bluuebunny/crossref_metadata_2025_split huggingface dataset:
Perception of the risk of adverse drug reactions: differences between health professionals and non health professionals
Authors: Bongard V. , Ménard‐Taché S. , Bagheri H. , Kabiri K. , Lapeyre‐Mestre M. , Montastruc J. L. 
Published: March 2003

Aims
To investigate how risk of adverse drug reactions (ADRs) of several drug classes is perceived by health vs non health professionals.
Methods
Four hundred health professionals (i.e. 278 general practitioners, 76 pharmacists and 46 pharmacovigilance professionals) and 153 non health professionals were interviewed. Visual analogue scales were used to define a score of perceived risk of ADRs associated with each drug class (ranking from 0 to 10).
Results
Anticoagulants were ranked as the most dangerous drugs by general practitioners [median score (25th‐75th centiles): 7.9 (6.7–9.0)], pharmacists [8.7 (7.8–9.7)] and pharmacovigilance professionals [8.1 (7.2–9.0)]. For non health professionals, the class ranked first was sleeping pills [8.7 (7.2–9.4)] followed by tranquillisers [8.2 (6.4–9.2)] and antidepressants [8.0 (5.9–9.1)]. Aspirin was listed in the last position by non health professionals [3.4 (1.5–5.4)].
Conclusions
There are major differences in the perception of risk of ADRs between health professionals and non health professionals.
Pharmacodynamic effects and pharmacokinetics of a new HMG‐CoA reductase inhibitor, rosuvastatin, after morning or evening administration in healthy volunteers
Authors: Martin Paul D. , Mitchell Patrick D. , Schneck Dennis W. 
Published: March 2003

Aims  To compare the lipid‐regulating effects and steady‐state pharmacokinetics of rosuvastatin, a new synthetic hydroxy methylglutaryl‐coenzyme A (HMG‐CoA) reductase inhibitor, following repeated morning and evening administration in volunteers with fasting serum low‐density lipoprotein cholesterol (LDL‐C) concentrations < 4.14 mmol l−1.Methods  In this open‐label two‐way crossover trial 24 healthy adult volunteers were randomized to receive rosuvastatin 10 mg orally each morning (07.00 h) or evening (18.00 h) for 14 days. After a 4 week washout period, volunteers received the alternative regimen for 14 days. Rosuvastatin was administered in the absence of food.Results  Reductions from baseline in serum concentrations of LDL‐C (−41.3%[morning]vs−44.2%[evening]), total cholesterol (−30.9%vs−31.8%), triglycerides (−17.1%vs−22.7%), and apolipoprotein B (−32.4%vs−35.3%) were similar following morning and evening administration. AUC(0,24 h) for plasma mevalonic acid (MVA), an in vivo marker of HMG‐CoA reductase activity, decreased by −29.9% (morning) vs−32.6% (evening). Urinary excretion of MVA declined by −33.6% (morning) vs−29.2% (evening). The steady‐state pharmacokinetics of rosuvastatin were very similar following the morning and evening dosing regimens. The Cmax values were 4.58 vs 4.54 ng ml−1, and AUC(0,24 h) values were 40.1 vs 42.7 ng ml−1 h, following morning and evening administration, respectively. There were no serious adverse events during the trial, and rosuvastatin was well tolerated after morning and evening administration.Conclusions  The pharmacodynamic effects and pharmacokinetics of rosuvastatin are not dependent on time of dosing. Morning or evening administration is equally effective in lowering LDL‐C.
Population pharmacokinetics of nevirapine in an unselected cohort of HIV‐1‐infected individuals
Authors: De Maat M. M. R. , Huitema A. D. R. , Mulder J. W. , Meenhorst P. L. , Van Gorp E. C. M. , Beijnen J. H. 
Published: March 2003

