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Background: An especially significant event in the patient–oncologist relationship is the initial consultation, where many complex topics—diagnosis, treatment intent, and often, prognosis—are discussed in a relatively short period of time. This study aimed to measure patients' understanding of the information discussed during their first medical oncology visit and their satisfaction with the communication from medical oncologists. Methods: Between January and August 2021, patients without prior systemic treatment of their gastrointestinal malignancy (GI) attending the Princess Margaret Cancer Centre (PMCC) were approached within 24 h of their initial consultation to complete a paper‐based questionnaire assessing understanding of their disease (diagnosis, treatment plan/intent, and prognosis) and satisfaction with the consultation. Medical oncology physicians simultaneously completed a similar questionnaire about the information discussed at the initial visit. Matched patient–physician responses were compared to assess the degree of concordance. Results: A total of 184 matched patient–physician surveys were completed. The concordance rates for understanding of diagnosis, treatment plan, treatment intent, and prognosis were 92.9%, 59.2%, 66.8%, and 59.8%, respectively. After adjusting for patient and physician variables, patients who reported treatment intent to be unclear at the time of the consultation were independently associated with lower satisfaction scores (global p = 0.014). There was no statistically significant association between patient satisfaction and whether prognosis was disclosed (p = 0.08). Conclusion: An in‐depth conversation as to what treatment intent and prognosis means is reasonable during the initial medical oncology consultation to ensure patients and caregivers have a better understanding about their cancer. [ABSTRACT FROM AUTHOR]

Background: End‐of‐life (EOL) chemotherapy administration rates for solid tumours are 12–20% and are associated with a reduced quality of life, increased hospitalisation and incidence of death within an acute care facility. Aim: We sought to determine the rate of EOL chemotherapy in government and private hospitals and determine the impact on hospitalisations and location of death in lung and pancreatic cancer patients. Methods: Data were obtained from the Queensland Oncology Repository between 2005 and 2014. Lung (n = 16 501) and pancreatic cancer (n = 4144) deaths were analysed. EOL chemotherapy was determined to be within 30 days of death. Demographics, location of treatment and death are reported. Results: Chemotherapy was administered to 6518 (40%) lung cancer and 1694 (41%) pancreatic cancer patients. A total of 1474 (9%) and 477 (12%) patients, respectively, received EOL chemotherapy. EOL chemotherapy was more common in males and those with distant metastatic disease, while less likely in the elderly and those with a lower socioeconomic status. EOL chemotherapy was more prevalent in large hospitals and was more common in private compared with government hospitals for pancreatic cancer (30 vs 26%; P < 0.001), while it was similar for lung cancer (24 vs 22%; P = 0.115). Death after EOL chemotherapy compared with all cancer deaths was more common in an acute care facility (lung cancer: 60 vs 37%; P < 0.001; pancreatic cancer: 53 vs 36%; P < 0.001). Conclusions: EOL chemotherapy rates were similar to Australian yet marginally lower than international rates, with variation dependent on the size and type of facility and increased the rate of deaths within an acute care facility. [ABSTRACT FROM AUTHOR]

Aim: Hospital admissions secondary to immune‐related adverse events (irAE) arising from immune checkpoint inhibitors (ICI) are likely to increase with increasing use of this class of drug. We sought to determine the characteristics and outcomes of hospital admissions due to irAE. Methods: A retrospective analysis of patients treated with ICI at two tertiary hospitals in Queensland (Australia) was performed. Patients who received at least one dose of ICI for a nonhaematological malignancy between the 1st January 2016 and 1st January 2017 were included. All subsequent hospital admissions were analyzed. Results: A total of 140 patients were included, with the most common malignancies being non‐small‐cell‐cell lung cancer (41%) and melanoma (18%), and most patients received anti‐PD1 treatment (78%). A sum of 76 patients accounted for 116 admissions. Comparing admissions due to irAE and non‐irAE, those admitted for irAE had a significantly longer duration on ICI prior to admission (173 vs 105 days, P = 0.04) but durations of admissions were similar (9.0 vs 8.5 days, P = 0.85). Fifteen patients (11% overall cohort) accounted for 18 admissions attributable to 16 separate irAE. irAE was not considered as a differential diagnosis on admission in 7 patients (38%). In those patients, commencement of corticosteroids was delayed (1.5 days, P = 0.01) but this did not translate into adverse outcomes such as prolonged admissions, prolonged steroid use or long‐term complications. All patients with irAE were managed with high‐dose corticosteroids. One death resulted from irAE (pneumonitis). Conclusions: A sum of 11% patients receiving ICI required hospital admission for irAE. The relatively high rate of irAE as a missed differential diagnosis on admission suggests a need for improved cross‐discipline awareness, education, and institutional management guidelines. [ABSTRACT FROM AUTHOR]

