bluuebunny/crossref_metadata_2025_split huggingface dataset:
Voriconazole potentiates warfarin‐induced prothrombin time prolongation
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Nichols Don 
Published: November 2003

Aims  Voriconazole is a novel triazole with broad‐spectrum antifungal activity. It is likely that some patients receiving voriconazole may also require treatment with the anticoagulant warfarin. Cytochrome P450 isoenzymes are important in the metabolism of both these drugs. This study investigated the effect of voriconazole on the pharmacodynamics of warfarin by measuring prothrombin time, and also evaluated the safety and tolerability of the coadministered drugs.Methods  This was a double‐blind, placebo‐controlled, two‐way crossover study in which healthy male subjects received either 300 mg voriconazole or placebo twice daily on days 1–12, plus a single oral dose of 30 mg warfarin on day 7 of each study period. Volunteers were randomized to one of the following treatment sequences: voriconazole + warfarin followed by placebo + warfarin or placebo + warfarin followed by voriconazole + warfarin. There was a washout of at least of 7 days between treatment periods.Results  The mean Cmax, AUCτ and tmax for voriconazole were 3736 ng ml−1, 25 733 ng·h  ml−1, and 1.66 h, respectively. Both the mean maximum change from baseline prothrombin time and the mean area under the effect curve (AUEC) for prothrombin time during coadministration with voriconazole (17 s and 3211 s·h , respectively) were statistically significantly greater than the mean values observed during the placebo period (8 s and 2282 s·h ). Prothrombin times were still increased by a mean value of 5.4 s 144 h post warfarin dose following coadministration with voriconazole compared with a mean value of 0.6 s in the placebo treatment period.Conclusions  Coadministration of voriconazole and warfarin potentiates warfarin‐induced prothrombin time prolongation. Regular monitoring of prothrombin time is recommended if these drugs are coadministered, with appropriate adjustment of the dose of warfarin.
Coadministration of voriconazole and phenytoin: pharmacokinetic interaction, safety, and toleration
Authors: Purkins Lynn , Wood Nolan , Ghahramani Parviz , Love Edward R. , Eve Malcolm D. , Fielding Anitra 
Published: November 2003

Aims  Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19, and, to a lesser extent, by CYP3A4. Phenytoin is an inducer of CYP3A4 activity, and a substrate and inducer of CYP2C9 and CYP2C19. The present studies investigated the pharmacokinetic interactions of voriconazole and phenytoin when coadministered.Methods  Two placebo‐controlled parallel‐group studies were conducted in healthy male volunteers. Study A was an open‐label study and investigated the effect of phenytoin (300 mg once daily) on the steady‐state pharmacokinetics of voriconazole (200 mg and 400 mg twice daily). Study B was a double‐blind randomized study to investigate the effects of voriconazole (400 mg twice daily) on the steady‐state pharmacokinetics of phenytoin (300 mg once daily). Cmax and AUCτ were compared at days 7, 21, and 28 (Study A), and at days 7 and 17 (Study B). All adverse events were recorded.Results  Study A: 21 subjects were evaluable (10 voriconazole + phenytoin, 11 voriconazole + placebo). For subjects receiving voriconazole (200 mg twice daily) plus phenytoin, the day 21/day 7 ratios for voriconazole Cmax and AUCτ were 60.7%[90% confidence interval (CI) 50.1, 73.6] and 35.9% (90% CI 29.7, 43.3), respectively. Adjusted for voriconazole + placebo, the ratios between the means were 50.7% (90% CI 38.8, 66.1) and 30.6% (90% CI 23.5, 39.7), respectively. When the dose of voriconazole was increased to 400 mg twice daily, the day 28/day 7 ratios for voriconazole Cmax and AUCτ were 134% (90% CI 89.2, 200) and 139% (90% CI 97.3, 199), respectively. Study B: 15 subjects were evaluable for pharmacokinetic assessments (six phenytoin + voriconazole, nine phenytoin + placebo). The ratios between the means for phenytoin + voriconazole/phenytoin + placebo on day 17 vs. day 7 were: phenytoin Cmax 167% (90% CI 144, 193) and phenytoin AUCτ 181% (90% CI 156, 210). All treatments were well tolerated: most adverse events were mild/moderate and transient.Conclusions  Repeat dose administration of phenytoin decreased the mean steady‐state Cmax and AUCτ of voriconazole by approximately 50% and 70%, respectively. Increasing the dose of voriconazole from 200 mg to 400 mg b.d. compensated for this effect. Repeat dose administration of 400 mg b.d. voriconazole increased the mean steady‐state Cmax and AUCτ of phenytoin by approximately 70% and 80%, respectively. It is therefore recommended that plasma phenytoin concentrations are monitored and the dose adjusted as appropriate when phenytoin is coadministered with voriconazole.
Effect of omeprazole on the steady‐state pharmacokinetics of voriconazole
Authors: Wood Nolan , Tan Keith , Purkins Lynn , Layton Gary , Hamlin Julia , Kleinermans Diane , Nichols Don 
Published: November 2003