Nevirapine (NVP) is a non‐nucleoside reverse transcriptase inhibitor that is frequently used as part of the currently recommended combination therapy in the treatment of HIV‐1 infection. NVP has been proven to be safe and effective, but when administered in suboptimal regimens, highly drug‐resistant virus emerges rapidly limiting future options for treatment. Patient characteristics (e.g. demographics, co‐morbidity) may have a large impact on the pharmacokinetics of nevirapine. Therefore, we explored the population pharmacokinetics of NVP in an unselected cohort of HIV‐1‐infected individuals.Included patients were ambulatory HIV‐1‐infected patients from the outpatient clinic of the Slotervaart Hospital, Amsterdam, The Netherlands. Data were retrospectively collected from January 1997 to April 2000. The pharmacokinetics of NVP were described with a one‐compartment model with first‐order absorption and elimination using nonlinear mixed effect modelling (NONMEM V1.1). Population pharmacokinetic parameters (clearance (CL/F), volume of distribution (V/F), absorption rate constant (Ka)) were estimated. Interindividual (IIV) and interoccasion variability (IOV) were estimated with a proportional error model. Furthermore, the influence of patient characteristics on the pharmacokinetics of NVP were determined. From a small fraction of patients, baseline liver function test results were not available. In order to avoid bias, a covariate was included in the model indicating missing data.From 173 outpatients a total number of 757 NVP plasma concentrations at a single random timepoint and full pharmacokinetic curves of 13 patients were available resulting in a database of 1329 NVP plasma concentrations. CL/F of NVP was 3.49 l h−1 with an IIV and IOV of 28 and 21%, respectively. V/F was 93.1 l (IOV=46%) and the Ka was 1.65 h−1 (IIV=60%). CL/F of NVP was correlated with weight (WT), chronic hepatitis C infection (HepC), ASAT>1.5×upper limit of normal (ULN) at baseline, and the black race (RACE). These correlations are described by the following equation: CL/F=(3.49+0.0205×[WT‐70])×0.483HepC× 0.66ASAT×(1−MISS)×0.671MISS×0.731RACE, in which HepC is 1 for individuals with hepatitis C infection and 0 for all others, ASAT is 1 for patients with baseline ASAT>1.5×ULN and 0 for all others, MISS is 1 for patients with no baseline ASAT value and 0 for all others, and RACE is 1 for black patients and 0 for all others. Thus, HepC, ASAT>1.5×ULN, and the black race reduce CL/F of NVP by 52%, 34%, and 27%, respectively, whereas an increase in WT of 10 kg increases the CL/F by 0.21 l h−1.The pharmacokinetics of NVP were adequately described with the developed population pharmacokinetic model. Weight, chronic hepatitis C infection, baseline ASAT>1.5×ULN, and the black race were found to be significant covariates for CL/F of NVP. The described model including these significant covariates could be an aid in optimizing NVP‐containing therapy.
Paracetamol‐related deaths in Scotland, 1994–2000
Authors: Sheen Christopher L. , Dillon John F. , Bateman D. Nicholas , Simpson Kenneth J. , MacDonald Thomas M. 
Published: March 2003

Aims
To investigate the death rate due to paracetamol poisoning in Scotland and what effect the reduction in over‐the‐counter paracetamol pack sizes in 1998 had on the death rate.
Methods
Records from 1994 to 2000 were examined to identify the number and annual incidence of paracetamol‐related deaths. Numbers of deaths before and after the pack size reduction were compared.
Results
No significant differences were shown due to the pack size reduction. The Scottish paracetamol‐related death rate was twice as high as in England and Wales.
Conclusions
Further measures to reduce paracetamol‐related morbidity and mortality in Scotland should be considered.
No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans
Authors: Affolter Jonathan T. , Newby David E. , Wilkinson Ian B. , Winter Matthew J. , Balment Richard J. , Webb David J. 
Published: March 2003

