bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessing efficacy of non‐opioid analgesics in experimental pain models in healthy volunteers: an updated review
Authors: Staahl Camilla , Olesen Anne Estrup , Andresen Trine , Arendt‐Nielsen Lars , Drewes Asbjørn Mohr 
Published: May 2009

AIMExperimental pain models may help to evaluate the mechanisms of analgesics and target the clinical indications for their use. This review, the second in a series of two, addresses how the efficacy of non‐opioid analgesics have been assessed in human volunteers using experimental pain models.METHODSA literature search was completed for randomized controlled studies that included human experimental pain models, healthy volunteers and non‐opioid analgesics.RESULTSNonsteroidal anti‐inflammatory drugs worked against various types of acute pain as well as in hyperalgesia. Analgesia from paracetamol was difficult to detect in experimental pain and the pain needed to be assessed with very sensitive methods like evoked brain potentials. The N‐methyl‐D‐aspartate antagonists exemplified by ketamine generally needed strong, long‐lasting or repeated pain in the skin for detectable analgesia, whereas pain in muscle and viscera generally was more easily attenuated. Gabapentin worked well in several models, particularly those inducing hyperalgesia, whereas lamotrigine was weak in modulation of experimental pain. Imipramine attenuated pain in most experimental models, whereas amitriptyline had weaker effects. Delta‐9‐tetrahydrocannabinol attenuated pain in only a few models.CONCLUSIONSPain induction and assessment are very important for the sensitivity of the pain models. Generally, experimental pain models need to be designed with careful consideration of the pharmacological mechanisms and pharmacokinetics of analgesics. The drawback with the different study designs is also discussed. This knowledge can aid the decisions that need to be taken when designing experimental pain studies for compounds entering Phase I and II trials.
Gefitinib–phenytoin interaction is not correlated with the14C‐erythromycin breath test in healthy male volunteers
Authors: Chhun Stephanie , Verstuyft Celine , Rizzo‐Padoin Nathalie , Simoneau Guy , Becquemont Laurent , Peretti Ilana , Swaisland Alan , Wortelboer Robert , Bergmann Jean Francois , Mouly Stephane 
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The response to gefitinib is variable and could be explained partly by the interindividual variability in gefitinib exposure.• Gefitinib is mainly metabolized by CYP3A4 and CYP2D6, and is to a lesser extent a P‐glycoprotein (P‐gp) substrate.• Patients with cancer are at high risk of drug–drug interactions, such as with phenytoin, a potent CYP3A4 inducer.WHAT THIS STUDY ADDS• The reduced systemic exposure of gefitinib with multiple‐dose phenytoin treatment.• An effect attributed to the possible induction of intestinal CYP3A4 because of the lack of correlation between changes in gefitinib disposition and the erythromycin breath test and the lack of association between allelic variant in the ABCB1 gene and baseline and induced oral gefitinib clearance.• The CYP2D6 extensive metabolizer seems to be less sensitive to the interaction with phenytoin, as the magnitude of induction of gefitinib clearance was greater in CYP2D6 poor metabolizers than in CYP2D6 extensive metabolizers.AIMSWe aimed to describe the pharmacokinetic interaction between phenytoin, a potent CYP3A4 and P‐glycoprotein (P‐gp) (ABCB1) inducer, and gefitinib, a CYP3A4, CYP2D6 and P‐gp substrate.METHODSAn open‐label, randomized, two‐phase crossover study was conducted. Eighteen healthy male volunteers (nine homozygous CC and nine homozygous TT as determined by theirABCB1C3435T polymorphism in exon 26) received a single oral dose of 250 mg gefitinib alone or after 5 days treatment with phenytoin (5 mg kg−1daily). Gefitinib plasma concentrations were determined by high‐performance liquid chromatography. Hepatic CYP3A4 activity was evaluated by the14C‐erythromycin breath test (ERMBT) and theABCB1andCYP2D6genetic polymorphisms were determined by the TaqMan allelic discrimination assay and long polymerase chain reaction, respectively.RESULTSFollowing treatment with phenytoin, mean gefitinibCmaxand AUC0–∞decreased by 26 ± 44% [95% confidence interval (CI) for the difference 5–48%,P= 0.005] and 47 ± 26% (95% CI for the difference 34–60%,P= 0.001), respectively, and apparent oral clearance increased by 126 ± 93% (95% CI for the difference 80–172%,P= 0.004). Concomitantly, phenytoin increased the mean ERMBT by 91 ± 44% (95% CI 75–105%,P< 0.001) from baseline, but the extent of liver CYP3A4 induction was not correlated to the extent of interaction. Furthermore, this interaction was independent ofABCB1genetic polymorphism. TheCYP2D6genotype was slightly but significantly related to gefitinib clearance (P= 0.04) during the control phase.CONCLUSIONSThe significant interaction between gefitinib and phenytoin was not correlated with the erythromycin breath test and was independent ofABCB1polymorphism, but may involve presystemic CYP3A‐mediated intestinal first‐pass.
Effects ofGinkgo bilobaextract on the pharmacokinetics of bupropion in healthy volunteers
Authors: Lei He‐Ping , Ji Wei , Lin Jian , Chen Hao , Tan Zhi‐Rong , Hu Dong‐Li , Liu Li‐Juan , Zhou Hong‐Hao 
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Bupropion, an antidepressant and smoking cessation drug, is metabolized to its active metabolite hydroxybupropion almost exclusively by CYP2B6.• Ginkgo bilobais among the most commonly used herbal extract in the general population, and is likely to be used by depressed patients receiving bupropion.• Studies have reported thatG. bilobaadministration to rats markedly increased the CYP content and CYP2B mRNA in the liver, and intake ofG. bilobaalso induced various hepatic CYP enzymes, especially CYP2B‐type enzymes.• There may be drug interactions betweenG. bilobaextract and bupropion (CYP2B6 substrate).WHAT THIS STUDY ADDS• Fourteen‐day oral administration ofG. bilobaextract had no statistically significant effect on the pharmacokinetics of bupropion or its active metabolite hydroxybupropion, as measured by AUC, which suggestsG. bilobadoes not significantly affect the metabolism of bupropion following a single oral dose in healthy Chinese men.AIMSTo assess the effects ofGinkgo bilobaextract on the pharmacokinetics of bupropion in healthy volunteers.METHODSFourteen healthy male volunteers (age range 19–25 years) received orally administered bupropion (150 mg) alone and during treatment withG. biloba240 mg day−1(two 60‐mg capsules taken twice daily) for 14 days. Serial blood samples were obtained over 72 h after each bupropion dose, and used to derive pharmacokinetic parameters of bupropion and its CYP2B6‐catalysed metabolite, hydroxybupropion.RESULTSGinkgo bilobaextract administration resulted in no significant effects on the AUC0–∞of bupropion and hydroxybupropion. Bupropion mean AUC0–∞value was 1.4 µg·h ml−1[95% confidence interval (CI) 1.2, 1.6] prior toG. bilobatreatment and 1.2 µg·h ml−1(95% CI 1.1, 1.4) after 14 days of treatment. Hydroxybupropion mean AUC0–∞value was 8.2 µg·h ml−1(95% CI 6.5, 10.4) beforeG. bilobaadministration and 8.7 µg·h ml−1(95% CI 7.1, 10.6) after treatment. TheCmaxof hydroxybupropion increased from 221.8 ng ml−1(95% CI 176.6, 278.6) to 272.7 ng ml−1(95% CI 215.0, 345.8) (P = 0.038) and thet1/2of hydroxybupropion fell from 25.0 h (95% CI 22.7, 27.5) to 21.9 h (95% CI 19.9, 24.1) (P = 0.000).CONCLUSIONSGinkgo bilobaextract administration for 14 days does not significantly alter the basic pharmacokinetic parameters of bupropion in healthy volunteers. AlthoughG. bilobaextract treatment appears to reduce significantly thet1/2and increase theCmaxof hydroxybupropion, no bupropion dose adjustments appear warranted when the drug is administered orally withG. bilobaextract, due to the lack of significant change observed in AUC for either bupropion or hydroxybupropion.
Frequency and nature of drug–drug interactions in a Dutch university hospital
Authors: Zwart‐van Rijkom Jeannette E. F. , Uijtendaal Esther V. , Ten Berg Maarten J. , Van Solinge Wouter W. , Egberts Antoine C. G. 
Published: May 2009