Background: Malnutrition and sarcopenia are poor prognostic factors in many cancers. Studies in gastric and esophageal (GE) cancer have focused on curative intent patients. This study aims to evaluate the prognostic utility of malnutrition and sarcopenia in de novo metastatic GE adenocarcinoma. Methods: Patients with de novo metastatic GE adenocarcinoma seen at the Princess Margaret Cancer Centre from 2010 to 2016 with an available pre‐treatment abdominal computed tomography (CT) were included. Malnutrition was defined as nutritional risk index (NRI) <97.5. Skeletal muscle index (SMI) was measured at the L3 level (sarcopenia defined as SMI <34.4 cm2/m2 in women and <45.4 cm2/m2 in men). Patients receiving chemotherapy had NRI and SMI recalculated at the time of first restaging CT. Results: Of 175 consecutive patients, 33% were malnourished and 39% were sarcopenic at baseline. Patients with pretreatment malnourishment had significantly shorter overall survival (OS; 5.8 vs. 10.9 months, p = 0.000475). Patients who became malnourished during chemotherapy had worse OS compared to those who maintained their nutrition (12.2 vs. 17.5 months p = 0.0484). On univariable analysis, ECOG (p < 0.001), number of metastatic sites (p = 0.029) and NRI (p < 0.001) were significant prognostic factors while BMI (p = 0.57) and sarcopenia (p = 0.19) were not. On multivariable analysis, ECOG (p < 0.001), baseline NRI (p = 0.025), and change in NRI during treatment (p < 0.001) were significant poor prognostic factors for OS. Conclusions: In de novo metastatic GE adenocarcinoma patients, ECOG, pretreatment NRI and change in NRI were significant prognostic factors for OS while sarcopenia was not. Use of NRI at baseline and during treatment can provide useful prognostic information. [ABSTRACT FROM AUTHOR]

BACKGROUND Macroalgae are gaining increasing interest as an important biomass feedstock. Yet when valorising marine biomass, the presence of salt can pose a substantial obstacle to the effectiveness of downstream biological and chemical processes, as well as the engineering infrastructure required. Accordingly, dewatering, washing and drying are often considered the first and crucial primary steps in processing marine biomass such macroalgae. The high costs of these processes can make further marine biorefinery commercialisation prohibitive. This investigation assesses simple pre‐treatments for macroalgal biomass in saltwater, thereby reducing the freshwater footprint, and removing the need for an energy‐intensive washing and drying stage. RESULTS: Using acid and basic catalysts, the carbohydrate and soluble protein components were fractionated into a soluble aqueous phase, for further fermentation and a solid phase suitable for hydrothermal liquefaction. The presence of saltwater was found to aid the fractionation process, solubilising more of the biomass. The use of H2SO4 produced more monosaccharides, whereas NaOH solubilised higher levels of biomass at lower temperatures. The aqueous phase was demonstrated to be suitable for biological processing with the salt tolerant yeast Metschnikowia pulcherrima, and the residual solids suitable for processing via hydrothermal liquefaction. CONCLUSION: By contrast with existing pre‐treatment strategies, we demonstrate that an entirely salt‐based biochemical conversion route is a potentially viable option. For the first time this work demonstrates that, rather than a hindrance, the presence of saltwater can be advantageous, and could provide an alternative, more cost‐effective pathway to achieving a successful macroalgal‐based biorefinery. [ABSTRACT FROM AUTHOR]

