bluuebunny/crossref_metadata_2025_split huggingface dataset:
A study of the effects of long‐term use on individual sensitivity to temazepam and lorazepam in a clinical population
Authors: Van Steveninck Alfred L. , Wallnöfer Andreas E. , Schoemaker Rik C. , Pieters Monique S. M. , Danhof Meindert , Van Gerven Joop M. A. , Cohen Adam F. 
Published: October 2003

Aims The central effects of benzodiazepines may be attenuated after chronic use by changes in pharmacokinetics, pharmacodynamics or both. This attenuation may be influenced by the dosing pattern and the characteristics of the user population. The objectives of this study were to evaluate drug sensitivity in long‐term users of temazepam and lorazepam in a clinical population. Methods The sensitivity to benzodiazepine effects in chronic users (1–20 years) of lorazepam (n=14) or temazepam (n=13) was evaluated in comparison with age and sex matched controls. Drug sensitivity was evaluated by plasma concentration in relation to saccadic eye movement parameters, postural stability and visual analogue scales. Results Pharmacokinetics of lorazepam and temazepam did not differ between patients and control subjects. Chronic users of lorazepam showed clear evidence of reduced sensitivity, indicated by lack of any pharmacodynamic difference between patients and controls at baseline, when drug concentrations were similar to the peak values attained in the control subjects after administration of 1–2.5 mg of lorazepam. In addition, there was a two‐ to four fold reduction in the slopes of concentration‐effect plots for measures of saccadic eye movements and body sway (all; P≤0.01). By contrast, sensitivity in chronic users of temazepam was not different from controls. The difference between the temazepam and the lorazepam group appears to be associated with a more continuous drug exposure in the latter, due to the longer half‐life and a more frequent intake of lorazepam. This pattern of use may be partly related to the more anxious personality traits that were observed in the chronic users of lorazepam. Conclusions Chronic users of lorazepam show evidence of tolerance to sedative effects in comparison with healthy controls. Tolerance does not occur in chronic users of temazepam. The difference may be related to pharmacological properties, in addition to different patterns of use, associated with psychological factors.
An evaluation of the interaction of meloxicam with frusemide in patients with compensated chronic cardiac failure
Authors: Müller F. O. , Middle M. V. , Schall R. , Terblanché J. , Hundt H. K. L. , Groenewoud G. 
Published: October 2003

Aims To evaluate the interaction of meloxicam with frusemide in patients with compensated cardiac failure. Methods Nineteen patients with Grade II or III compensated chronic cardiac failure completed this randomized, double‐blind, cross‐over study. The patients received 40 mg frusemide day−1 for 7 days. Thereafter, patients received either 15 mg meloxicam plus 40 mg frusemide day−1, or one placebo tablet plus 40 mg frusemide day−1 for 7 days. After a washout period of 7 days during which patients received 40 mg frusemide day−1 for 7 days, the patients were crossed over to the alternate treatment. The effect of concomitant ingestion of meloxicam and frusemide on frusemide‐induced diuresis, urine and serum electrolytes, urinary frusemide excretion, and plasma frusemide pharmacokinetics was also determined. Results The estimate (90% confidence interval) of the ‘(frusemide+meloxicam)/(frusemide alone)’ mean ratio of the variables Cmax, AUCss and Cmax/AUCss for plasma frusemide were 121% (101% to 145%), 106% (96.4% to 117%), and 114% (98.3% to 132%), respectively. Similarly, the estimate (90% confidence interval) of the ‘(frusemide+meloxicam)/(frusemide alone)’ of the mean ratio of the variable cumulative urinary frusemide excretion after multiple doses of frusemide were 123% (101% to 150%) for the period 0–8 h, and 122% (105% to 142%) for the period 0–24 h after drug administration on day 7. The estimate (90% confidence interval) of the ‘(frusemide+meloxicam)/(frusemide alone)’ mean ratio of the pharmacodynamic variables cumulative sodium excretion was 105% (95.2% to 116%) for the period 0–8 h and 108% (96.5% to 121%) for the period 0–24 h after drug administration on day 7. Conclusions Meloxicam may lead to slightly increased maximum concentrations of frusemide in plasma, as well as to slightly increased urinary excretion of frusemide, without affecting the pharmacodynamics of frusemide. Thus there is no clinically significant pharmacokinetic or pharmacodynamic interaction of meloxicam with frusemide following repeated co‐administration of meloxicam and frusemide to patients with compensated chronic cardiac failure.
Decreased oral availability of cyclosporin A at second administration in humans
Authors: Lee Young‐Joo , Chung Suk‐Jae , Shim Chang‐Koo 
Published: October 2003