Aims  Voriconazole, a novel triazole antifungal agent, is metabolized by the cytochrome P450 isoenzymes CYP2C19, CYP2C9, and to a lesser extent by CYP3A4. Omeprazole, a proton pump inhibitor used widely for the treatment of gastric and duodenal ulcers, is predominantly metabolized by CYP2C19 and CYP3A4. The aim of this study was to determine the effects of omeprazole on the steady‐state pharmacokinetics of voriconazole. A secondary objective was to characterize the pharmacokinetic profile of an oral loading dose regimen of 400 mg twice‐daily voriconazole on day 1.Methods  This was an open, randomized, placebo‐controlled, two‐way crossover study of 18 healthy male volunteers. Subjects received oral voriconazole (400 mg twice daily on day 1 followed by 200 mg twice daily on days 2–9 and a single 200‐mg dose on day 10) with either omeprazole (40 mg once daily) or matched placebo for 10 days. There was a minimum 7‐day washout between treatment periods.Results  Mean Cmax and AUCτ of voriconazole were increased by 15%[90% confidence interval (CI) 5, 25] and 41% (90% CI 29, 55), respectively, with no effect on tmax during coadministration of omeprazole. Visual inspection of predose plasma concentrations (Cmin) indicated that steady‐state plasma concentrations were achieved following the second loading dose. One subject withdrew from the study during the voriconazole + omeprazole treatment period because of treatment‐related abnormal liver function test values. All other treatment‐related adverse events resolved without intervention.Conclusions  Omeprazole had no clinically relevant effect on voriconazole exposure, suggesting that no voriconazole dosage adjustment is necessary for patients in whom omeprazole therapy is initiated. Administration of a 400‐mg twice‐daily oral loading dose regimen on day 1 resulted in steady‐state plasma levels of voriconazole being achieved following the second loading dose.
No clinically significant pharmacokinetic interactions between voriconazole and indinavir in healthy volunteers
Authors: Purkins Lynn , Wood Nolan , Kleinermans Diane , Love Edward R. 
Published: November 2003

Aims  Voriconazole is a new triazole antifungal agent, and is metabolized by the cytochrome P450 isoenzymes CYP2C9, CYP2C19 and to a lesser extent by CYP3A4. Protease inhibitors, such as indinavir, are also metabolized by cytochrome P450 (mainly CYP3A4). As these drugs are likely to be coadministered, these studies were performed to assess the pharmacokinetic interactions, safety and toleration of these drugs when taken together.Methods  Two randomized placebo‐controlled studies were conducted in healthy male volunteers. Study A was an open parallel‐group study of the effect of indinavir on the steady‐state pharmacokinetics of voriconazole in 18 volunteers (nine subjects in each group). Subjects received voriconazole 200 mg twice daily (days 1–7), then voriconazole 200 mg twice daily + indinavir 800 mg or placebo three times daily (days 8–17). Study B was a double‐blind, randomized, two‐way crossover study of the effect of voriconazole on the steady‐state pharmacokinetics of indinavir in 14 volunteers. They received indinavir 800 mg three times daily + voriconazole 200 mg or placebo twice daily for two 7‐day treatment periods separated by a washout period of at least 7 days. Pharmacokinetic parameters were compared within treatment groups at days 7 and 17 in Study A and between treatment groups on day 7 of each period in Study B. All adverse events were recorded.Results  Study A: Seventeen subjects were evaluable for pharmacokinetic analysis (eight voriconazole + indinavir, nine voriconazole + placebo). The day 17/day 7 ratios for Cmax and AUCτ were estimated as 102%[90% confidence interval (CI) 91, 114] and 107% (90% CI 98, 118), respectively. Study B: Fourteen subjects were evaluable for pharmacokinetic analysis in each treatment period. The ratios between the geometric means for indinavir + voriconazole vs. indinavir + placebo were: Cmax, 91% (90% CI 83, 101), AUCτ, 87% (90% CI 77, 100), and Cmin, 101% (90% CI 82, 125). Trough plasma concentrations of indinavir were above the concentration required to inhibit HIV replication (IC95) in both treatment periods. Voriconazole coadministered with indinavir was well tolerated in both studies.Conclusions  The coadministration of voriconazole and indinavir in healthy volunteers had no clinically significant effect on the pharmacokinetics of either voriconazole or indinavir.
Minimal residual disease in acute myelogenous leukaemia and myelodysplastic syndromes: a follow‐up of patients in clinical remission
Authors: Engel Heike , Goodacre Angela , Keyhani Afsaneh , Jiang Shuwei , Van Nguyen T. , Kimmel Marek , Sanchez‐Williams Gisela , Andreeff Michael 
Published: November 2003