Aims In rodent and primate studies, urotensin II is an extremely potent vasoconstrictor peptide with effects in the central aortic and arterial vasculature as well as on cardiac function. The aim of the present study was to assess systemic haemodynamic responses to intravenous urotensin II infusion in humans.Methods In 10 healthy male volunteers, intravenous urotensin II (3, 30 and 300 pmol min−1) and saline placebo were given on separate occasions in a single‐blind randomized manner. Systemic haemodynamics and arterial stiffness were assessed by sphygmomanometry, transthoracic bioimpedance, and pulse wave analysis. Plasma urotensin II immuno‐reactivity was measured by radio‐immunoassay.Results Intravenous urotensin II infusions were well tolerated with no adverse clinical effects and no electrocardiographic changes. Circulating plasma urotensin II immuno‐reactivity increased from baseline of 16 ± 1 to 1460 ± 82 pmol l−1 (mean ± s.e. mean) during infusion of urotensin II at 300 pmol min−1 (P < 0.001). However, there were no significant placebo adjusted changes in heart rate (95% confidence intervals: −3.6, + 4.4 min−1), mean arterial pressure (−5.8, + 1.7 mmHg) or cardiac index (−0.1, + 0.4 l min−1 m−2). There were also no changes in augmentation index (−4.1, + 5.2%) or pulse wave velocity (−1.3, + 0.3 m s−1).Conclusions Intravenous urotensin II infusion did not affect systemic haemodynamics or arterial stiffness, despite achieving an ∼100‐fold increase in plasma immuno‐reactivity. We conclude that urotensin II is unlikely to have a physiological role in the short term regulation of vascular tone or blood pressure in man. Further confirmatory studies with urotensin II receptor antagonists are required.
The effect of ketoconazole on the in vivo intestinal permeability of fexofenadine using a regional perfusion technique
Authors: Tannergren Christer , Knutson Tina , Knutson Lars , Lennernäs Hans 
Published: March 2003

Aims To investigate whether the drug–drug interaction between fexofenadine and ketoconazole is localized to efflux transport proteins of the small intestine, and to determine and classify the effective jejunal permeability (Peff) of fexofenadine according to the Biopharmaceutics Classification System (BCS).Methods Two separate jejunal perfusion experiments were performed using the Loc‐I‐Gut® technique in eight healthy volunteers. During treatment 1 (T1), we investigated the acute effect of ketoconazole on the Peff and plasma pharmacokinetics of fexofenadine. In treatment 2 (T2) we examined the effect of oral pretreatment with ketoconazole (200 mg daily for 5 days) on the same absorption parameters. Each experiment was divided into two periods of 100 min and the jejunal segment was perfused with 93 µm fexofenadine during both periods. In period 2 of each treatment, fexofenadine was coadministered with 94 µm ketoconazole. The concentrations of fexofenadine in intestinal perfusate and plasma were measured by liquid chromatography with mass detection.Results During T1, the mean (± s.d.) Peff of fexofenadine was low according to the BCS (0.11 ± 0.11 and 0.04 ± 0.13·10−4 cm s−1 in periods 1 and 2, respectively), and the coadministration of ketoconazole in period 2 had no significant acute effect on Peff (95% confidence interval (CI) on the difference −0.37, 0.51). After pretreatment with ketoconazole (T2), the jejunal Peff of fexofenadine increased to 0.29 ± 0.47 and 0.22 ± 0.31·10−4 cm s−1 in both periods 1 and 2, respectively, but the change was not statistically significant when compared with T1 (95% CI on the difference −0.62, 0.27 for T1 0–100 min vs T2 0–100 min; −0.54, 0.34 for T1 0–100 min vs T2 100–200 min). Fexofenadine plasma AUC from 0–100 mg showed no significant difference after pretreatment with ketoconazole (55 ± 101 and 51 ± 33 µg ml−1 min−1 respectively; 95% CI on the difference −108, 115). Total plasma AUC (0–720 min) was 318 ± 426 and 426 ± 232 ng ml−1 min in T1 and T2, respectively (95% CI on the difference −622, 405).Conclusions No significant effect of acute coadministration or pretreatment with ketoconazole on the in vivo intestinal absorption of fexofenadine was detected in this study.
Lipodystrophy associated with protease inhibitors
Authors: Panse I. , Vasseur E. , Raffin-Sanson M.L. , Staroz F. , Rouveix E. , Saiag P. 
Published: March 2003