Aims The objective of this study was to determine the extent of period effect on the pharmacokinetics of cyclosporin A (CsA) during consecutive dosing. Methods Sandimmune Neoral® and Neoplanta® capsules were administered to twenty‐four healthy Korean male subjects at a single CsA dose of 175 mg in a 2×2 crossover investigation with a 2‐week wash‐out phase. Concentrations of CsA in blood were measured by a r.i.a. method for a period of 48 h. Results The two formulations were found bioequivalent, but analysis of variance (ANOVA) indicated that there is a significant (P<0.01) period effect in AUC(0,last) (area under the blood concentration‐time curve above the assay limit) and Cmax (maximum blood concentration) between the administrations. A 6 and 9% decrease in the AUC(0,last) and Cmax, respectively was seen at the second administration. Conclusions This period effect on the pharmacokinetics of CsA may be relevant for the patients who need consecutive administration of the drug.
Clinical trials and clinical practice: do doctors use the same criteria to judge outcome?
Authors: Mark Chaput de Saintonge D. , Evans S. J. W. , Crane G. J. , Kirwan J. R. 
Published: October 2003

Aims The results of clinical trials often seem to have little influence on the practice of individual doctors. This could be because trial information is presented in the style of a scientific experiment which cannot often be clearly related to the context of everyday patient care. We tested the hypothesis that such framing effects would cause doctors to assess the clinical significance of treatment outcomes differently when presented as clinical trial results rather than as individual patient data. Methods Fourteen rheumatologists independently reviewed the same 50 sets of data obtained from patients with rheumatoid arthritis. The data consisted of 10 commonly used clinical and laboratory variables measured before and after a period of treatment. The same data were presented in two formats on two separate occasions. The patient data format was a collection of typed sheets attributing each set of results to an individual patient. The clinical trial format was a professionally printed and bound booklet in which each set of results was laid out as summary results of a small uncontrolled clinical trial. Doctors judged the degree of improvement or deterioration and its clinical importance for each data set for both formats. These changes were converted into units of ‘Clinical Importance’. Results Although some statistically significant differences emerged in the individual doctors’ judgements between the formats none of these was of a clinically important size. The median of the mean trial—patient difference between the formats for all 14 doctors was 0.035 units of clinical importance [ 95% CI −0.244 to 0.074]. Conclusions This evidence does not support the hypothesis that framing effects are a major cause of the failure of clinical trials to influence clinical practice.
Effect of simvastatin on cyclosporine unbound fraction and apparent blood clearance in heart transplant recipients
Authors: Akhlaghi Fatemeh , McLachlan Andrew J. , Keogh Anne M. , Brown Kenneth F. 
Published: October 2003

Aims To investigate the effects of lipid lowering therapy on the fraction unbound and dosage requirement of cyclosporine in heart transplant recipients. Methods Cyclosporine fraction unbound (fu) was measured ex vivo in plasma obtained from heart transplant recipients (n=12) before and after lipid lowering treatment, using equilibrium dialysis. Cyclosporine trough concentration data were also collected from cardiac transplant recipients (n=32) who received simvastatin for the treatment of hyperlipidaemia. Cyclosporine daily dosage and total concentration (monoclonal FPIA method) were recorded for periods up to 6 months before and after simvastatin administration. The total number of dose rate‐concentration observations was 172 before and 135 after simvastatin administration respectively. Using a population pharmacokinetic approach (implemented in P‐PHARM software) the ratio of dose rate to trough concentration at steady state (DR/Csstrough ), an estimation of apparent clearance, was determined. The posterior Bayesian estimate of DR/Csstrough was calculated for each patient before and after simvastatin administration. Results The mean fu increased by 29%, from 1.40±0.1% (mean±s.d.) to 1.82±0.22% after simvastatin administration (P<0.01). Mean trough concentrations of cyclosporine in whole blood were 349 μg l−1 before and 242 μg l−1 after simvastatin administration (P<0.0001). The mean cyclosporine daily dosage was 2.87 mg kg−1 and 2.33 mg kg−1 (NS), before and after simvastatin administration respectively. The average cyclosporine DR/Csstrough was significantly increased from 24.5 l h−1 before to 28.9 l h−1 after simvastatin administration (P<0.05). Furthermore the median increase in cyclosporine DR/Csstrough was 18 l h−1 (−3.1 to 42.1 l h−1, interquartile range). Conclusions Cyclosporine fraction unbound and clearance are increased following co‐administration of lipid lowering agents, necessitating closer monitoring of cyclosporine total blood concentration when lipid lowering agents are administered concomitantly with cyclosporine.
Trimetazidine does not modify blood levels and immunosuppressant effects of cyclosporine A in renal allograft recipients
Authors: Simon Nicolas , Brunet Philippe , Roumenov Dimitri , Dussol Bertrand , Barre Jerome , Duche Jean‐Claude , Albengres Edith , D’Athis Philippe , Chauvet‐Monges Anne‐Marie , Berland Yvon , Tillement Jean‐Paul 
Published: October 2003

