bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of chronic disulfiram administration on the activities of CYP1A2, CYP2C19, CYP2D6, CYP2E1, and N‐acetyltransferase in healthy human subjects
Authors: Frye Reginald F. , Branch Robert A. 
Published: March 2003

Aims  Short‐term disulfiram administration has been shown to selectively inhibit CYP2E1 activity but the effects of chronic disulfiram administration on the activities of drug metabolizing enzymes is unclear. The purpose of this study was to evaluate the effects of disulfiram given for 11 days on selected drug metabolizing enzyme activities.Methods  Seven healthy volunteers were given disulfiram 250 mg daily for 11 days. Activities of the drug metabolizing enzymes CYP1A2, CYP2C19, CYP2D6, CYP2E1 and N‐acetyltransferase were determined using the probe drugs caffeine, mephenytoin, debrisoquine, chlorzoxazone, and dapsone, respectively. Chlorzoxazone was administered before disulfiram administration and after the second and eleventh doses of disulfiram, while the other probe drugs were given before disulfiram administration and after the eleventh disulfiram dose.Results  Disulfiram administration markedly inhibited chlorzoxazone 6‐hydroxylation by more than 95%, but did not affect metabolism of debrisoquine or mephenytoin. Caffeine N3‐demethylation was decreased by 34% (P < 0.05). Monoacetyldapsone concentrations were markedly elevated by disulfiram administration resulting in a nearly 16‐fold increase in the dapsone acetylation index, calculated as the plasma concentration ratio of monoacetyldapsone to dapsone. CYP‐mediated dapsone N‐hydroxylation was not significantly altered.Conclusions  These data suggest that disulfiram‐mediated inhibition is predominantly selective for CYP2E1. The magnitude of CYP2E1 inhibition was similar after both acute and chronic disulfiram administration. The effects on caffeine N3‐demethylation (CYP1A2) and dapsone metabolism suggest that chronic disulfiram administration may affect multiple drug metabolizing enzymes, which could potentially complicate the use of chronically administered disulfiram as a diagnostic inhibitor of CYP2E1.
Web based information on clinical toxicology for the United Kingdom: uptake and utilization of TOXBASE in 2000
Authors: Bateman D. Nicholas , Good Alison M. , Kelly Catherine A. , Laing William J. 
Published: March 2003

Aims  To examine the use and uptake of TOXBASE, an Internet database for point of care provision of poisons information in the United Kingdom during its first calendar year of web‐based access.Methods  Interrogation of the database software to examine: use by different types of user and geographical origin; profile of ingredient and product access; time of access to the system; profile of access to other parts of the database.Results  Registered users of the system increased in the first full year of operation (1224 new users) and usage of the system increased to 111 410 sessions with 190 223 product monograph accesses in 2000. Major users were hospitals, in particular accident and emergency departments. NHS Direct, a public access information service staffed by nurses, also made increasing use of the system. Usage per head of population was highest in Northern Ireland and Scotland, and least in southern England. Ingredients accessed most frequently were similar in all four countries of the UK. Times of use of the system reflect clinical activity, with hospitals making many accesses during night‐time hours. The most popular parts of the database other than poisons information were those dealing with childhood poisoning, information on decontamination procedures, teratology information and slang terms for drugs of abuse.Conclusions  This Internet system has been widely used in its first full year of operation. The provision of clinically relevant, up to date, information at the point of delivery of patient care is now possible using this approach. It has wide implications for the provision of other types of therapeutic information in clinical areas. Web‐based technology represents an opportunity for clinical pharmacologists to provide therapeutic information for clinical colleagues at the bedside.
Surrogacy in antiviral drug development
Authors: Shaunak Sunil , Davies Donald S. 
Published: March 2003

The coming of age of molecular biology has resulted in an explosion in our understanding of the pathogenesis of virus related diseases. New pathogens have been identified and characterized as being responsible for old diseases. Empirical clinical evaluation of morbidity and mortality as outcome measures after a therapeutic intervention have started to give way to the use of an increasing number of surrogate markers. Using a combination of these markers, it is now possible to measure and monitor the pathogen as well as the host's response. Nowhere is this better exemplified in virology than in the field of AIDS. We have utilized the advances in pathogenesis and new antiretroviral drug development to:

• develop a new class of drugs which block the entry of HIV‐1 into cells.
• develop a new approach for effectively delivering these drugs to those tissues in which most viral replication takes place.