The majority of patients with acute myelogenous leukaemia (AML) and myelodysplastic syndromes (MDS) relapse, especially those with unfavourable cytogenetics.This study was designed to investigate the presence and frequency of minimal residual disease (MRD) in patients with AML or MDS (n = 35) and numerical abnormalities of chromosomes 6, 7, 8, 9, 10, 17 and 18 in clinical remission by using a combination of fluorescence activated cell sorting (FACS), fluorescence in‐situ hybridization (FISH) and labelling with bromodeoxyuridine (BUdR). The technique enables the detection of as few as three leukaemic cells in 105 normal cells.MRD was detected in 33/35 patients in complete remission (CR). 16 patients relapsed (8/11 with monosomy 7, 4/17 with trisomy 8, and 4/7 with other cytogenetic abnormalities) after a median of 4.8 months (range 3–13). Levels of MRD (P = 0.007) and proliferation index (P = 0.011) were significantly higher in patients with monosomy 7 than in patients with trisomy 8 or other cytogenetic abnormalities. The percentage of cells in S‐phase, the number of abnormal cells and cytogenetic class were related to time to relapse (P = 0.001) with S‐phase being the single most important prognostic factor (P = 0.0001).We conclude that the combination of FACS/FISH/BUdR, which determines the number, phenotype and proliferation rate of very rare leukaemic cells in patients with AML or MDS in clinical remission, provides information that is useful in the identification of patients with high and low likelihood of relapse.
The presence of 19‐kDa Bcl‐2 in dividing cells
Authors: Hoetelmans R. W. M. , Van de Velde C. J. H. , Van Dierendonck J. H. 
Published: November 2003

Abstract.  The 26‐kDa bcl‐2 gene product inhibits apoptosis and cell proliferation. Cleavage of Bcl‐2 into a 22‐kDa fragment inactivates its anti‐apoptotic activity and is a key event in apoptosis. Here, and in recent work, we describe massive 19‐kDa Bcl‐2 immunoreactivity in non‐apoptotic cells, suggesting a link with viability rather than cell death. Loss of 19 kDa Bcl‐2 in adriamycin‐induced apoptotic cells underlines this. G2/M‐phase accumulation of cells by nocodazole‐treatment also results in loss of 19 kDa Bcl‐2. Next to its well‐documented cytoplasmic localization, a substantial pool of Bcl‐2 resides in nuclei. Hampered nuclear localization of Bcl‐2 leads to a loss of cell cycle repression. This has led us to point at a pivotal role for nuclear Bcl‐2 in cellular proliferation. In this report, cellular fractionation of bcl‐2 transfected cells in various phases of the cell cycle reveals a constitutive cytoplasmic pool of 19 kDa Bcl‐2. Nuclear 19‐kDa Bcl‐2 immunoreactivity is far more pronounced in rapidly dividing nuclei compared with more quiescent nuclear fractions. This implicates that ongoing cell proliferation involves cleavage of nuclear Bcl‐2 with a 19‐kDa fragment.
The hierarchical spatial distribution of chloroplast DNA polymorphism across the introduced range of Silene vulgaris
Authors: McCauley D. E. , Smith R. A. , Lisenby J. D. , Hsieh C. 
Published: November 2003