Aims In renal allograft recipients, trimetazidine (Vastarel® ) was proposed to be associated with the classic immunosuppressant treatments because it displays anti‐ischaemic effects which may protect against cyclosporine A nephrotoxicity. The objective of this work was to assess the possibility of coadministering cyclosporin A, Sandimmun®, and trimetazidine. Methods Twelve renal transplant patients were selected on the basis of the stability of their cyclosporine A blood concentrations for the previous 3 months. They received trimetazidine, 40 mg twice daily orally for 5 days. Other coadministered drugs were kept unchanged during the study. Before and after trimetazidine administration, cyclosporine A blood concentrations, plasma interleukin‐2 and soluble interleukin‐2 receptor levels were measured. Results The data showed that neither cyclosporin A blood pharmacokinetic parameters, Cmax, tmax, AUC, nor the concentrations of interleukin‐2 and soluble interleukin‐2 receptors were significantly modified. Conclusions Therefore, it was suggested that trimetazidine may be coadministered with cyclosporine A without cyclosporine A dosage adjustment.
The interaction between propranolol and the novel antimigraine agent zolmitriptan (311C90)
Authors: Peck Richard W. , Seaber Emma J. , Dixon* Ruth , Gillotin† Catherine G. , Weatherley Barry C. , Layton** Gary , Posner‡ John 
Published: October 2003

Aims Zolmitriptan (Zomig, formerly known as 311C90), a selective 5HT1B/1D agonist is under development as an acute oral treatment for migraine. Despite the use of prophylactic medication, such as propranolol, breakthrough attacks often occur in patients. Consequently we investigated the effects of propranolol on the pharmacokinetics of, and cardiovascular responses to, zolmitriptan. Methods A double‐blind, randomized, crossover study of the effects of pre‐treatment with propranolol 160 mg daily for 7 days or placebo on the pharmacokinetics and effects on blood pressure of a single 10 mg dose of zolmitriptan in 12 healthy volunteers. Results Propranolol increased mean zolmitriptan Cmax and AUC by 56% and 37% respectively; mean t1/2 was prolonged from 3.1 to 4.0 h. Mean Cmax and AUC of the pharmacologically active N‐desmethyl metabolite were reduced by 24% and 11% respectively and the metabolite:parent AUC ratio (AUCm/AUCp ) fell from 0.46 to 0.26. Mean Cmax and AUC for the inactive indole acetic acid metabolite were both reduced by 13% and AUCm/AUCp from 1.04 to 0.59. A small pressor effect of short duration was observed following zolmitriptan with mean peak rises of 13 and 11 mmHg in systolic and diastolic pressures respectively; propranolol had no effect on the pressor response. Conclusions The results suggest that propranolol inhibits biotransformation of zolmitriptan but with no change in the small pressor response to zolmitriptan. It is therefore unlikely that the pharmacokinetic changes will lead to clinically important changes in pharmacological effects and dosage adjustment of zolmitriptan is not required in patients taking propranolol for migraine prophylaxis.
Clinical relevance of residual disease monitoring by polymerase chain reaction in patients with ALL‐1/AF‐4 positive‐acute lymphoblastic leukaemia
Authors: Cimino Giuseppe , Elia Loredana , Rivolta Anna , Rapanotti Maria Cristina , Rossi Vincenzo , Alimena Giuliana , Annino Luciana , Canaani Eli , Lo Coco Francesco , Biondi Andrea 
Published: October 2003