Over the last 10 years, our work has progressed from concept to clinical trial. Our laboratory based evaluation of the new molecules developed as well as our clinical evaluation of their safety and efficacy have had to respond and adapt to the rapid changes taking place in AIDS research. This paper discusses the problems encountered and the lessons learnt.
Early clinical experience with the novel proteasome inhibitor PS–519
Authors: Shah I. M. , Lees K. R. , Pien C. P. , Elliott P. J. 
Published: March 2003

Aims
The main objective of this study was to investigate the safety, tolerability and pharmacodynamics of the novel proteasome inhibitor PS−519 in young male volunteers. Many pro‐inflammatory mediators such as cytokines and cell adhesion molecules that are responsible for the development of the cerebral infarct are under the control of the transcription factor Nuclear Factor kappa‐B (NF‐κB). The activity of NF‐κB is itself tightly regulated through the multicatalytic enzyme known as the proteasome. PS‐519 is a novel and highly selective small molecule that inhibits the proteasome.   An   ex   vivo  assay   of   20S   proteasome   activity   allows   monitoring   of the drug effect in blood. PS‐519 is protective in multiple animal models of cerebral ischaemia over a range of doses that achieve 20S inhibition of 40%−80%.
Methods
PS‐519 has been administered to healthy male volunteers as single and repeated doses up to 1.6 mg m−2. It was given as an intravenous bolus over 20–30 s in a double blind, randomized, placebo‐controlled phase I study, examining vital signs, safety, tolerability and blood 20S proteasome inhibition.
Results
Thirty‐nine subjects received single doses of 0.012 mg m−2−1.6 mg m−2 and 28 subjects received doses of 0.5 mg m−2−1.6 mg m−2 on three consecutive days. The drug was well tolerated. There was no clear treatment‐emergent symptom or abnormality of laboratory tests. Proteasome inhibition in blood samples as measured by 20S assay achieved the intended maximum target level of 70–80% with 1.6 mg m−2, and was reproducible with repeated dosing.
Conclusions
This study has demonstrated that proteasome inhibition is well tolerated by healthy subjects at levels that are maximally neuroprotective in experimental conditions. Further clinical evaluation appears justified.
Absolute bioavailability of midazolam after subcutaneous administration to healthy volunteers
Authors: Pecking M. , Montestruc F. , Marquet P. , Wodey E. , Homery M.‐C. , Dostert P. 
Published: March 2003

Aims
Midazolam is given intravenously for induction of anaesthesia and conscious sedation and by subcutaneous infusion in patients in palliative care units. The objective of the present study was to determine the absolute bioavailability of subcutaneous midazolam and its pharmacokinetics in young, healthy, male volunteers.
Methods
Eighteen volunteers were given single doses of 0.1 mg kg−1 midazolam i.v. and s.c. after a wash‐out period of 7–15 days in an open‐label, randomized, cross‐over study. Blood samples were collected up to 12 h post‐infusion. Plasma concentrations of midazolam and of its two metabolites, 1′‐OHM and 4‐OHM, were assessed using an h.p.l.c.‐MS method (LOQ 0.5 ng ml−1 for each analyte). Vital signs, cardiac parameters and oximetry were monitored. Local tolerance was determined and adverse events were also monitored.
Results
After   s.c.   infusion  tmax   and  Cmax   were   0.51 ± 0.18 h   and 127.8 ± 29.3 ng ml−1 (mean ± s.d.), respectively. No statistically significant difference was detected in AUC(0,∞) after i.v. and s.c. administration. The mean (± s.d.) absolute bioavailability of subcutaneous midazolam was 0.96 (± 0.14) (CI 0.84, 1.03).   Mean   (± s.d.)  t1/2   was   similar   after   s.c.   (3.2   (± 1.0)   h)   and   i.v.   infusion   (2.9   (± 0.7)   h),   although   a   statistically   significant   difference   was   reached   (P < 0.05). Mean CL and V of i.v. midazolam were 4.4 ± 1.0 ml min−1 kg−1 and 1.1 ± 0.2 l kg−1 (mean ± s.d.), respectively. Plasma concentrations of 1’‐OHM were higher than those of 4‐OHM. Few mild and transient adverse events were noted and there were no clinically significant effects on EEG, blood pressure and laboratory parameters.
Conclusions
This study has shown that subcutaneous midazolam has excellent bioavailability and that administration of midazolam by this route could be preferable when the intravenous route is inappropriate.
Effect of plastic spacer handling on salbutamol lung deposition in asthmatic children
Authors: Lipworth Brian J. , Lee Daniel K. C. , Anhøj Jacob , Bisgaard Hans 
Published: March 2003

