bluuebunny/crossref_metadata_2025_split huggingface dataset:
Knowledge creation about ADRs – turning the perspective from the rear mirror to the projector?
Authors: Aagaard Lise , Soendergaard Birthe , Stenver Doris I. , Hansen Ebba Holme 
Published: October 2007

What is already known about this subject?• Serious and unexpected adverse drug reactions (ADRs) have been reported shortly after marketing of a number of drugs.• Review of ADR cases by the regulatory authorities has resulted in suspension of drugs or restrictions in product information.What this study adds?• Information about serious and unexpected ADRs of three drugs with reported serious ADRs was already present in the registration files.• Observations of these ADRs were not investigated further before marketing.• A more active utilization of the ADR information in premarketing studies could probably prevent the appearance of unexpected and serious ADR cases after marketing.AimsSpontaneous reports of adverse drug reactions (ADRs) are often the only documentation used to justify the recall of drugs from the market. The purpose of this study was to investigate whether it would have been possible to foresee serious ADR cases based on available information on ADRs reported in Phase II and III clinical trials before marketing.MethodsWe conducted a retrospective analysis of reported ADR data in Phase II/III clinical trials in the registration material for three different ADR scenarios: (i) trovafloxacin/alatrofloxacin and hepatotoxicity; (ii) tolcapone and hepatotoxicity and neuroleptic malignant syndrome; and (iii) rituximab and cytokine release syndrome. We chose the scenarios because they were of serious character and caused great damage to the patients and because of different outcomes of the scientific discussions in the regulatory agencies.ResultsIn all three cases, the registration material contained observations of ADRs, but there had been no follow‐up on these observations. ADRs were mentioned in the summary of product information (SPC) purely as information, to some extent accompanied by recommendations. The information was not converted into new knowledge and remained tacit knowledge embedded in the SPCs disseminated to health professionals/prescribers.ConclusionsThe registration material analysed contained information about ADRs that were reported later, meaning that it would have been possible to foresee the occurrence of the ADRs at the time of licensing. More active utilization of the information from Phase II/III clinical trials is recommended to prevent the appearance of unexpected ADRs and further emphasis in SPC warnings to doctors about possible serious ADRs.
Effect of danshen extract on pharmacokinetics of theophylline in healthy volunteers
Authors: Qiu Furong , Wang Guangji , Zhao Yanan , Sun Hua , Mao Guoguang , A Jiyi , Sun Jian 
Published: October 2007

What is already known about this subject • Danshen extract is widely used for the treatment and prevention of coronary heart disease and other diseases of senility in Asia.• Danshen extract and theophylline may be prescribed together to treat patients with asthma.• In human, theophylline with low therapeutic index is mainly metabolized by CYP1A2.• In vitro findings have shown that human CYP1A2 is inhibited by the ethyl acetate extract of danshen and danshen pharmaceutical product.• There may be drug interactions between danshen extract and theophylline (CYP1A2 substrate). What this study adds • This study concerned drug interactions between danshen extract and theophylline in Chinese volunteers.• Long‐term oral intake of danshen extract does not change the basic pharmacokinetic parameters of theophylline.• Dose adjustment of theophylline thus may not be necessary in patients receiving concomitant therapy with danshen extract.AimsTo examine the potential effect of danshen extract on the pharmacokinetics of theophylline.MethodsIn a sequential cross‐over study with two phases, 12 volunteers took 100 mg theophylline on day 1 and day 15. From day 2 to day 15, volunteers received danshen extract tablets three times daily, four tablets each time for 14 days. On day 15, they received four danshen extract tablets with 100 mg theophylline. Plasma concentrations of theophylline were measured on days 1 and 15 periodically for 24 h.ResultsThe 90% confidence interval of Cmax, t1/2 and CL/F of theophylline with 14‐day danshen extract tablets vs. without comedication were (101.42, 121.36) (84.57, 106.72) and (88.82, 105.72), respectively. The time to peak plasma theophylline concentration was unchanged by danshen (P > 0.05). The pharmacokinetics parameter of theophylline was unaffected by danshen extract.ConclusionsDanshen extract does not influence the metabolism of theophylline in healthy volunteers. Dose adjustment of theophylline thus may not be necessary in patients receiving concurrent therapy with danshen extract tablets.
Population pharmacokinetics of gemcitabine and its metabolite in patients with cancer: effect of oxaliplatin and infusion rate
Authors: Jiang Xuemin , Galettis Peter , Links Matthew , Mitchell Paul L. , McLachlan Andrew J. 
Published: October 2007

