bluuebunny/crossref_metadata_2025_split huggingface dataset:
TGF‐β and TNF‐α stimulate MMP‐9 production in murine epidermal keratinocytes
Authors: FUJISAWA Chie , INADA Noriko , MOCHIZUKI Rika , ARAI Katsuhiko , UEHARA Kohkichi 
Published: December 2004

ABSTRACTMatrix metalloproteinases 2 and 9 (MMP‐2 and ‐9) are zinc‐dependent metalloenzymes and have gelatin‐degrading activity. Both MMP are known to be secreted by many types of cells and play important roles in several biological changes including tissue remodeling and wound healing. In the present study, a primary culture of murine epidermal keratinocytes was prepared and effects of transforming growth factor‐β (TGF‐β), tumor necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ) on expression of MMP‐2 and MMP‐9 by the keratinocytes was examined. Gelatin zymography revealed that murine epidermal keratinocytes secreted proenzyme forms of MMP‐2 and MMP‐9, but the active forms of both MMP were hardly detectable, indicating that in vitro autoactivation of these proenzymes did not occur. Both TGF‐β and TNF‐α stimulated MMP‐9 production in a dose‐dependent manner, but the MMP‐2 level was not changed. Interferon‐γ hardly affected production of MMP‐2 or MMP‐9. Ribonuclease protection assay demonstrated that TNF‐α increased the level of MMP‐9 mRNA 6‐fold compared to the control, whereas TGF‐β slightly up‐regulated it. These results suggest that expression of MMP‐9 could be regulated by several cytokines in murine epidermal keratinocytes.
DNA polymorphism in the chicken growth hormone gene: Association with egg production
Authors: KANSAKU Norio , NAKADA Asako , OKABAYASHI Hisato , GUÉMENÉ Daniel , KUHNLEIN Urs , ZADWORNY David , SHIMADA Kiyoshi 
Published: December 2004

ABSTRACTRestriction fragment length polymorphic markers in the chicken growth hormone (GH) gene were tested for their association with egg production traits. Alleles of GH were determined in 3 non‐inbred strains from different genetic bases. The frequency of PS1 (+) allele in the three strains was very low in contrast to the layer strain previously reported. Results of the present study indicate that the frequency of PS (+) is related to egg production and that the PS1 (+) allele may be used as a genetic marker for selection in egg production.
A computer model for the measurement of compliance using a dual tracer technique‘pa
Authors: Shine D. , McDonald J. 
Published: December 2004

Aims We aimed to determine whether simultaneous use of two tracer compounds with long and differing elimination half‐lives may permit more precise recognition of percent compliance and discrimination among remote, intermediate, and recent patterns of daily dosing. Methods We have derived, through computer modelling, the potential utility of digitoxin and phenobarbitone as simultaneous tracers. From kinetic data on these reliably measured compounds with long half‐lives we defined the percentage error below which this pair of tracers can be expected to discern the precise, and the approximate, pattern and number of daily doses taken over a month. Results The longer the half‐lives of the tracers the greater the sensitivity of our model to percentage compliance. At extremely long half‐lives, relative to the period of dosing being monitored, sensitivity approaches 100% if measurement error is in the 1–2% range. The ratio of the half‐lives between the two tracers that is optimal for detection of percentage compliance is 0.2 to 0.8. The detection of pattern does not depend importantly either on the tracer half‐lives or on their ratio to each other. The greater the percentage compliance, the more accurately our two‐tracer model determines the pattern of dosing. Conclusions Precise characterization of compliance using tracers must probably await the development of compounds with half‐lives measured in weeks or months. The probability of compliance of a given degree can be derived from our two‐tracer technique with best‐fit analysis such as we describe.
The effect of the neutral endopeptidase inhibitor drug, candoxatril, on circulating levels of two of the most potent vasoactive peptides
Authors: McDowell G. , Coutie W. , Shaw C. , Buchanan K. D. , Struthers A. D. , Nicholls D. P. 
Published: December 2004