Aims  To study the effects of electrostatics in a plastic spacer on the lung deposition of salbutamol in asthmatic children.Methods  Twenty‐five children (5–12 years) with mild asthma were given salbutamol hydrofluoroalkane pressurized metered dose inhaler 400 µg via a 750 ml plastic spacer on separate days. Blood samples were taken for plasma salbutamol at 5, 10, 15 and 20 min after inhalation to measure lung bioavailability as a surrogate for relative lung dose. With immediate inhalation following actuation, a new rinsed spacer (NewRinsed ) was compared with a used spacer after repeated daily use (Used ), a spacer rinsed after repeated use (UsedRinsed ) and a spacer primed with benzalkonium chloride to avoid electrostatics (Primed1). In addition, spacers were evaluated using a 15 s inhalation delay following actuation with primed (PrimedDelay) and rinsed (RinsedDelay) spacers. Data were log transformed and expressed as geometric mean fold difference for the average plasma salbutamol concentration (Cav) over 20 min.Results  There were significant differences (P < 0.05) in Cav (as geometric mean fold difference and 95% CI) between Primed1 vs NewRinsed 1.92 fold (95% CI 1.15, 3.20) and between Used vs NewRinsed 1.75 fold (1.11, 2.76). There were no significant differences comparing Primed1, Used or UsedRinsed. There were also significant differences (P < 0.05) between Primed1 vs PrimedDelay 2.34 fold (1.31, 4.19), or vs RinsedDelay 3.59 fold (2.15, 5.99); and for Used vs PrimedDelay 2.14 fold (1.24, 3.69), or vs RinsedDelay 3.28 fold (2.13, 5.04).Conclusions  The relative lung dose of salbutamol from a plastic spacer may differ considerably depending on spacer handling suggesting that nonelectrostatic spacers may be the best way forward.
Pharmacokinetics and electrocardiographic pharmacodynamics of artemether‐lumefantrine (Riamet®) with concomitant administration of ketoconazole in healthy subjects
Authors: Lefèvre Gilbert , Carpenter Polly , Souppart Claire , Schmidli Heinz , McClean Mark , Stypinski Daria 
Published: March 2003

Aims  To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co‐artemether (artemether‐lumefantrine) in healthy subjects.Methods  Sixteen subjects were randomized in an open‐label, two period crossover design study. Subjects received a single dose of co‐artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine.Results  The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0,∞) was increased from 320 to 740 ng ml−1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml−1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 µg ml−1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half‐life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side‐effects or changes in electrocardiographic parameters. The study medications were well tolerated.Conclusions  The concurrent administration of ketoconazole with co‐artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co‐artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.
Failure of prescribers to adjust antibiotic dose to impaired renal function in daily clinical practice
Authors: Vogtländer N. P. J. , Van Kasteren M. E. F. , Natsch S. , Kullberg B. J. , Hekster Y. A. , Van Der Meer J. W. M. 
Published: March 2003