What is already known about this subject • Gemcitabine is an anticancer drug which is metabolized to a number of metabolites, administered using different dosing regimens and increasingly used in combination with oxaliplatin.• The impact of dosing strategies and combination therapy on the pharmacokinetics of gemcitabine and its main metabolite is not clearly understood. What this study adds • This study has characterized the pharmacokinetics of gemcitabine and its main metabolite in people with cancer, including the variability between patients and on different occasions.• Gemcitabine metabolite (but not gemcitabine) pharmacokinetics were significantly affected by co‐administration with oxaliplatin and were dependent on the order of administration.• The clinical implications of this observation remain to be established.AimsTo characterize the population pharmacokinetics of gemcitabine and its metabolite (dFdU) in patients with cancer and identify factors that are influential in gemcitabine dose regimen design.MethodsGemcitabine and dFdU plasma concentration–time and clinical data from 94 patients with cancer and nonlinear mixed effect modelling were used to characterize gemcitabine and metabolite pharmacokinetic variability and identify influential covariates.ResultsGemcitabine and dFdU pharmacokinetics were described by a two‐compartment model with first‐order elimination. The population mean (and between‐subject variability, CV%) for clearance and volume of distribution of the central compartment (VC) for gemcitabine were 2.7 l min−1 (31%) and 15 l (39%), respectively, and 0.04 l min−1 (35%) and 46 l (15%), respectively, for dFdU. Oxaliplatin co‐administration significantly decreased dFdU VC by 35% when gemcitabine was administered first and by 46% when oxaliplatin was administered first compared with patients who received gemcitabine alone.ConclusionsCo‐administration of gemcitabine with oxaliplatin significantly affected the pharmacokinetics of dFdU. The clinical significance of this observation in the context of gemcitabine safety and efficacy is worthy of further investigation.
Risks, diagnosis and outcomes of invasive fungal infections in haematopoietic stem cell transplant recipients
Authors: Barnes Penelope D. , Marr Kieren A. 
Published: October 2007

SummaryInvasive fungal infections (IFIs) continue to cause considerable morbidity and mortality in haematopoietic stem cell transplant (HSCT) recipients. This review focuses on the risks for, and diagnosis of, IFIs (candidiasis, aspergillosis and other mould infections), and factors that affect current outcomes. Diagnosis of IFI is difficult, with the sensitivity of the gold standard tests (culture and histopathology) often <50%. Therefore, physicians rely on a constellation of clinical signs, radiography, culture, histopathology and adjunctive tests to establish diagnosis. HSCT recipients often have multiple co‐morbidities, and understanding the current outcomes and prognostic variables is therefore important for overall management. This paper reviews historical trends and current data.
Proteomic evaluation of pathways associated with dexamethasone‐mediated apoptosis and resistance in multiple myeloma
Authors: Rees‐Unwin Karen S. , Craven Rachel A. , Davenport Emma , Hanrahan Sarah , Totty Nicholas F. , Dring Ann M. , Banks Rosamonde E. , J.Morgan Gareth , Davies Faith E. 
Published: October 2007

SummaryWe have used global protein expression analysis to characterize the pathways of dexamethasone‐mediated apoptosis and resistance in myeloma. Analysis of MM.1S cells by two‐dimensional polyacrylamide gel electrophoresis (2D‐PAGE) identified a series of proteins that were up‐ and downregulated following dexamethasone treatment. Downregulated proteins included proteins involved in cell survival and proliferation, whereas upregulated proteins were involved in post‐translational modification, protein folding and trafficking. A comparison with published gene expression studies identified FK binding protein 5 (FKBP5) (also known as FKBP51), a key regulatory component of the Hsp90‐steroid‐receptor complex to be increased at the mRNA and protein level postdexamethasone exposure. Quantitative real time polymerase chain reaction and 2D‐PAGE analysis of the dexamethasone resistant cell line MM.1R demonstrated no increase in FKBP5, consistent with its association with dexamethasone‐mediated apoptosis. Western blot analysis of FKBP5 and other members of the Hsp90‐receptor complex showed an increase in FKBP5 whilst FKBP4 (also known as FKBP52) and Hsp90 expression remained constant. No changes were observed in MM.1R. In conclusion, we demonstrated that following steroid receptor signalling, the cell carries out a number of adaptive responses prior to cell death. Interfering with these adaptive responses may enhance the myeloma killing effect of dexamethasone.
High activity 90Y‐ibritumomab tiuxetan (Zevalin®) with peripheral blood progenitor cells support in patients with refractory/resistant B‐cell non‐Hodgkin lymphomas
Authors: Ferrucci Pier F. , Vanazzi Anna , Grana Chiara M. , Cremonesi Marta , Bartolomei Mirco , Chinol Marco , Ferrari Mahila , Radice Davide , Papi Stefano , Martinelli Giovanni , Paganelli Giovanni 
Published: October 2007