In all biorefinery systems, excess water represents a key challenge, and its removal by drying is often a necessary and crucial pre‐treatment. Second‐generation feedstocks have often fallen at this hurdle, particularly microalgae‐derived biomasses, which require extensive (and costly) dewatering. Hydrothermal liquefaction (HTL) has gained increasing attention in recent years as a technology that uses the water present in the feedstock as a versatile reaction medium, which functions as a solvent, reactant, and catalyst for a cascade of organic reactions. Converting organic biomasses into oil, aqueous, solid, and gas fractions, the development of HTL provides the opportunity to exploit previously unsuitable biomasses in a versatile bio‐refinery approach. Marine macroalgae (seaweeds) offer a sustainable source of renewable biomass, which require no land or freshwater to cultivate or harvest. With 70% of the surface of the planet covered in seawater and levels of eutrophication increasing, seaweeds are an underutilized resource with excellent potential for relieving the pressure on fossil resources. Hitherto, this exploitation has been hindered by a lack of suitable and economical processing tools. Here we review the potential for applying HTL to processing marine macroalgae and discuss the potential products and services that can be derived from this potential biorefinery system. © 2019 Society of Chemical Industry and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Intense anthropogenic activity continues to expose the natural environment to heavy metal contamination. Whilst a number of physical and chemical solutions for remediation exist, the use of higher plants and algae for clean‐up of contaminated landscapes, termed 'phytoremediation' and 'phycoremediation', respectively, offer an attractive and sustainable alternative. However, these remediation processes will always lead to a high‐moisture, heavy metal‐contaminated biomass, which must be further processed to partition, or render inert, the metal contaminants. Conversion of this metal‐rich biomass into second‐generation biofuels offers a useful route to subsidise the economics of remediation activities. Here we briefly review the various methods for bioremediation of heavy metals, and discuss the potential to produce bioenergy from these biomass sources. Coupling the bioremediation activity to bioenergy production gives far‐reaching social and economic benefits; however, established processes such as direct combustion and anaerobic digestion risk releasing heavy metals back into the environment. Alternatively, thermochemical conversions such as pyrolysis or hydrothermal liquefaction (HTL) offer significant advantages in terms of the segregation of metals into a relatively inert and compact solid phase while producing a biocrude oil for bioenergy production. In addition, preliminary work suggests that the HTL process can also be used to partition essential macronutrients, such as N, P and K, into an aqueous medium, allowing additional nutrient recycling. © 2019 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Summary: Plant triterpenoids constitute a diverse class of organic compounds that play a major role in development, plant defence and environmental interaction. Several triterpenes have demonstrated potential as pharmaceuticals. One example is betulin, which has shown promise as a pharmaceutical precursor for the treatment of certain cancers and HIV. Major challenges for triterpenoid commercialization include their low production levels and their cost‐effective purification from the complex mixtures present in their natural hosts. Therefore, attempts to produce these compounds in industrially relevant microbial systems such as bacteria and yeasts have attracted great interest. Here, we report the production of the triterpenes betulin and its precursor lupeol in the photosynthetic diatom Phaeodactylum tricornutum, a unicellular eukaryotic alga. This was achieved by introducing three plant enzymes in the microalga: a Lotus japonicus oxidosqualene cyclase and a Medicago truncatula cytochrome P450 along with its native reductase. The introduction of the L. japonicus oxidosqualene cyclase perturbed the mRNA expression levels of the native mevalonate and sterol biosynthesis pathway. The best performing strains were selected and grown in a 550‐L pilot‐scale photobioreactor facility. To our knowledge, this is the most extensive pathway engineering undertaken in a diatom and the first time that a sapogenin has been artificially produced in a microalga, demonstrating the feasibility of the photo‐bio‐production of more complex high‐value, metabolites in microalgae. [ABSTRACT FROM AUTHOR]

ABSTRACT Discussed in a global context, the issue of scale is important to consider as it relates to climate change. As climatological studies utilize temporally and spatially static definitions of seasonal definitions, the understanding of seasonal change may be limited by the way in which seasons are defined. This research serves as a challenge to this perspective by examining the changes in seasons by incorporating variability into the way in which seasons are defined. Temporally and spatially variable seasons were defined based on thresholds of apparent temperature and upper-level circulation patterns for the period 1948-2012. Using 60 US surface stations, two apparent air temperature metrics were used to define seasons that vary spatially and temporally. Stations represented major cities found in the contiguous United States. A large-scale circulation approach utilized synoptic categorizations based on 250-mb geopotential heights from the NCEP-NCAR reanalysis ( NNR) as a metric of seasonal delineation. In this method, seasons varied temporally but not spatially. Despite the different methodological approaches, consistent trends were found. Since 1948, late starts of autumn and winter have been observed while earlier onsets of spring and summer have taken place. For the individual stations, the largest shifts occurred along coasts and in larger, more urbanized environments. Individual locations also showed increased variability in start date, and significant changes were found for all four seasons in the circulation approach. Seasons have been shown to be important for a variety of processes including phenological responses and human adaptation to extreme temperature environments; therefore, the consideration of season variability may be appropriate for future climatological research. [ABSTRACT FROM AUTHOR]