Dose adjustment of antibiotics to renal function is recommended for many antibiotics, which are eliminated by the kidney. Avoiding dose adjustment to renal function leads to unnecessary high plasma concentrations, adverse drug reactions, costs and workload for the nurses.The aims were to evaluate adherence to hospital guidelines concerning dose adjustment, investigate possible barriers to follow up guidelines, and addressing them through a multifaceted intervention aimed at improving adherence.The study was performed at a university hospital (953 beds). Data were collected in a pre‐intervention and a post‐intervention period of 3 months each. All consecutive patients with a first prescription of antibiotics at the wards of internal medicine, surgery and neurology were included. Renal function was calculated according to Cockroft & Gault's formula [1]. A table for dose adjustment of antibiotics to renal function was available for every doctor in the written antibiotic guidelines of the hospital.Sixty‐nine of 225 (31%) patients in the pre‐intervention period had an impaired renal function (renal clearance <50 ml min−1). They received 168 antibiotic prescriptions, of which 129 needed dose adjustment. The dose was actually adjusted in 58 of these 129 cases (45%). The risk for non‐adjustment above the age of 65 as well as 75 years was high (odds ratio 3.1 and 3.5, respectively). A serum‐creatinine level below 140 µmol l−1 was also an important factor for non‐adjustment (odds ratio 5.4). Barriers for not adjusting the dose were underestimation of the prevalence of renal insufficiency, and lack of time to calculate actual renal clearance.An intervention consisting of audit and feedback to prescribers and nurses, peer discussions with opinion leaders, written information to all prescribers, installation of a calculation program on the desktop of all computers on the wards, and distribution of stickers with a table to estimate renal function to paste in the antibiotic formulary was carried out.In the post‐intervention period, 68 of 224 (30%) patients had impaired renal function. Dose adjustment was necessary in 129 of 171 prescriptions. This was correctly done in 67 (52%) cases.We discovered a high prevalence of patients with impaired renal function in our hospital (30%). Especially in the elderly with a serum‐creatinine level in the normal range, renal function is overestimated and hence, overdosing of antibiotics takes place. Despite a multifaceted intervention, the rate of dose adjustment to renal function could only slightly been improved from 45% to 52% (not significant). The complexity of current care of these patients, and a high workload for physicians and nurses makes it hard to increase awareness for this problem in daily practice. Electronic support for prescribing linked to laboratory values may be of much help in the future.
Pharmacokinetics of oral betaine in healthy subjects and patients with homocystinuria
Authors: Schwahn Bernd C. , Hafner Dieter , Hohlfeld Thomas , Balkenhol Nina , Laryea Maurice D. , Wendel Udo 
Published: March 2003

Aims Large oral doses of betaine have proved effective in lowering plasma homocysteine in severe hyperhomocysteinaemia. The pharmacokinetic characteristics and metabolism of betaine in humans have not been assessed and drug monitoring for betaine therapy is not available. We studied the pharmacokinetics of betaine and its metabolite dimethylglycine (DMG) in healthy subjects and in three patients with homocystinuria.Methods Twelve male volunteers underwent an open‐label study. After one single administration of 50 mg betaine kg−1 body weight and during continuous intake of twice daily 50 mg kg−1 body weight, serial blood samples and 24 h urines were collected to determine betaine and DMG plasma concentrations and urinary excretion, respectively. Patients were evaluated after one single dose of betaine.Results We found rapid absorption (t½,abs 00.28 h, s.d. 0.17) and distribution (t½,λ1 00.59 h, s.d. 0.22) of betaine. A Cmax of 0.94 mmol l−1 (s.d. 0.19) was reached after tmax 00.90 h (s.d. 0.33). The elimination half life t½,z was 14.38 h (s.d. 7.17). After repeated dosage, t½,λ1 (01.77 h, s.d. 0.75) and t½,z (41.17 h, s.d. 13.50) increased significantly (95% CI 0.73, 01.64 h and 19.90, 33.70 h, respectively), whereas absorption remained unchanged. DMG concentrations increased significantly after betaine administration and accumulation occurred to the same extent as with betaine. Renal clearance was low and urinary excretion of betaine was equivalent to 4% of the ingested dose. Distribution and elimination kinetics in homocystinuric patients appeared to be accelerated.Conclusions Betaine plasma concentrations change rapidly after ingestion. Elimination half‐life increased during continuous dosing over 5 days. Betaine is mainly eliminated by metabolism. More pharmacokinetic and pharmacodynamic studies in hyperhomocysteinaemic patients are needed to refine the current treatment with betaine.
MMR vaccine and idiopathic thrombocytopaenic purpura
Authors: Black Corri , Kaye James A. , Jick Hershel 
Published: March 2003