Aims Candoxatril is a specific neutral endopeptidase (NEP) 24.11 inhibitor, and previous work has documented the effect of NEP inhibition on atrial and brain natriuretic peptides (ANP, BNP). The aim of the present study was to ascertain the effect of NEP inhibition on circulating levels of vasoactive peptides. Methods We studied seven patients with chronic heart failure who were randomized to receive candoxatril, candoxatril/captopril, captopril and placebo in a four way cross over, double‐blind pattern. Results The mean circulating level of endothelin (ET) was increased 2 h after placebo (10 to 20 pg ml−1 ) and also calcitonin gene‐related peptide (CGRP) (27 to 51 pg ml−1 ), but ANP levels changed little during this time (73 to 75 pg ml−1 ). Following candoxatril, however, ET (10 to 39 pg ml−1, P<0.05), CGRP (34 to 99 pg ml−1, P<0.05) and ANP (72 to 108 pg ml−1, P<0.05) increased further. A similar result was observed following combined treatment with candoxatril and captopril. Conclusions We conclude that neutral endopeptidase inhibition increases circulating plasma levels of ET and CGRP in addition to the natriuretic peptides.
Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole
Authors: Lefebvre Romain A. , Van Peer Achiel , Woestenborghs Robert 
Published: December 2004

Aims The aim of this study was to investigate the influence of chronic itraconazole treatment on the pharmacokinetics and cardiovascular effects of single dose astemizole in healthy subjects was studied. Methods Twelve male volunteers were taking orally 200 mg twice daily itraconazole or placebo for 14 days with a washout period of 4 weeks in between. Approximately 2 h after the morning dose of itraconazole or placebo on day 11, 10 mg astemizole was orally administered. The plasma concentrations of astemizole and desmethylastemizole were measured by radioimmunoassay up to 504 h after administration; electrocardiograms with analysis of the QTc interval were recorded up to 24 h post administration. Results Itraconazole treatment did not significantly change the peak concentration of astemizole (0.74 vs 0.81 ng ml−1 ) but it increased the area under the curve from 0 to 24 h (5.46 to 9.95 ng ml−1 h) and from 0 to infinity (17.4 to 48.2 ng ml−1 h), and the elimination half‐life (2.1 to 3.6 days). The systemic bioavailability of desmethylastemizole was also increased. The QTc interval did not increase after astemizole administration and there was no difference in the QTc intervals between the itraconazole and placebo session. Conclusions Chronic administration of itraconazole influences the metabolism of single dose astemizole in normal volunteers without changes of cardiac repolarization during the first 24 h after astemizole administration. However, the reduction in astemizole clearance under concomitant administration of itraconazole may result in a marked increase in astemizole plasma concentrations and QTc alterations during chronic combined intake of astemizole with itraconazole.
Twenty‐four hour plasma profile of sustained‐release isosorbide mononitrate in healthy volunteers and in patients with chronic stable angina. Two open label trials
Authors: Baxter T. , Eadie C. J. 
Published: December 2004

Aims The plasma profile of a single dose of isosorbide mononitrate 25 mg (Elantan LA25) in healthy volunteers and in angina patients was examined. Methods In volunteers and patients, blood samples for pharmacokinetics were obtained pre‐dosing and at intervals for 24 h after dosing. Results This formulation exhibited rapid absorption and plasma levels were maintained at >100 ng ml−1 for up to 9 to 12 h. Conclusions A comparison of the pharmacokinetics of Elantan® LA25 in volunteers and patients indicates that the profiles are similar.
Pharmacokinetics of vanadium in humans after intravenous administration of a vanadium containing albumin solution
Authors: Heinemann Günter , Fichtl Burckhard , Vogt Wolfgang 
Published: December 2004

Aims
Vanadium is currently undergoing clinical trials as an oral drug in patients with noninsulin‐dependent diabetes mellitus. Furthermore, vanadium occurs in elevated concentrations in the blood of patients receiving intravenous albumin solutions containing large amounts of the metal ion as an impurity. The present study was performed to examine the pharmacokinetics of vanadium in humans following a single intravenous (i.v.) dose of a commercial albumin solution containing a high amount of vanadium.
Methods
The study was conducted in five healthy volunteer subjects who received intravenously 90 ml of a commercial 20% albumin infusion solution containing 47.6 µg vanadium as an impurity. Vanadium concentrations in serum and urine were determined by electrothermal atomic absorption spectrometry.
Results
Vanadium serum concentrations after i.v. administration were measured for 31 days. The data could be fitted by a triexponential function corresponding formally to a three‐compartment model. There was an initial rapid decrease in serum concentrations with half‐lives of 1.2 and 26 h. This was followed by a long‐terminal half‐life time of 10 days. The terminal phase accounted for about 80% of the total area under the serum concentration‐time curve (AUC). The mean apparent volume of distribution of the central compartment was found to be 10 l. The volume of distribution at steady state was 54 l, and total clearance was 0.15 l h−1. Vanadium was mainly excreted by the kidneys. About 52% of the dose was recovered in the urine after 12 days.
Conclusions
This study provides data on vanadium pharmacokinetics in healthy humans.
Glutathione, glutathione‐dependent enzymes and antioxidant status in erythrocytes from children treated with high‐dose paracetamol
Authors: Kozer Eran , Evans Sandra , Barr Joseph , Greenberg Revital , Soriano Ingrid , Bulkowstein Mordechai , Petrov Irena , Chen‐Levi Zehava , Barzilay Bernard , Berkovitch Matitiahu 
Published: December 2004