In this study we used reverse transcriptase‐polymerase chain reaction (RT‐PCR) for the longitudinal monitoring of minimal residual disease in 12 patients with ALL‐1/AF‐4 positive ALL. Of these, seven also showed at presentation a typical t(4;11) cytogenetic translocation. Seven patients were infants <18 months of age and five were adults.Eleven patients were treated with high‐dose intensive induction and consolidation chemotherapy without bone marrow transplantation and one received conservative treatment due to poor performance status. Three had resistant disease, four relapsed within 12 months after achieving complete remission, and five are in continuous complete remission (CCR) at 32, 39, 52, 53 and 61 months from diagnosis, respectively. The sequential analysis of the ALL‐1/AF‐4 hybrid transcript showed a persistently negative RT‐PCR in the five CCR long‐term survivors. The PCR analysis resulted persistently positive in the remaining seven cases, including the four cases who relapsed after the achievement of clinical CR.These data emphasize the clinical relevance of PCR monitoring analysis in t(4;11) ALL patients and should be considered in order to better determine variable post‐remission treatment according to risk prediction.
N‐acetylcysteine induces beneficial changes in the acinar cell cycle progression in the course of acute pancreatitis
Authors: Sevillano S. , De Dios I. , De La Mano A. M. , Manso M. A. 
Published: October 2003

Abstract.  Oxygen free radicals (OFR) are produced in the course of acute pancreatitis (AP). In addition to injurious oxidative effects, they are also involved in the regulation of cell growth. The aim of the present study was to examine the relationship between the effectiveness of N‐acetyl‐l‐cysteine (NAC) to prevent the generation of OFR and the changes in the cell‐cycle pattern of acinar cells in the course of AP induced in rats by pancreatic duct obstruction (PDO). NAC (50 mg/kg) was administered 1 h before and 1 h after PDO. Flow‐cytometric measurement of OFR generation in acinar cells was carried out using dihydrorhodamine as fluorescent dye. Plasma amylase activity, pancreatic glutathione (GSH) content and TNF‐α plasma levels were also measured. The distribution of acinar cells throughout the different cell‐cycle phases was analysed at different AP stages by flow cytometry using propidium iodide staining. NAC administration reduced the depletion of pancreatic GSH content and prevented OFR generation in acinar cells of rats with PDO‐induced acute pancreatitis. As a result, AP became less severe as reflected by the significant improvement of hyper‐amylasaemia and maintenance of plasma TNF‐α levels at values not significantly different from controls were found. NAC administration inhibited progression of cell‐cycle phases, maintaining acinar cells in quiescent state at early PDO times. The protection from oxidative damage by NAC treatment during early AP, allows the pancreatic cell to enter S‐phase actively at later stages, thereby allowing acinar cells to proliferate and preventing the pancreatic atrophy provoked by PDO‐induced AP. The results provide evidence that OFR play a critical role in the progression of acinar cell‐cycle phases. Prevention of OFR generation of acinar cells in rats with PDO‐induced AP through NAC treatment, not only protects pancreas from oxidative damage but also promotes beneficial changes in the cell cycle progression which reduce the risk of pancreatic atrophy.
‘Entopy’: localized mucosal allergic disease in the absence of systemic responses for atopy
Authors: Powe D. G. , Jagger C. , Kleinjan A. , Carney A. S. , Jenkins D. , Jones N. S. 
Published: October 2003

SummaryBackground
The Th2 immune response in the nasal mucosa of subjects with allergic rhinitis is mediated by allergen‐specific IgE. Moreover, these subjects show positive responses for markers of systemic atopy, including allergen‐specific skin sensitivity and raised serum IgE titres. In contrast, idiopathic rhinitis (IR) subjects with similar histological nasal mucosal features differ in being defined as non‐allergic because they have negative atopic responses.Objective
We hypothesized that it is possible to have an allergic Th2 disease pathway localized in the nasal mucosa of ‘non‐allergic’ rhinitis subjects despite an absence of atopic responses.Methods
The presence of house dust mite and grass pollen‐specific IgE antibodies was investigated in non‐atopic (n=10) and atopic (n=11) subjects with persistent rhinitis and compared to normal (n=12) control subjects. Biotin‐labelled allergen was used to localize specific allergen‐binding antibodies in situ in sections of nasal mucosa.Results
Grass pollen allergen binding was detected in the nasal mucosa of 3/10 non‐atopic IR subjects but, in contrast, dust mite‐specific antibodies were not detected. Specific antibodies were present in a total of 8/11 mucosal samples from the allergic group, but none was detected in normal control tissues.Conclusion
These findings support the concept of localized nasal allergy in ‘non‐atopic’ rhinitis subjects. We propose the term ‘entopy’ to define this phenomenon and believe that this concept has a wider implication for localized allergic responses in other mucosal sites.
CpG DNA and immunotherapy of allergic airway diseases
Authors: Jain V. V. , Kitagaki K. , Kline J. N. 
Published: October 2003