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Drug–drug interactions (DDIs) may lead to often preventable adverse drug events and health damage.• In Dutch community pharmacies approximately 6% of all prescriptions generate a DDI alert.• Hospitalized patients may be especially at risk, as they are more severely ill and multiple medications may be prescribed simultaneously; however, only limited data are available on the frequency and nature of DDIs during hospitalization. WHAT THIS STUDY ADDS • In a Dutch university hospital 10% of all prescriptions generated a DDI alert; overall 25% of patients encountered at least one potential DDI.• Besides the risk of decreased effectiveness (25% of the DDIs), the most frequently occurring potential clinical consequence of the DDIs was an increased risk of side‐effects, such as an increased bleeding risk (22% of DDIs), hypotension (15%) and nephrotoxicity (13%).• Almost half of the DDIs could be managed by monitoring laboratory values.AIMDrug–drug interactions (DDIs) may lead to often preventable adverse drug events and health damage. Especially within hospitals, this might be an important factor, as patients are severely ill and multiple medications may be prescribed simultaneously. The objective of this study was to measure the frequency and nature of DDI alerts in a Dutch university hospital.METHODSAll patients hospitalized in the University Medical Centre Utrecht in 2006 who were prescribed at least one medication were included. The frequency of DDIs was calculated as: (i) the percentage of patients experiencing at least one DDI, and (ii) the percentage of prescriptions generating a DDI alert. Based on the national professional guideline, DDIs were classified into categories of potential clinical outcome, management advice, clinical relevance (A–F) and available evidence (0–4).RESULTSOf the 21 277 admissions included, 5909 (27.8%) encountered at least one DDI. Overall, the prescribing physician received a DDI alert in 9.6% of all prescriptions. The most frequently occurring potential clinical consequence of the DDIs was an increased risk of side‐effects such as increased bleeding risk (22.0%), hypotension (14.9%), nephrotoxicity (12.6%) and electrolyte disturbances (10.5%). Almost half (48.6%) of the DDIs could be managed by monitoring laboratory values.CONCLUSIONSComputerized DDI alerts may be a useful tool to prevent adverse drug events within hospitals, but they may also result in ‘alert fatigue’. The specificity of alerts could significantly improve by the use of more sophisticated clinical decision support systems taking into account, for example, laboratory values.
Timed feeding of mice modulates light‐entrained circadian rhythms of reticulated platelet abundance and plasma thrombopoietin and affects gene expression in megakaryocytes
Authors: Hartley Paul S. , Sheward John , Scholefield Emma , French Karen , Horn Jacqueline M. , Holmes Megan C. , Harmar Anthony J. 
Published: May 2009