Abstract Silene vulgaris was introduced into North America sometime prior to 1800. In order to document the population structure that has developed since that time, collections were made from 56 local populations distributed among 9 geographical regions in eastern North America. Individual plants were characterized for chloroplast DNA (cpDNA) haplotype by restriction fragment size analysis of four noncoding regions of cpDNA amplified by polymerase chain reaction. A total of 19 cpDNA haplotypes were detected using this method. The overall gene diversity of 0.85 is quite similar to the diversity detected in these same regions of cpDNA in a previously published sample of S. vulgaris taken from across much of Europe. The spatial distribution of the North American cpDNA diversity was quantified by hierarchical F‐statistics that partitioned the genetic variance into variation among local populations within regions, and variation among regions. The average FST among populations within regions was 0.66 and the FST among regions was 0.09. The among‐region variation was due to both differences among regions in the frequency of two most common haplotypes, and to the presence of a number of region‐specific haplotypes. In order to test for isolation by distance at the regional level, FST values were calculated for all possible pairs of regions, and regressed against the geographical distance between those regions. There was no evidence for isolation by distance. It is suggested that the local population structure is generated by recent extinction/colonization dynamics, and that the among‐region structure reflects demographic events associated with range expansion following introduction to North America.
Genetic structure in a montane ranid frog: restricted gene flow and nuclear–mitochondrial discordance
Authors: Monsen Kirsten J. , Blouin Michael S. 
Published: November 2003

AbstractThere is substantial debate over the criteria that should be used to group populations of a species into distinct units for conservation (e.g. evolutionarily significant units, management units, distinct population segments). However, in practice molecular genetic differentiation is often the only or main criterion used to identify such units. Most genetic studies attempting to define conservation units in animals use a single molecular marker, most often mitochondrial, and use samples from a limited number of populations throughout the species’ range. Although there are many benefits to using mtDNA, certain features can cause it to show patterns of differentiation among populations that do not reflect the history of differentiation at the nuclear genome where loci controlling traits of adaptive significance presumably occur. Here we illustrate an example of such mitochondrial–nuclear discordance in a ranid frog, and show how using mtDNA or nuclear loci alone could have led to very different conservation recommendations. We also found very high genetic differentiation among populations on a local scale, and discuss the conservation implications of our results.
Comparative phylogeography of short‐tailed bats (Carollia: Phyllostomidae)
Authors: Hoffmann F. G. , Baker R. J. 
Published: November 2003

AbstractThis is the first study of comparative phylogeography involving closely related species of Neotropical bats of the family Phyllostomidae. We compared patterns of geographical variation within the five species of fruit‐eating bats currently recognized in the genus Carollia using the complete mitochondrial cytochrome‐b gene. Our results suggest that the combined effect of the uplift of the Andes and the Panamanian land bridge has been as important for bats as for terrestrial mammals in shaping present‐day biodiversity in the New World tropics. Species in this genus can be arranged in two highly supported clades, with a deep subdivision within each that corresponds well to differences across the Andes. We found three congruent phylogeographical patterns across species in this genus. First, the closer relationship between samples from western Ecuador and those from Central America, compared with populations east of the Andes in C. brevicauda, C. castanea and C. perspicillata. Second, the likelihood of a similar timing in South America for the arrival and diversification of C. brevicauda and C. perspicillata from their Central America ancestors. Third, the expansion of C. perspicillata and C. sowelli into northwestern Central America in the relatively recent past. Using a molecular clock, with rates ranging from 2.3 to 5% per 106 years, diversification within Carollia would have occurred over the last 1–4.5 Myr. These estimates agree well with the last rise of the Northern Andes and the Panama isthmus.
Fine‐scale genetic pattern and evidence for sex‐biased dispersal in the túngara frog, Physalaemus pustulosus
Authors: Lampert Kathrin P. , Rand A. Stanley , Mueller Ulrich G. , Ryan Michael J. 
Published: November 2003

AbstractTúngara frogs (Physalaemus pustulosus) are a model system for sexual selection and communication. Population dynamics and gene flow are of major interest in this species because they influence speciation processes and microevolution, and could consequently provide a deeper understanding of the evolutionary processes involved in mate recognition. Although earlier studies have documented genetic variation across the species’ range, attempts to investigate dispersal on a local level have been limited to mark–recapture studies. These behavioural studies indicated high mobility at a scale of several hundred metres. In this study we used seven highly polymorphic microsatellite loci to investigate fine‐scaled genetic variation in the túngara frog. We analysed the influence of geographical distance on observed genetic patterns, examined the influence of a river on gene flow, and tested for sex‐biased dispersal. Data for 668 individuals from 17 populations ranging in distance from 0.26 to 11.8 km revealed significant levels of genetic differentiation among populations. Genetic differentiation was significantly correlated with geographic distance. A river acted as an efficient barrier to gene flow. Several tests of sex‐biased dispersal were conducted. Most of them showed no difference between the sexes, but variance of Assignment Indices exhibited a statistically significant male bias in dispersal.
Weed communities of winter wheat as influenced by input level and rotation
Authors: BARBERI P. , SILVESTRI N. , BONARI E. 
Published: November 2003