SummaryAtopic asthma is a highly prevalent and serious health problem for which no therapy currently offers the hope of a cure. Preindustrialized and rural populations appear relatively protected from the asthma epidemic; the hygiene hypothesis ascribes this protection to the effects of microbes and microbial products. An important immunostimulant component of microbes is DNA; bacterial DNA contains sequence motifs centred on the CpG dinucleotide, which are suppressed in mammalian DNA. Oligonucleotides containing these motifs (CpG ODN), like bacterial DNA, promote Th1 and regulatory‐type immune responses. Using CpG ODN, we and others have demonstrated in murine studies that CpG ODN are effective in preventing the development of atopic airways disease. Moreover, when administered in conjunction with experimental allergen, they promote the reversal of established eosinophilic inflammation. These data suggest that CpG ODN may be a novel therapeutic tool for the treatment of atopic asthma.
Interleukin‐1β and interleukin‐1ra levels in nasal lavages during experimental rhinovirus infection in asthmatic and non‐asthmatic subjects
Authors: De Kluijver J. , Grünberg K. , Pons D. , De Klerk E. P. A. , Dick C. R. , Sterk P. J. , Hiemstra P. S. 
Published: October 2003

SummaryBackground
Exacerbations of asthma are often associated with rhinovirus (RV)‐induced common colds. During experimental RV‐infection in healthy subjects, increased levels of the pro‐inflammatory mediator IL‐1β and the anti‐inflammatory IL‐1 receptor antagonist (IL‐1ra) have been found in nasal lavage.Objective
We postulated that the balance between nasal pro‐ and anti‐inflammatory mediator expression is disturbed in asthma, resulting in more extensive inflammation following RV‐exposure in asthma.Methods
We determined IL‐1ra, IL‐1β, and IL‐8 in nasal lavages (days −2, 3, and 6) of non‐asthmatics and asthmatics (with and without pre‐treatment with the inhaled steroid budesonide) before and after experimental RV16‐infection (days 0 and 1).Results
Following RV16‐infection, a significant increase in IL‐8 was observed in the placebo‐ and budesonide‐treated asthmatics (P=0.033 and 0.037, respectively), whereas IL‐1β only increased in the two asthma groups combined (P=0.035). A small, but significant, increase in IL‐1ra was only observed in the budesonide‐treated asthmatics (P=0.047). At baseline, IL‐1ra levels were significantly higher in the non‐asthmatics than in the placebo‐treated asthmatics (P=0.017).Conclusion
These results demonstrate differences between non‐asthmatic and asthmatic subjects in the basal levels of nasal cytokines and their inhibitors, and in the effect of experimental RV‐infection on these levels. The results indicate that RV may enhance inflammation more markedly in asthmatics, and suggest that this may in part be explained by lower IL‐1ra levels. In addition, the observation that budesonide‐treatment may result in higher nasal IL‐1ra levels supports the hypothesis that steroids act in part by increasing the endogenous anti‐inflammatory screen.
Role of carbohydrates in repair of human respiratory epithelium using an in vitro model
Authors: Adam E. C. , Holgate S. T. , Fildew C. J. , Lackie P. M. 
Published: October 2003

SummaryBackground
The epithelial layer in the conducting airway provides a primary protective barrier. Repair of this barrier normally occurs rapidly after damage, but is compromised in diseases such as asthma.Objective
We have developed a human in vitro model system to test our hypothesis that cell surface glycoconjugate‐based interactions are required for the normal repair of damaged epithelium.Methods
Lectins having narrow carbohydrate specificities were used to identify and block specific carbohydrate moieties on human airway‐derived epithelial cells in culture.Results
The lectin wheat germ agglutinin bound to N‐acetyl glucosamine and inhibited the repair of epithelial damage while having little effect on cell viability. In contrast, other N‐acetyl glucosamine binding lectins had no effect even when bound to the cell surface. The involvement of glycoconjugates was confirmed by pre‐incubating the lectin with its specific sugar, preventing the inhibition of repair.Conclusion
These results indicate that lectin‐binding sites are involved in epithelial repair and may be important in the repetitive cycles of injury and repair seen in asthma. This model system provides an insight into the role of glycoconjugates and will help to determine the function of specific carbohydrate groups in epithelial repair. These may present a target for therapeutic intervention in respiratory and other diseases.