SummaryCircadian (c. 24 h) rhythms of physiology are entrained to either the environmental light‐dark cycle or the timing of food intake. In the current work the hypothesis that rhythms of platelet turnover in mammals are circadian and entrained by food intake was explored in mice. Mice were entrained to 12 h light‐dark cycles and given either ad libitum (AL) or restricted access (RF) to food during the light phase. Blood and megakaryocytes were then collected from mice every 4 h for 24 h. It was found that total and reticulated platelet numbers, plasma thrombopoietin (TPO) concentration and the mean size of mature megakaryocytes were circadian but not entrained by food intake. In contrast, a circadian rhythm in the expression of Arnt1 in megakaryocytes was entrained by food. Although not circadian, the expression in megakaryocytes of Nfe2, Gata1, Itga2b and Tubb1 expression was downregulated by RF, whereas Ccnd1 was not significantly affected by the feeding protocol. It is concluded that circadian rhythms of total platelet number, reticulated platelet number and plasma TPO concentration are entrained by the light‐dark cycle rather than the timing of food intake. These findings imply that circadian clock gene expression regulates platelet turnover in mammals.
Quantification of seminal germ cells in azoospermia: correlations with testicular histology and TESE outcome
Authors: Yeung C. H. , Beiglböck‐Karau L. , Luetjens C. M. , Wunsch A. , Nieschlag E. 
Published: May 2009