Aim
To investigate glutathione and antioxidant status changes in erythrocytes from febrile children receiving repeated supratherapeutic paracetamol doses.
Methods
Fifty‐one children aged 2 months to 10 years participated in the study. Three groups were studied: group 1 (n = 24) included afebrile children who did not receive paracetamol; and groups 2 (n = 13) and 3 (n = 14) included children who had fever above 38.5°C for more than 72 h. Patients in group 2 received paracetamol at a dose of 50 ± 15 (30–75) mg kg−1 day−1 and those in group 3 received paracetamol above the recommended therapeutic dose, ie 107 ± 28 (80–180) mg kg−1 day−1. A blood sample was taken for the measurement of liver transaminases, gammaglutamil transferase (GGT), reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPX), glutathione S‐transferase (GST), superoxide dismutase (SOD) and antioxidant status.
Results
Aspartate aminotransferase activity in group 3 was higher than in the other groups (P = 0.027). GSH, SOD and antioxidant status were significantly lower in group 3 compared with groups 1 and 2 (mean differences: for GSH 3.41 µmol gHb−1, 95% confidence interval (CI) 2.10–4.72, and 2.15 µmol gHb−1, 95% CI 0.65–3.65, respectively; for SOD 856 U min−1 gHb−1, 95% CI 397–1316, and 556 U min−1 gHb−1, 95% CI 30–1082, respectively; and for antioxidant status 0.83 mmol l−1 plasma, 95% CI 0.30–1.36, and 0.63 mmol l−1 plasma, 95% CI 0.02–1.24, respectively). GR activity was significantly lower in groups 3 and 2 in comparison with group 1 (mean differences 3.44 U min−1 gHb−1, 95% CI 0.63–6.25, and 5.64 U min−1 gHb−1, 95% CI 2.90–8.38, respectively). Using multiple regression analysis, paracetamol dose was found to be the only independent variable affecting GR, GST and SOD activities (P = 0.007, 0.003 and 0.008, respectively).
Conclusions
In febrile children, treatment with repeated supratherapeutic doses of paracetamol is associated with reduced antioxidant status and erythrocyte glutathione concentrations. These significant changes may indicate an increased risk for hepatotoxicity and liver damage.
Who receives lipid‐lowering drugs: the effects of comorbidities and patient characteristics on treatment initiation
Authors: Yang Chen‐Chang , Jick Susan S. , Testa Marcia A. 
Published: December 2004

Aims
Little is known about the effects of comorbidities and patient characteristics on treatment initiation of lipid‐lowering drugs (LLDs), which can be helpful in the evaluation of the risks and benefits of LLDs.
Methods
Baseline characteristics among subjects who received their first ever‐recorded LLD prescription in general practice between 1 January  1990 and 31 December  1997, and hyperlipidaemic patients without LLD therapy during the same period were obtained from the UK General Practice Research Database. Differences between patients who received and patients who did not receive LLDs, as well as patients who received different classes of LLDs were compared by fitting multivariate logistic regression models that adjusted for age, sex, body mass index, smoking status, and year of treatment initiation or hyperlipidaemia diagnosis.
Results
We found that there were many differences in the baseline characteristics, such as number of general practitioner visits, diagnosis and severity of cardiovascular diseases, and concurrent medications, between the 25 331 patients who received and the 16 287 patients who did not receive LLDs. We also noted that patients with statin therapy had more prior hospitalization, more recent myocardial infarction/stroke, and more concurrent cardiovascular medications, than those patients who received other LLDs.
Conclusions
Patients who received LLDs in primary care, especially patients with statin therapy, were more likely to be elderly and to have more concomitant severe cardiovascular comorbidities than those hyperlipidaemic patients who did not receive LLDs. Examining the medical records of individuals eligible for LLD therapy is an important first step in selectively targeting who will experience the greatest benefit to risk ratio for the treatment of hyperlipidaemia, and is an important step in avoiding confounding by indication when designing epidemiological studies comparing the risks and benefits of treatments for hyperlipidaemia.
Bronchodilator effects of intravenous olprinone, a phosphodiesterase 3 inhibitor, with and without aminophylline in asthmatic patients
Authors: Myou Shigeharu , Fujimura Masaki , Kamio Yumie , Hirose Tatsuki , Kita Toshiyuki , Tachibana Hideki , Ishiura Yoshihisa , Watanabe Kazuyoshi , Hashimoto Takuma , Nakao Shinji 
Published: December 2004