Viruses are a major cause of coccolithophore bloom demise in both temperate and sub-temperate oceanic regions. Most infection studies on coccolithoviruses have been conducted with a single virus strain, and the effect of intragenus competition by closely related coccolithoviruses has been ignored. Here we conducted combined infection experiments, infecting E miliania huxleyi CCMP 2090 with two coccolithoviruses: EhV-86 and EhV-207 both simultaneously and independently. EhV-207 displayed a shorter lytic cycle and increased production potential than EhV-86 and was remarkably superior under competitive conditions. Although the viruses displayed identical adsorption kinetics in the first 2 h post infection, EhV-207 gained a numerical advantage as early as 8 h post infection. Quantitative polymerase chain reaction ( PCR) revealed that when infecting in combination, EhV-207 was not affected by the presence of EhV-86, whereas EhV-86 was quickly out-competed, and a significant reduction in free and cell-associated EhV-86 was seen as early as 2 days after the initial infection. The observation of such clear phenotypic differences between genetically distinct, yet similar, coccolithovirus strains, by flow cytometry and quantitative real-time PCR allowed tentative links to the burgeoning genomic, transcriptomic and metabolic data to be made and the factors driving their selection, in particular to the de novo coccolithovirus-encoded sphingolipid biosynthesis pathway. This work illustrates that, even within a family, not all viruses are created equally, and the potential exists for relatively small genetic changes to infer disproportionately large competitive advantages for one coccolithovirus over another, ultimately leading to a few viruses dominating the many. [ABSTRACT FROM AUTHOR]

Reservoirs are important resources utilized by millions of freshwater anglers annually, but as reservoirs age the quality of the habitat that they provide for fish deteriorates. In 2007, a large-scale habitat improvement project began on Table Rock Lake, Missouri, with the goal of supplementing existing fish habitat in this large reservoir. Over 2,000 habitat structures composed of cedar, pine, hardwoods, stumps, and rocks were installed between 2007 and 2013. By means of scuba surveys, we evaluated the use of these structures by black bassMicropterusspp. and crappiesPomoxisspp. to determine whether it varied among fish species, fish sizes, and structure types. Black bass were observed utilizing all structure types but appeared to utilize hardwoods most. Covariates such as water depth and visibility at the structure confounded our analysis of black bass use, however, limiting our ability to clearly document differences in use. Crappies never used rock structures, and more crappies were observed on cedar structures than any other type. In Table Rock Lake, black bass were attracted to all structure types and crappies were attracted to all structure types except rock. Since fish use is similar across nearly all habitat types, other factors such as cost and installation times should be considered when planning habitat enhancement projects on large reservoirs. Received August 12, 2013; accepted October 30, 2013 [ABSTRACT FROM AUTHOR]