SummaryIn the treatment of male infertility by intra‐cytoplasmic injection of spermatozoa (ICSI) extracted from testicular tissue (TESE), the high incidence of negative TESE outcome calls for non‐invasive prognostic methods. Literature suggests that seminal haploid germ cell detection could be one. For this purpose, a multi‐parametric stringent flow cytometric method was applied to 50 TESE patients for the quantification of ejaculated germ cells. Cells from 50 ejaculates were identified and quantified as spermatozoa (HC, highly condensed), round spermatids (1N), primary spermatocytes (SPC) (4N) or diploid cells (2N, including somatic and non‐testicular cells) by their DNA and mitochondria staining and laser scatter characteristics, and compared with testicular biopsy histology and TESE outcome. Whereas 96% of patients displayed a diploid peak in the distribution histograms, the HC, 1N and 4N peaks were absent from the majority of samples. In 13 ejaculates, either a HC or 1N or 4N peak, or a combination of these, was discernible. Although seminal germ cell numbers bore no overall association with elongated spermatids (ES) in histology or spermatozoa retrieval in TESE outcome, 4N cells per ejaculate were correlated with the percentage of tubule sections showing SPC as the most advanced germ cells. The incidence of HC peaks was higher in patients showing some ES in histology or sperm retrieval than in the sperm‐negative groups. In groups with suspected obstruction showing nearly full spermatogenesis and maximal sperm retrieval, there was no incidence of a HC peak. Germ cell peaks were associated with germ cell degeneration noted in testicular histology. In conclusion, seminal germ cells cannot provide good prognosis for TESE, although their presence could indicate the spermatogenic activity in the testis.
Intimate partner abuse factors associated with women’s health: a general population study
Authors: Svavarsdottir Erla Kolbrun , Orlygsdottir Brynja 
Published: May 2009

AbstractTitle.  Intimate partner abuse factors associated with women’s health: a general population study. Aim.  This paper is a report of a study to investigate the correlates of physical and psychological health in a general population‐based sample of Icelandic women who experienced abuse in close relationships.Background.  Most studies examining the health concerns associated with intimate partner abuse have been based on clinical populations; however, their findings may not be representative of the general population of women experiencing intimate partner abuse.Method.  A cross‐sectional correlational study was conducted. The Women’s Response to Battering Model was used to guide the choice of variables. Questionnaires were mailed to 7523 randomly‐selected Icelandic women. Data collection started in December 2005 and ended a year later. A total of 1974 married and 772 cohabiting women answered the questionnaires (n = 2746). Independent t‐tests and stepwise regression were used to analyse the data.Findings.  Health risk behaviours (e.g. alcohol misuse, smoking), chronic health conditions/illnesses (e.g. sleep disturbance, depression, eating disorders) and currently being victim of intimate partner violence predicted the women’s physical and psychological health.Conclusion.  Interventions designed to decrease health risk behaviours, treat chronic health conditions/illnesses and offer best practice first response to women who are victims of intimate partner violence can be offered to reduce the short‐ and long‐term effects of violence on their physical and psychological health. Public health policy needs to focus specifically on intimate partner violence against women and the role that public health nurses can have in early identification and offering appropriate interventions within primary healthcare settings.
The lack of mitochondrial AtFtsH4 protease alters Arabidopsis leaf morphology at the late stage of rosette development under short‐day photoperiod
Authors: Gibala Marta , Kicia Marta , Sakamoto Wataru , Gola Edyta M. , Kubrakiewicz Janusz , Smakowska Elwira , Janska Hanna 
Published: May 2009

SummaryAtFtsH4 is one of four inner membrane‐bound mitochondrial ATP‐dependent metalloproteases in Arabidopsis thaliana, called AAA proteases, whose catalytic site is exposed to the intermembrane space. In the present study, we used a reverse‐genetic approach to investigate the physiological role of the AtFtsH4 protease. We found that loss of AtFtsH4 did not significantly affect Arabidopsis growth under optimal conditions (long days); however, severe morphological and developmental abnormalities in late rosette development occurred under short‐day conditions. The asymmetric shape and irregular serration of expanding leaf blades were the most striking features of the ftsh4 mutant phenotype. The severe abnormal morphology of the leaf blades was accompanied by ultrastructural changes in mitochondria and chloroplasts. These abnormalities correlated with elevated levels of reactive oxygen species and carbonylated mitochondrial proteins. We found that two classes of molecular chaperones, Hsp70 and prohibitins, were over‐expressed in ftsh4 mutants during late vegetative growth under both short‐ and long‐day conditions. Taken together, our data indicate that lack of AtFtsH4 results in impairment of organelle development and Arabidopsis leaf morphology under short‐day conditions.
The relative importance of birds and bees in the pollination ofMetrosideros excelsa(Myrtaceae)
Authors: SCHMIDT‐ADAM GABRIELE , MURRAY BRIAN G. , YOUNG ANDREW G. 
Published: May 2009