SummaryRadioimmunotherapy (RIT) is an alternative approach in the treatment of resistant/refractory B‐cell non‐Hodgkin lymphoma (NHL). We performed a feasibility and toxicity pilot study of escalating activity of 90Y‐ibritumomab tiuxetan followed by autologous stem cell transplantation (ASCT). Three activity levels were fixed – 30 MBq/kg (0·8 mCi/kg), 45 MBq/kg (1·2 mCi/kg) and 56 MBq/kg (1·5 mCi/kg) – and 13 patients enrolled. One week before treatment all patients underwent dosimetry. ASCT was performed 13 d after Zevalin® administration. Treatment was well tolerated and all patients engrafted promptly. No differences in terms of haematological toxicities were observed among the three levels, apart from a delayed platelet recovery in heavily pretreated patients receiving 56 MBq/kg. Non‐haematologic toxicity was mainly related to infections and liver toxicity. One patient died 4 months after treatment because of hepatitis C virus reactivation. One patient developed a myelodysplastic syndrome 2 years after treatment. In conclusion, high‐activity Zevalin® with ASCT is feasible and could be safely delivered in elderly and heavily pretreated NHL patients, including those who previously received high‐dose chemotherapy and ASCT. Maximum tolerated dose was not clearly defined according to dosimetry and clinical toxicities, and further studies are needed to confirm the toxicity profile and evaluate efficacy.
Bacille–Calmette–Guerin vaccination and the development of allergic disease in children: a randomized, prospective, single‐blind study
Authors: Steenhuis T. J. , Van Aalderen W. M. C. , Bloksma N. , Nijkamp F. P. , Van Der Laag J. , Van Loveren H. , Rijkers G. T. , Kuis W. , Hoekstra M. O. 
Published: October 2007

SummaryBackground
The increase in the prevalence of allergic diseases in countries with a so‐called western lifestyle may be due to a decrease in exposure to infectious agents in early life.Objective
To establish the effect of Bacille–Calmette–Guerin (BCG) vaccination in 6‐week‐old high‐risk infants in a prospective single‐blind, randomized, placebo‐controlled trial on the prevalence of allergic disease at the age of 4 and 18 months.Methods
Subjects were 121 predominantly Caucasian high‐risk newborns, having either a mother, or both a father and at least one sibling with past or present allergic disease. BCG or placebo was administered at the age of 6 weeks, and repeated once when both a post‐vaccination scar and a positive TB skin test were absent at the age of 4 months.Results
At the age of 18 months, the prevalence of allergic disease was not significantly different between the two groups. A trend towards less eczema (P=0.07) and significantly less use of medication for eczema was shown in the BCG group compared with the placebo group (P=0.04).Conclusion
A single (or once repeated) BCG vaccination in 6‐week‐old high‐risk Caucasian infants was not associated with a 50% reduction in the prevalence of allergic disease. However, there could be a smaller beneficial effect of BCG, especially because a trend towards less eczema and significantly less use of medication for eczema was shown. For definite proof, a larger study should be carried out.
Serum total and high molecular weight adiponectin levels are correlated with the severity of diabetic retinopathy and nephropathy
Authors: Kato Kenichi , Osawa Haruhiko , Ochi Masaaki , Kusunoki Yukiko , Ebisui Osamu , Ohno Keizo , Ohashi Jun , Shimizu Ikki , Fujii Yasuhisa , Tanimoto Mitsune , Makino Hideichi 
Published: October 2007

