‐butyric acid in vivo has been improved by the synthesis of monosaccharide stable pro‐drugs of butyric acid. We studied the effects of D1 (O‐n‐butanoyl‐2,3‐O‐isopropylidene‐alpha‐
D‐mannofuranoside), G1 (1‐O‐n‐butanoyl‐
D,
L‐xylitol), and F1 (1‐O‐n‐butanoyl 2,3‐O‐isopropylidene‐
D,
L‐xylitol) on the maturation and proliferation of AML cell lines HL 60 and FLG 29.1 and of purified blast cells from 10 cases of de novo acute myeloid leukaemia (AML). AML cell maturation was measured by surface antigen expression, morphology and cytochemistry. Toxicology in mice was also evaluated (DL50 1000 mg/kg). In HL 60 cells G1 and D1 increased the expression of CD15 and CD11a (presenting 62% of promyelo‐metamyelocytes), and in 7/10 cases of primary AMLs that of CD11a, CD11b, CD15, and myeloperoxidase. D1, G1 and F1 induced a dose‐dependent inhibition of tritiated thymidine uptake. Apoptosis (evaluated by flow cytometry and agarose gel electrophoresis) was induced in AML blasts by D1 and F1 (79% and 94% respectively for HL 60 cells) and, with less effect, by G1 (27%). The persistence of maturative and apoptotic activity in these new pro‐drugs of butyric acid, hydrolysed only inside the tumour cell, suggests a possible use in differentiation therapy of myelodysplastic syndromes and AMLs.
Monocyte B7 and Sialyl Lewis X modulates the efficacy of IL‐10 down‐regulation of LPS‐induced monocyte tissue factor in whole blood
Authors: Warnes Gary , Biggerstaff John P , Francis John L
Published: March 2003

Recent studies have investigated the use of anti‐inflammatory cytokine, interleukin 10 (IL‐10) to control the development of disseminated intravascular coagulation (DIC) in sepsis by down‐regulation of monocyte tissue factor (MTF) induced by lipopolysaccharide (LPS) in the initial phase of the disease. In vitro and in vivo human studies have shown that a minimal (<1 h) delay in IL‐10 treatment significantly reduces the cytokines ability to inhibit LPS‐induced MTF expression and the end products of coagulation. In this whole blood in vitro study we investigated the role of lymphocyte and platelet interactions with monocytes to up‐regulate MTF expression in the presence of IL‐10 in the initial phase of exposure to LPS. Individual blockade of monocyte B7 or platelet P‐selectin significantly (35%) reduced MTF expression (P<0.05). IL‐10 showed a dose‐dependent inhibition of LPS (0.1 μg/ml) induced MTF expression, with 56% inhibition at 1 ng/ml, maximizing at 5 ng/ml IL‐10 (75%; P<0.05). Simultaneous exposure to LPS and IL‐10 (1 ng/ml) or addition of IL‐10 1 h after LPS, with individual B7 and P‐selectin blockade significantly enhanced the inhibition of MTF expression by IL‐10 (P<0.05). We conclude that the efficacy of IL‐10 to control DIC could be enhanced by a simultaneous B7 and P‐selectin blockade.