Abstract
Lipodystrophies, characterized by reduction of subcutaneous fat over part or all of the body surface, are uncommon. Their causes are unknown. Recently, lipodystrophy has been reported in human immunodeficiency virus (HIV)-infected patients taking protease inhibitors, which have been recommended since 1996 as standard therapy for HIV disease in combination with nucleoside analogues. In these cases, lipodystrophy consists of an association of peripheral lipoatrophy with central adiposity. We report four HIV-infected men on protease inhibitors who developed a disfiguring lipodystrophy. In three of them, the protease inhibitor was administered for a mean duration of 21·5 months (range 19–23) with good immunological and virological responses. Patient 4 had been treated for 2 years with successive combinations of protease inhibitors with nucleoside analogues without success. The four patients progressively developed an increase in abdominal girth associated with fat wasting of the face and legs. Two of them had recurrent paronychia of the great toes. Triglyceride levels were moderately increased in all patients, and one had a slightly increased cholesterol level. One patient had elevated glucose and insulin plasma levels during a glucose tolerance test. In two patients, a deep biopsy taken from the thigh showed thinning of the subcutaneous fat without other morphological changes. Computed tomographic scans of the face and abdomen confirmed the loss of almost all subcutaneous fat of the cheek and temporal regions, and abdominal perivisceral fat accumulation. For patients 1–3, the protease inhibitor was replaced by a non-nucleoside reverse transcriptase inhibitor. Nine months later, dysmorphic changes had not regressed, but lipid abnormalities had returned to normal and the paronychia had disappeared.
N-acetyltransferase 1 and 2 polymorphisms inpara-substituted arylamine-induced contact allergy
Authors: Westphal G.A. , Reich K. , Schulz T.G. , Neumann C. , Hallier E. , Schnuch A. 
Published: March 2003

AbstractSensitization to arylamines such as p-phenylenediamine is frequently diagnosed in patients with allergic contact dermatitis. Reactive metabolites of p-phenylenediamine might be produced in the skin by O-acetylation of N-hydroxylamines catalysed by local N-acetyltransferases (NATs). In this study, we tested whether genetic polymorphisms of NATs, which are known to affect enzyme activity, may influence the susceptibility to para-substituted arylamine-induced contact eczema. Using polymerase chain reaction and restriction enzyme analysis, the distribution of polymorphisms of NAT1 and NAT2 was investigated in 88 patients sensitized to para-substituted aryl compounds and 123 healthy controls. NAT2 rapid acetylators, i.e. carriers of the NAT2*4 wild-type allele, were more common in the contact allergy (44%) than in the healthy control group [30%; P = 0·042, odds ratio 1·9 (95% confidence interval, CI 1·05–3·27)]. Slow acetylators carrying the NAT2*5b/2*6a genotype were significantly less frequent among patients [13% vs. 38% in controls; P = 0·009, odds ratio 0·39 (95% CI 0·19–0·78)]. The carriage rate of the NAT1*10 allele, which is supposed to encode for a rapid NAT1 phenotype, was not significantly different between patients and controls [43% vs. 36%; odds ratio 1·5 (95% CI 0·88–2·68)]. Interactions between NAT2*4 and NAT1*10 were suggested by the increased frequency of the NAT2*4/NAT1*10 haplotype in patients (27%) compared with controls [15%; P = 0·039, odds ratio 2·1 (95% CI 1·04–4·04)]. As the NAT1 and NAT2 encoding genes are located in close proximity on chromosome 8p22, the latter finding could at least partly be due to genetic linkage. In fact, a linkage disequilibrium between NAT2*4 and NAT1*10 was observed in the contact allergy (P = 0·0025) and in the control group (P = 0·042). Our data indicate an association between the NAT2*4/NAT1*10 haplotype and contact sensitization to para-substituted aryl compounds. Therefore, acetylation may either enhance contact sensitization or NAT2*4 and NAT1*10 might be linked to an unknown susceptibility factor.
Absence of Bruton's tyrosine kinase (Btk) mutations in patients with acute myeloid leukaemia
Authors: Ritis Konstantinos , Speletas Matthaios , Tsironidou Victoria , Pardali Evaggelia , Kanariou Maria , Moschese Viviana , Orlandi Paola , Skordala Mariana , Rossi Paolo , Kartalis Georgios , Bourikas Georgios , Sideras Paschalis 
Published: March 2003