SummaryObjective  Adiponectin is secreted specifically from adipocytes, and improves insulin sensitivity. Of its isoforms, the high molecular weight (HMW) complex is thought to be the most active. The aim of this study was to determine the relationship between serum total or HMW adiponectin and diabetic microangiopathy.Design, patients and measurements  We analysed 198 Japanese patients with type 2 diabetes mellitus (T2DM) whose fasting serum samples were available. Serum total adiponectin and HMW adiponectin were measured using an enzyme‐linked immunosorbent assay (ELISA).Results  Serum total adiponectin was found to have increased in the advanced stages of diabetic retinopathy (mean ± SE, none, 6·9 ± 0·3; simple, 8·3 ± 1·0; preproliferative, 8·4 ± 0·8; proliferative, 12 ± 1·1 mg/l; anovaP = 0·0004) and nephropathy (stage I, 7·0 ± 0·3; II, 7·7 ± 0·5; III, 9·5 ± 0·9; IV, 16 ± 4·5 mg/l, P < 0·0001). Similarly, serum HMW adiponectin had increased in the advanced stages of retinopathy (3·7 ± 0·2, 4·6 ± 0·5, 4·6 ± 0·6 and 6·9 ± 0·8 mg/l, respectively, P = 0·0005) and nephropathy (3·7 ± 0·2, 4·3 ± 0·4, 5·3 ± 0·7 and 7·9 ± 2·2 mg/l, respectively, P = 0·0007). Neither serum total nor HMW adiponectin was correlated with neuropathy. The HMW/total adiponectin ratio was not correlated with microangiopathy. Multiple regression analysis revealed that serum total and HMW adiponectin were independent factors for retinopathy stage (P = 0·0055 and P = 0·0027, respectively) and nephropathy stage (P = 0·0003 and P = 0·0018, respectively), when adjusted for age, gender, body mass index (BMI) and the duration of T2DM. This correlation remained significant when serum creatinine (or estimated glomerular filtration rate) and hypertension were added as independent variables. Treatment with thiazolidinediones (TZDs) did not affect these findings.Conclusions  Serum total adiponectin and HMW adiponectin were found to be positively correlated with the severity of retinopathy and nephropathy but not with neuropathy in T2DM.
Three years prospective investigation of anterior pituitary function after traumatic brain injury: a pilot study
Authors: Tanriverdi Fatih , Ulutabanca Halil , Unluhizarci Kursad , Selcuklu Ahmet , Casanueva Felipe F. , Kelestimur Fahrettin 
Published: October 2007

SummaryObjective   It has been recently demonstrated that traumatic brain injury (TBI)‐mediated hypopituitarism could be more frequent than previously known. However, most of the previous data were obtained from retrospective studies, and the natural history of the hypopituitarism due to TBI is still unclear. So far no study has been reported in which the pituitary function of the same patients has been investigated more than 1 year after TBI. Therefore, we report the results of 3 years prospective follow‐up of anterior pituitary function in patients with mild, moderate and severe TBI.Patients and design   Thirty patients (25 males, 5 females; age 37·2 ± 2·4 years) with TBI were included in the study. Pituitary function was evaluated at 1 and 3 years after TBI.Results   After individual evaluation of GH deficiency from 1 year to 3 years after TBI, 7 of 13 (53·8%) GH‐deficient patients at 1st year recovered after 3 years of TBI, and GH deficiency detected at 3 years in one patient was new onset. Additionally, five of six (83·3%) ACTH‐deficient patients at 1st year recovered after 3 years of TBI, and ACTH deficiency detected at 3 years in one patient was new onset.Conclusions   GH deficiency is the most common pituitary deficit 1 and 3 years after TBI. In patients with mild and moderate TBI, pituitary function improves over time in a considerable number of patients, but it may also worsen rarely over the 3‐year period. In patients with severe TBI, ACTH and GH deficiencies at 1st year evaluation persist at 3rd year.
Factors influencing spontaneous mobilization of CD34+ and CD133+ progenitor cells after myocardial infarction
Authors: Turan R. G. , Brehm M. , Koestering M. , Tobias Z. , Bartsch T. , Steiner S. , Picard F. , Ebner P. , Schannwell C. M. , Strauer B. E. 
Published: October 2007

AbstractBackground  Bone marrow‐derived circulating progenitor cells (BM‐CPCs) are mobilized into adult peripheral blood (PB) during acute myocardial infarction (AMI) and may contribute to the regeneration of infarcted myocardium. The purpose of the present study is to determine whether mobilization of BM‐CPCs into PB depends on cardiovascular risk factors (CVRFs), age of patients, infarct associated inflammatory markers, and left ventricular function after AMI.Materials and methods  Peripheral blood concentrations of CD34/45+ and CD133/45+ BM‐CPCs were measured by flow cytometry in 44 patients after AMI and in 16 subjects with atypical chest pain acting as controls.Results  Mobilization of CD34/45+ and CD133/45+ BM‐CPCs on day 1 after AMI showed significant negative correlation with age, the number of CVRFs, infarct size, creatine phosphokinase peak in bivariate as well as in multivariate analyses. We additionally found a positive correlation of CD34/45+ and CD133/45+ BM‐CPCs mobilization on day 1 after AMI with global ejection fraction (EF) in bivariate analysis but could not confirm this in multivariate analysis. Elevated of C‐reactive protein (CRP) and leukocyte levels on day 1 after AMI were significantly associated with decreased concentrations of CD34/45+ BM‐CPCs. The concentrations of CD34/45+ and CD133/45+ BM‐CPCs significantly increased in AMI patients, with the peak on day 7 as compared to the control group.Conclusions  The mobilization of CD34/45+ and CD133/45+ BM‐CPCs into the PB depends on many factors, i.e. the number of CVRFs, age, infarct size and inflammatory markers of patients. Most importantly, the severity of the circulatory dysfunction and the amount of necrotic myocardial tissue are the main determinants. Moreover, this spontaneous mobilization of BM‐CPCs may serve as a very important surrogate for infarct size as well as for global EF and it may determine the regenerative potency after AMI.
HMG CoA reductase inhibition and left ventricular mass in hypertrophic cardiomyopathy: a randomized placebo‐controlled pilot study
Authors: Bauersachs J. , Störk S. , Kung M. , Waller C. , Fidler F. , Hoyer C. , Frantz S. , Weidemann F. , Ertl G. , Angermann C. E. 
Published: October 2007