Aims  To estimate the relationship between idiopathic thrombocytopaenic purpura (ITP) and the measles, mumps and rubella (MMR) vaccination in children; calculating the relative risk estimate for ITP with in 6 weeks after MMR vaccination and the attributable risk of ITP within 6 weeks after MMR vaccination.Methods  Using the General Practice Research Database we identified children with a first‐time diagnosis of ITP from a base population of children aged less than 6 years between January 1988 and December 1999. After describing the characteristics of all the children identified with ITP, we focused on cases aged 13–24 months to perform a population‐based, case–control analysis to estimate the relative risk of developing ITP within 6 weeks after MMR vaccination. We also calculated the risk of ITP attributable to the MMR vaccination.Results  Sixty‐three children with a first time diagnosis of ITP were identified; 23 cases were between 13 and 24 months old. The relative risk estimate for ITP within 6 weeks after MMR vaccination, compared to the combined group of unvaccinated children and children vaccinated with MMR more than 26 weeks previously was 6.3 (95% CI 1.3–30.1). The attributable risk of developing ITP within 6 weeks after MMR vaccination was estimated to be 1 in 25 000 vaccinations (95% confidence interval 21 300, 89 400).Conclusion  This study confirms the increased risk of ITP within 6 weeks after MMR vaccination. However, the attributable risk of ITP within 6 weeks after MMR vaccination is low.
Effects of hormone replacement therapies on fibrinogen and plasma viscosity in postmenopausal women
Authors: Fröhlich  , Schunkert  , Hense  , Tropitzsch  , Hendricks  , Döring  , Riegger  , Koenig  
Published: March 2003

In women, cardiovascular morbidity and mortality sharply increase after the onset of menopause. There is substantial evidence that hormone replacement therapy (HRT) may decrease the risk of coronary heart disease (CHD); however, the mechanisms of this preventive effect are unclear.We investigated the association between HRT and plasma viscosity as well as fibrinogen levels in postmenopausal women of a population‐based sample (n=300, age 52–65 years). A total of 94 women used HRT; of these, 50 took oestrogen monotherapy and 44 used oestrogen–progesterone combinations.HRT was associated with significantly lower fibrinogen concentrations (2.32v2.68 g/l,P<0.001) and decreased plasma viscosity (1.147v1.176 mPa/s,P=0.01). Multivariate analyses controlling simultaneously for the effects of age, smoking, body mass index, and use of diuretics confirmed decreased fibrinogen and plasma viscosity values in women using HRT. A trend towards lower plasma viscosity (1.139v1.160 mPa/s) and plasma fibrinogen (2.28v2.44 g/l) was observed in women on oestrogen–progesterone combinations as compared with oestrogen monotherapy users; however, after controlling for the above‐mentioned variables these differences were not statistically significant.This study demonstrates decreased plasma viscosity in women on HRT. Improved rheology offers a mechanism by which HRT lowers the risk of CHD in postmenopausal women.
Accumulation of catalytically active PKC‐ζ into the nucleus of HL‐60 cell line plays a key role in the induction of granulocytic differentiation mediated by all‐trans retinoic acid
Authors: Bertolaso Lucia , Gibellini Davide , Secchiero Paola , Previati Maurizio , Falgione Daniela , Visani Giuseppe , Rizzoli Riccardo , Capitani Silvano , Zauli Giorgio 
Published: March 2003

The effect of differentiating doses of all‐trans retinoic acid (ATRA, 10−6 m) and vitamin D3 (10−7 m) was investigated on the nuclear levels of endogenous ceramide and protein kinase C‐ζ (PKC‐ζ) catalytic activity in HL‐60 myeloid cells. ATRA induced a parallel increase of ceramide and catalytically active PKC‐ζ into the nuclear compartment of HL‐60 cells (peak at 72 h). On the other hand, vitamin D3 increased the levels of nuclear ceramide and PKC‐ζ activity to a lesser extent and with a delayed kinetics compared to ATRA (peak at 96 h).Pretreatment of HL‐60 cells with high pharmacological concentrations of exogenously‐added C2‐ceramide (10−6 m) completely blocked the ATRA‐mediated activation of nuclear PKC‐ζ. Exogenous C2‐ceramide (10−6 m) also inhibited the granulocytic differentiation induced by ATRA, whereas it did not affect monocytic differentiation mediated by vitamin D3.Transient transfection experiments performed with a plasmid construct containing a constitutively active mutated form of the PKC‐ζ cDNA fused in 3′ to a fluorescent tag protein (pEGFP‐PKC‐ζ) demonstrated that the overexpression of catalytically active PKC‐ζ was not accompanied by the appearance of a differentiated morphology. These findings suggest that nuclear PKC‐ζ is necessary but not sufficient to induce granulocytic differentiation of HL‐60 myeloid malignant cells.