Bruton's tyrosine kinase (Btk) is a non‐receptor protein tyrosine kinase (PTK) that is expressed in all haemopoietic lineages except mature T cells and plasma cells. Despite the broad range of expression, mutations that inactivate this molecule affect primarily the development of the B‐cell lineage. As a PTK, Btk could potentially be involved directly or indirectly in the processes that relate to the malignant transformation of all the cell lineages where this molecule is expressed. Previous studies have failed to demonstrate mutations in patients with B‐cell origin acute lymphoblastic leukaemia (ALL).We have utilized a recently developed method that enables the rapid and convenient detection of mutations at the cDNA level, namely, the non‐isotopic RNase cleavage assay (NIRCA) to analyse Btk sequences from 27 patients with different types of acute myeloid leukaemia (AML). The only alteration that we observed was a polymorphism at position 2031. This polymorphism has already been seen in previous studies. Furthermore, using the same methodology, we identified the Btk mutations in six XLA (X‐linked agammaglobulinaemia) patients. Our results, although they do not exclude the involvement of Btk mutations in the development or progression of some type of AML, nevertheless suggest that such mutations do not constitute a major co‐factor in the development of myeloid malignancies.
Molecular characterization of the PK‐LR gene in pyruvate kinase deficient Spanish patients
Authors: Zarza  , Alvarez  , Pujades  , Nomdedeu  , Carrera  , Estella  , Remacha  , SÁnchez  , Morey  , Cortes  , PÉrez Lungmus  , Bureo  , Vives Corrons  
Published: March 2003

The PK‐LR gene has been studied in 12 unrelated patients with red cell pyruvate kinase deficiency and hereditary nonspherocytic haemolytic anaemia (CNSHA). The entire codifying region of the R‐type PK gene and the flanking intronic regions were analysed by single‐stranded conformation polymorphism (SSCP) followed by direct sequencing of abnormal DNA. 10 different mutations were identified in 22/24 alleles at risk. Eight of these were missense mutations that caused the following single amino acid changes: G514C (172Glu‐Gln), G1010A (337Arg‐Gln), G1015C (339Asp‐Gln), T1070C (357Ile‐Thr), C1223T (408Thr‐Ile), G1291A (431Ala‐Thr), C1456T (486Arg‐Trp) and G1595A (532Arg‐Gln). Two were nonsense mutations: G721T (241Glu‐Stop) and C1675T (559Arg‐Stop). 7/22 alleles demonstrated the same C1456→ T mutation. The study of the polymorphic site at nucleotide (nt) 1705 performed in all cases disclosed a 1705 C/C mutation in 10 and a 1705 A/C mutation in three.This is the first report on the presence of several different L‐type PK gene mutations within Spanish population. Furthermore, from the PK gene mutations found, six were unique and not previously described (1015C, 1070C, 1223T, 1291A, 1595A and 1675T) and one (C1456T) seems to be predominant in Spain. Interestingly, no case with the 1529A mutation commonly found in Northern European populations was present here.
Bolus administration of cladribine in the treatment of Waldenström macroglobulinaemia
Authors: Liu Eva S. , Burian Carol , Miller William E. , Saven Alan 
Published: March 2003