AbstractBackground  Statins reduce cardiomyocyte hypertrophy in animal models of hypertrophic cardiomyopathy, aortic banding and heart failure after myocardial infarction. We investigated the effect of the hydroxymethylglutaryl coenzyme A reductase inhibitor atorvastatin on left ventricular (LV) mass in patients with hypertrophic cardiomyopathy in a randomized placebo‐controlled double‐blind pilot study.Materials and methods  Patients with hypertrophic cardiomyopathy were randomized to be treated once daily by atorvastatin 80 mg or placebo for nine months. LV mass was assessed by serial cardiac magnetic resonance imaging. LV systolic and diastolic function was determined by echocardiography. Markers of collagen metabolism and inflammation were also assessed.Results  Out of 78 screened patients with hypertrophic cardiomyopathy 28 (2 × 14) patients were eligible for randomization. Eleven patients in each group completed the study with cardiac magnetic resonance imaging assessments meeting the evaluation standards at baseline and at follow‐up. Low‐density lipoprotein cholesterol levels in the atorvastatin group decreased from 3·24 ± 1·14 mmol L−1 (125 ± 44 mg dL−1) at baseline to 1·37 ± 0·49 mmol L−1 (53 ± 19 mg dL−1) at follow‐up (P < 0·001), but were unchanged in the placebo group. Baseline LV mass was 228 ± 51 g in the placebo and 232 ± 67 g in the atorvastatin group. The primary endpoint of change in LV mass from baseline to follow‐up was 2 ± 10% in the atorvastatin group versus 0 ± 13% in the placebo group (P = NS). Parameters of LV volumes and diameters, systolic and diastolic function, and markers of collagen metabolism were also unchanged in both groups.Conclusion  In patients with hypertrophic cardiomyopathy, this randomized placebo‐controlled double‐blind pilot study did not demonstrate an effect of 9‐month treatment with atorvastatin 80 mg on LV mass reduction.
Uptake and metabolism of nitrate in mycorrhizal plants as affected by water availability and N concentration in soil
Authors: Azcón R. , Rodríguez R. , Amora‐Lazcano E. , Ambrosano E. 
Published: October 2007

SummaryWe compare the effect of arbuscular mycorrhizal (AM) colonization and PO4−3 fertilization on nitrate assimilation, plant growth and proline content in lettuce plants growing under well‐watered (−0.04 MPa) or drought (−0.17 MPa) conditions. We also tested how AM‐colonization and PO4−3 fertilization influenced N uptake (15N) and the percentage of N derived from the fertilizer (% NdfF) by plants under a concentration gradient of N in soil. Growth of mycorrhizal plants was comparable with that of P‐fertilized plants only under well‐watered conditions. Shoot nitrogen content, proline and nitrate reductase activity were greater in AM than in P‐fertilized plants under drought. The addition of 100 μg g−1 P to the soil did not replace the AM effect under drought. Under well‐watered conditions, AM plants showed similar (at 3 mmol N), greater (at 6 mmol N) or lesser (at 9 mmol N) %NdfF than P‐fertilized plants. Comparing a control (without AM inoculation) to AM plants, differences in % NdfF ranged from 138% (3 mmol N) to 22.6% (6 mmol N) whereas no differences were found at 9 mmol N. In comparison with P fertilization, mycorrhizal effects on %NdfF were only evident at the lowest N levels, which indicated a regulatory mechanism for N uptake in AM plants affected by N availability in the soil. At the highest N level, P‐fertilized plants showed the greatest %NdfF. In conclusion, AM symbiosis is important for N acquisition and N fertilizer utilization but this beneficial mycorrhizal effect on N nutrition is reduced under large quantities of N fertilizer.