Aims There is no evidence demonstrating the clinical usefulness of phosphodiesterase (PDE) inhibitors in the treatment of asthma, although PDE3 and 4 inhibitors have received much attention for the treatment of bronchial asthma. We compared the bronchodilator effects of intravenously administered olprinone, a selective PDE3 inhibitor, and aminophylline, a nonselective PDE inhibitor, both alone and concomitantly.Methods In 12 patients with mild stable asthma, we compared the acute bronchodilator effects of the following two drugs, alone and together using a double‐blind crossover design: intravenous administration of olprinone, 30 µg min−1; aminophylline, 2.25 mg min−1; and olprinone plus aminophylline over a total period of 150 min.Results Mean maximal increase (95% confidence interval) in the FEV1 was 7.8% (2.4, 13.2), 17.1% (10.0, 24.2), 16.6% (11.2, 22.0), and 1.0% (−1.1, 3.1) during infusion of aminophylline, olprinone, aminophylline and olprinone, and saline, respectively. The magnitude of bronchodilatation produced by olprinone was greater than that by aminophylline. The combination of aminophylline and olprinone did not produce any greater bronchodilatation than olprinone alone. Olprinone alone or in combination with aminophylline lowered diastolic blood pressure, and increased heart rate.Conclusions These results suggest that the intravenous administration of PDE3 inhibitors exhibits a bronchodilatory effect. There are no additive or synergistic effects of administration of olprinone and aminophylline at the same time.
Undertreatment of hypercholesterolaemia: a population‐based study
Authors: Mantel‐Teeuwisse A. K. , Verschuren W. M. M. , Klungel O. H. , Kromhout D. , Lindemans A. D. , Avorn J. , Porsius A. J. , De Boer A. 
Published: December 2004

Aims  To assess the level of undertreatment of hypercholesterolaemia in the general population, taking intra‐person variability in serum cholesterol concentrations into account, and to identify determinants of undertreatment of hypercholesterolaemia.Methods  In this cross‐sectional study, data from two population‐based surveys on cardiovascular disease risk factors conducted between 1987 and 1997 in the Netherlands were used. For all 64 757 respondents aged 20–59 years, treatment eligibility for lipid‐lowering drug use was established according to the Dutch Cholesterol Consensus. Multivariate logistic models were used to identify determinants of undertreatment.Results  During the study period, 56.8% of the study population had undesirable cholesterol concentrations (serum total cholesterol> 5 mmol l−1) and 5.5% of those were eligible for pharmacological treatment based on their absolute risk of coronary heart disease. Of those eligible for pharmacological treatment, 16.3% were treated, and 19.6% of those treated had their serum total cholesterol concentration controlled. Only 3.2% of those eligible for pharmacological treatment were both treated and controlled. We identified several determinants for undertreatment, e.g. male gender and younger age for primary prevention and female gender and older age for secondary prevention. Treatment has improved slightly in more recent years.Conclusions  Over 95% of the population eligible for the pharmacological treatment of hypercholesterolaemia was either untreated or was uncontrolled. To decrease undertreatment, identification of high‐risk patients should be increased. Those who are treated with lipid‐lowering medication could further benefit from more aggressive treatment, especially with statins.
Low blood selenium concentrations in schizophrenic patients on clozapine
Authors: Vaddadi K. S. , Soosai E. , Vaddadi G. 
Published: December 2004