AbstractExclusion experiments were used to assess the effect of different pollinator groups on outcrossing and seed production inMetrosideros excelsa. The main study site was Little Barrier Island, New Zealand where indigenous bird and native solitary bees are the main flower visitors. Our results showed that native birds were more important pollinators ofM. excelsathan native bees. Seed production was much higher in open pollination than in two exclusion experiments where either birds were excluded and native bees only had access to flowers, or where all pollinators had been excluded. The number of fertile seeds per capsule was 45% higher after open pollination than in treatments with bee visitation only and 28% higher than in treatments where all flower visitors were excluded. Estimated outcrossing rates were significantly higher (tm = 0.71) for open pollination in the upper canopy (>4 m above‐ground level) where bird visitation is presumed to be more frequent than for a treatment with native bee access only (tm = 0.40). Our results also suggest that a large proportion of seeds (66%) arise from autonomous self‐pollination when all pollinators are excluded. In four trees of a modified mainland population with predominantly introduced birds and a mixture of introduced and native bees there was no decrease in seed production for the treatment allowing bee access only, indicating that – in contrast to native bees – honeybees may be more efficient pollinators ofM. excelsa. Observation of the foraging behaviour of both groups of bees showed that native bees contact the stigma of flowers less frequently than honeybees. This is likely to be a consequence of their smaller body size relative to honeybees.
The ecological value of Eryngium horridum in maintaining biodiversity in subtropical grasslands
Authors: FIDELIS ALESSANDRA , OVERBECK GERHARD E. , PILLAR VALÉRIO D. , PFADENHAUER JÖRG 
Published: May 2009

AbstractThe role of facilitation in the structuring of plant communities has been often demonstrated in environments under high abiotic stress, especially in semi‐arid and arid ecosystems and high elevations. Few studies, however, analysed facilitation in systems that are highly productive and rich in species, which are thought to be theoretically unlikely to demonstrate strong effects of facilitation. Here, we investigate the importance of Eryngium horridum, a rosette species, on the maintenance of plant diversity in subtropical grasslands in southern Brazil. We evaluated facilitation in areas under two different types of management: abandonment and grazing. Plots were established in areas with and without individuals of E. horridum and all species were identified and had their cover estimated. The Relative Neighbour Effect index was calculated in order to verify the presence of competition or facilitation. Our results indicated facilitation in both abandoned and in grazed grasslands, but apparently through different mechanisms. In the first case, the plant's architecture opens the canopy and allows more light to reach small forbs in the grass matrix. In the second case, E. horridum appears to protect more palatable species from herbivores. Otherwise considered an obnoxious species, E. horridum plays an important ecological role in subtropical grasslands in southern Brazil by facilitating other species and consequently, increasing local richness. Areas with this rosette species are important sources of diaspores, which are able to colonize new open sites and thus, maintain biodiversity.
SUCCESS, TRUTH, AND MODERNISM IN HOLOCAUST HISTORIOGRAPHY: READING SAUL FRIEDLÄNDER THIRTY‐FIVE YEARS AFTER THE PUBLICATION OF METAHISTORY1
Authors: KANSTEINER WULF 
Published: May 2009

ABSTRACTThis essay provides a close reading of Saul Friedländer's exceptionally successful comprehensive history of the Holocaust from the theoretical perspective of Hayden White's philosophy of history. Friedländer's The Years of Extermination has been celebrated as the first synthetic history of the “Final Solution” that acknowledges the experiences of the victims of Nazi genocide. But Friedländer has not simply added the voices of the victims to a conventional historical account of the Holocaust. Instead, by displacing linear notions of time and space and subtly deconstructing conventional concepts of causality, he has invented a new type of historical prose that performs rather than analyzes the victims' point of view. Friedländer's innovation has particularly radical consequences for the construction of historical explanations. On the one hand, Friedländer explicitly argues that anti‐Semitism was the single most important cause of the Holocaust. On the other hand, his transnational, multifaceted history of the “Final Solution” provides a wealth of data that escapes the conceptual grasp of his explicit model of causation. Friedländer chooses this radically self‐reflexive strategy of historical representation to impress on the reader the existential sense of disbelief with which the victims experienced Nazi persecution. To Friedländer, that sense of disbelief constitutes the most appropriate ethical response to the Holocaust. Thus the narratological analysis of The Years of Extermination reveals that the exceptional quality of the book, as well as presumably its success, is the result of an extraordinarily creative act of narrative imagination. Or, put into terms developed by White, who shares Friedländer's appreciation of modernist forms of writing, The Years of Extermination is the first modernist history of the Holocaust that captures, through literary figuration, an important and long neglected reality of the “Final Solution.”