This phase II clinical trial evaluated bolus cladribine as a single agent in Waldenström macroglobulinaemia (WM).Cladribine was administered to 20 patients at a dose of 0.12 mg/kg/d by 2 h intravenous infusion for 5 consecutive days at monthly intervals for three courses. Partially responding patients were continued on therapy until maximal response and/or prohibitive toxicity, to a maximum of eight courses. Complete responders were treated with one additional course of cladribine.After a median of three courses of cladribine, all 20 patients were evaluable; one achieved a complete response (CR) (5%) and 10 achieved a partial response (PR) (50%). The median duration of response follow‐up was 28 months (range 1–37 months). Four of 7 (57%) untreated and 7/13 (54%) previously treated patients responded. The major toxicity encountered was myelosuppression with 60% of patients demonstrating grade 3 or 4 neutropenia. Non‐haematological toxicities included two patients with herpes zoster and two patients with non‐melanoma skin cancers. At a median follow‐up duration of 20 months, 17 patients remain alive and three have died.We confirm that bolus cladribine is an effective and safe method of drug delivery in WM patients. Recommendations regarding the equivalence of the continuous infusion and bolus methods in untreated patients requires further study. Bolus cladribine is more convenient and less costly than infusional cladribine since it obviates the need for central catheters and infusional devices.
Persistent polyclonal B lymphocytosis with binucleated lymphocytes: a study of 25 cases
Authors: MOSSAFA H. , MALAURE H. , MAYNADIE M. , VALENSI F. , SCHILLINGER F. , GARAND R. , JUNG G. , FLANDRIN G. , TROUSSARD X. ,   et le Groupe Français d'Hématologie Cellulaire (GFHC)
Published: March 2003

Persistent and polyclonal lymphocytosis of B lymphocytes (PPBL) with binucleated lymphocytes is an entity characterized by a polyclonal lymphocytosis. The lymphocytosis is stable for years and binucleated lymphocytes are detected on peripheral blood smears. We previously described +i(3q) as a recurrent chromosomal abnormality in seven PPBL patients. In this study we report a large series of 25 PPBL patients and demonstrated that PPBL was associated with +i(3q) in 77% of cases, premature chromosome condensation (PCC) in 50% and both abnormalities in 41% of cases. Furthermore, we demonstrated that i(3q) was present in a minority of B cells, restricted to B lymphocytes independently of the kappa or lambda light Ig chain expression, and exclusively observed in non‐binucleated cells.The benign clinical course of PPBL and the lack of biological evolution in the majority of cases suggest that recognition of these disorders is so important that aggressive therapy in PPBL has to be avoided. Whether this syndrome represents a premalignant or benign disease remains unclear. The persistence of cytogenetic abnormalities after stopping tobacco use suggests no association with cigarette smoking.
Prognostic value of vertebral lesions detected by magnetic resonance imaging in patients with stage I multiple myeloma
Authors: Mariette Xavier , Zagdanski Anne‐Marie , Guermazi Ali , Bergot Catherine , Arnould Anne , Frija Jacques , Brouet Jean‐Claude , Fermand Jean‐Paul 
Published: March 2003

We assessed the role of spinal magnetic resonance imaging (MRI) and bone densitometry as prognostic factors in patients with asymptomatic stage I multiple myeloma (MM) and negative skeletal survey. 55 consecutive patients underwent spinal MRI and 41 of them underwent bone densitometry by dual‐energy X‐ray absorptiometry (DEXA).Spinal MRI studies showed evidence of bone marrow involvement in 17/55 patients (31%). A diffuse pattern was present in three patients and a focal pattern in 14 patients, nine of them with only one nodular lesion. During a median follow‐up of 25 months, 10 patients had disease progression, 8/17 patients with abnormal MRI and 2/38 patients with normal MRI. Median time to disease progression was not reached in both groups but was significantly different for patients with normal and those with abnormal patterns on MRI (P < 0.0001). Lumbar BMD was only slightly decreased compared with normal people (median lumbar Z score − 0.43) and was not of prognostic value. Using a multivariate analysis the only two independent significant prognostic parameters were abnormal MRI (P < 0.001, HR 30.4, 95% CI 4.3–213) and bone marrow plasmacytosis > 20% (P = 0.004, HR 16.4, 95% CI 2.6–104).Thus, spinal MRI but not bone densitometry, appeared to be justified in patients with stage I asymptomatic MM and negative skeletal survey.