Aims
To compare plasma and red‐cell selenium concentrations of schizophrenic patients treated with clozapine, with healthy controls and patients with mood disorders.
Methods
Plasma and red‐cell selenium concentrations were measured in random venous blood samples from four groups: mood disorder (n = 36), schizophrenics treated with clozapine (n = 54), schizophrenics not treated with clozapine (n = 41) and a healthy control group (n = 56). Assays were performed by an independent laboratory that was blinded to the patient groups and specializes in estimating trace metal concentrations.
Results
Selenium concentrations in plasma and red cells were found to be significantly lower in schizophrenic patients treated with clozapine as compared with all other groups.
Conclusions
Selenium is an essential antioxidant. Its deficiency has been implicated in myocarditis and cardiomyopathy. Low selenium concentrations in clozapine‐treated patients may be important in the pathogenesis of life threatening cardiac side‐effects associated with clozapine. Further clinical studies are being conducted to explore this important clinical observation and its therapeutic implications.
Development, implementation and cost‐effectiveness of a protocol for review of combination diuretic prescribing
Authors: Morgan Julie D. , Wright David J. , Chrystyn Henry , George Bethan , Booth Andrew C. , Shoesmith David J. 
Published: December 2004

Aims
To determine the extent of inappropriate prescribing of combination diuretics and the cost implications of protocol implementation.
Methods
Pharmacist‐run medication review clinics in two general practices in Bradford, UK.
Results
Sixty‐one patients, mean ± s.d. age 75.8 ± 12.0 years, were reviewed. Thirty‐six met protocol criteria; 30 (49.2%) patients had their potassium‐sparing diuretics (PSDs) discontinued. Mean (95% confidence interval) reduction in serum potassium concentrations after intervention in these 30 patients was 0.26 (0.09, 0.43) mmol l−1 (P < 0.01). Twenty‐eight (93.3%) patients were within the reference range at follow‐up; none was below.
Conclusions
Of prescribed PSDs, 59% were found to be unnecessary. Using the developed protocol potentially improves drug safety and enables cost savings.
The pharmacokinetics of pioglitazone in patients with impaired renal function
Authors: Budde Klemens , Neumayer Hans‐Hellmut , Fritsche Lutz , Sulowicz Wladyslaw , Stompôr Tomasz , Eckland David 
Published: December 2004

Aims To evaluate the effect of renal impairment on the pharmacokinetics and safety of pioglitazone and its metabolites M‐III and M‐IV with impaired renal function and normal renal function.Methods In a phase‐I, open‐label, parallel‐group study, six healthy subjects with normal renal function (creatinine clearance> 80 ml min−1), nine patients with moderate renal impairment (creatinine clearance 30–60 ml min−1) and 12 patients with severe renal impairment (creatinine clearance < 30 ml min−1) received single and multiple oral doses of pioglitazone 45 mg. The serum pharmacokinetic profiles of pioglitazone and its metabolites M‐III and M‐IV were assessed for the first and last dose administered (day 1 and day 12, respectively).Results Pharmacokinetic data revealed no significant accumulation of pioglitazone or its metabolites M‐III and M‐IV in patients with renal impairment. There was no significant difference in the pharmacokinetic profile of pioglitazone in subjects with normal and with moderately impaired renal function. After single oral doses, mean area under the concentration‐time curve (AUC) values were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (13 476 vs 17 387, P = 0.371; −23%; confidence interval (CI) −57, 38), M‐III metabolite (13 394 vs 15 071, P = 0.841; −11%; CI −74, 194) and M‐IV metabolite (27 991 vs 49 856, P = 0.006; −44%; CI −62, −17). After repeated oral doses of pioglitazone, mean AUC values (µg.h l−1) were decreased in patients with severe renal impairment compared with healthy subjects with normal renal function for pioglitazone (8744 vs 14,565, P = 0.004; −40%; CI −57, −16), M‐III (3991 vs 7,289, P = 0.0009; −45%; CI −60, −25) and M‐IV (21 080 vs 25 706, P = 0.181; −18%; CI 39, 10). The tolerability and safety profile of pioglitazone was comparable between groups.Conclusions Pioglitazone was well tolerated in patients with varying degrees of renal impairment. Although mean serum concentrations of pioglitazone and its metabolites are increased in patients with severe renal impairment, adjustment of starting and maintenance doses in these patients is probably unwarranted.