SummaryThe influence of cropping systems constituted by the combination of three input levels (low, intermediate and high) and four 2‐year rotations between a spring summer crop and winter wheat (Triticum aestivum L.) on the density and composition of the winter wheat weed flora was evaluated from 1989 to 1992. Spring summer crops were maize (Zea mays L.). soyabean (Glycine max (L.) Merr.). sugar beet (Beta vulgaris L.) and sunflower (Helianthus and L.) Total weed density at the end of the wheat tillering stage ranged from 2.5 to 128.7 plants m‐2 and generally decreased with cropping intensity, although to a differing extent, depending upon rotation. Differences among weed communities of the 12 cropping systems were mostly dependent upon input level. The effect of the preceding crop on the weed flora composition of winter wheat was evident only with reduced herbicide use (low‐input systems). Weed species could be ascribed to four categories: (a) species sporadically associated with cropping systems (most of the weeds); (b) species associated with a specific input level (e.g. Papaver rhoeas L. to low and intermediate input levels and Veronica persica Poiret to the high input ievel): (c) species associated with a specific rotation (e.g. Anm majus L. to sugar beet winter wheat): and (d) species associated with specitie plots that become important every other year (e.g. Convolvulus arvensis L. and Stellaria media (L.) Vill.).
Influence of weather on the efficacy of dichlorprop‐P/MCPA and trihenuron‐methyl
Authors: LUNDKVIST A. 
Published: November 2003

SummaryThe influence of weather on the efficacy of dichlorprop‐P/MCPA and tribenuron‐methyl on annual weeds in spritig barley was studied in the field during 4 years at six locations in southern Sweden. The herbicides were applied at one‐eighth to three‐quarters of the full dose at three application times with approximately 6‐day intervals. Weather stations, placed in the experiments, recorded climatic data, Maximum herbicide efficacy was obtained when spraying 1 week after the cotyledon stage with half or three‐quarters of the recommended dose. Dose‐response curves were estimated and the ED80 doses were calculated. On average, the herbicide dose required to obtain an effect of 80% was about 40% of the recommended dose. The influence of weather was analysed for seven different periods: 7 and 2 days before and after herbicide application, 1 day before and after application, and the day of herbicide treatment. The most pronounced eftects of weather were found for the day of and the day before herbicide application, revealing the strong influence of weather on herbicide uptake and plant metabolism. High air tetnperature and low global radiation during the day of treattnent reduced the ED80 dose of dichlorprop‐P/MCPA, whereas the ED80 dose of tribenuron‐methyl increased. For both herbicides, precipitation and high soil temperature increased the ED80 dose, which reflects the importance of rain on herbicide uptake and the effect of soil temperature on plant growth. The R2 values were higher in the analyses of dichlorprop‐P/MCPA than of tribenuron‐methyl, indicating that the effect of dichlorprop‐P/MCA was more weather‐dependent than that of tribenuron‐methyl. Separate analyses of the ED80 doses for Brassica napus L., Chenopodium, album L. and Stellaria media (L.) Vill. generally resulted in increased R2 values. but otherwise gave results similar to those for the total weed population. Although the analyses revealed significant effects of indivtdual weather factors on herbicide efficacy, it was not possible to discern a consistent and causal relationship between weather and herbicide performance.
Massive tongue swelling following the use of synthetic saliva
Authors: Kandala Vijay , Playfor Stephen 
Published: November 2003

SummaryA 5‐year‐old boy with cerebral palsy and severe learning difficulties developed massive tongue swelling of sudden onset following the use of synthetic saliva. Acute airway obstruction and severe stridor ensued which required tracheal intubation and transfer to paediatric intensive care. The child was treated with intravenous steroids, antihistamines and epinephrine. With cessation of synthetic saliva, the swelling gradually resolved and the child was extubated on day 5.