Abstract: The flavoprotein monooxygenase (FPMO) from Stenotrophomonas maltophilia (SMFMO, Uniprot: B2FLR2) catalyses the asymmetric oxidation of thioethers and is unusual amongst FPMOs in its ability to use the non-phosphorylated cofactor NADH, as well as NADPH, for the reduction of the FAD coenzyme. In order to explore the basis for cofactor promiscuity, structure-guided mutation of two residues in the cofactor binding site, Gln193 and His194, in SMFMO were performed in an attempt to imitate the cofactor binding site of the NADPH-dependent FMO from Methylophaga aminisulfidivorans sp. SK1 (mFMO), in which structurally homologous residues Arg234 and Thr235 bind the NADPH 2′-ribose phosphate. Mutation of His194 to threonine proved most significant, with a switch in specificity from NADH to NADPH [(k cat/K m NADH)/k cat/K m NADPH) from 1.5:1 to 1:3.5, mostly as a result of a reduced K m for NADPH of approximately sevenfold in the His194Thr mutant. The structure of the Gln193Arg/His194Thr mutant revealed no substantial changes in the backbone of the enzyme or orientation of side chains resulting from mutation. Mutation of Phe52, in the vicinity of FAD, and which in mFMO is an asparagine thought to be responsible for flavin hydroperoxide stabilisation, is, in SMFMO, a determinant of enantioselectivity in sulfoxidation. Mutation of Phe52 to valine resulted in a mutant that transformed para-tolyl methyl sulfide into the (S)-sulfoxide with 32% e.e., compared to 25% (R)- for the wild type. These results shed further light both on the cofactor specificity of FPMOs, and their determinants of enantioselectivity, with a view to informing engineering studies of FPMOs in the future. [Copyright &y& Elsevier]

Highlights: [•] Structure of a novel virus encoded cytochrome b5 solved. [•] The protein has identical spectral properties to purified human cytochrome b5. [•] The protein can substitute for yeast cytochrome b5 in the P450 51 mediated sterol 14α-demethylation. [•] The protein lacks a hydrophobic C-terminal anchor and is the first cytosolic cytochrome b5 characterised. [•] Suggests the importance of cytochrome b5 metabolic activity at the extremes of cellular scale. [Copyright &y& Elsevier]

Ostreococcus tauri virus (OtV-1) is a large double-stranded DNA virus and a prospective member of the family Phycodnaviridae, genus Prasinovirus. OtV-1 infects the unicellular marine green alga O. tauri, the smallest known free-living eukaryote. Here we present the 191 761 base pair genome sequence of OtV-1, which has 232 putative protein-encoding and 4 tRNA-encoding genes. Approximately 31% of the viral gene products exhibit a similarity to proteins of known functions in public databases. These include a variety of unexpected genes, for example, a PhoH-like protein, a N-myristoyltransferase, a 3-dehydroquinate synthase, a number of glycosyltransferases and methyltransferases, a prolyl 4-hydroxylase, 6-phosphofructokinase and a total of 8 capsid proteins. A total of 11 predicted genes share homology with genes found in the Ostreococcus host genome. In addition, an intein was identified in the DNA polymerase gene of OtV-1. This is the first report of an intein in the genome of a virus that infects O. tauri. Fifteen core genes common to nuclear-cytoplasmic large dsDNA virus (NCLDV) genomes were identified in the OtV-1 genome. This new sequence data may help to redefine the classification of the core genes of these viruses and shed new light on their evolutionary history. [ABSTRACT FROM AUTHOR]

The interactions between viruses and phytoplankton play a key role in shaping the ecological and evolutionary dynamics of oceanic ecosystems. One of the most fascinating examples of horizontal gene transfer between a eukaryotic host and its virus is a de novo sphingolipid biosynthesis pathway (SBP) found in the genomes of both Emiliania huxleyi and its coccolithovirus EhV-86. Here, we focus on a natural E. huxleyi/coccolithovirus system off the coast of Norway and investigate the dynamics of host and virus homologous gene expression for two of the most important sphingolipid biosynthesis enzymes, serine palmitoyl transferase (SPT) and dihydroceramide desaturase (DCD). Transcriptional dynamics display three defined stages along E. huxleyi bloom formation and decline, with the coccolithovirus transcripts taking over and controlling the SBP in stages 2 and 3. The observed patterns fit the hypothesis according to which viral sphingolipids are involved in the timing and physical processes of virion release from the host cells. This study provides a unique insight into the transcriptional interplay of homologous metabolic pathways between virus and host during temporal progression of oceanic E. huxleyi blooms. [ABSTRACT FROM AUTHOR]

The diversity among the coccolithovirus strains held in the Plymouth Virus Collection (PVC) was assessed using three complementary techniques: phylogeny based on DNA polymerase and major capsid protein gene sequence; host range; and a new, microarray-based genome-wide approach. The PVC is composed of three groups of strains that are geographically and temporally distinct. Virus strains clustered according to these groups in all three diversity assessments. Furthermore, the microarray approach based on genomic content showed that two strains, previously considered as identical to others in the PVC, are actually distinct. These results show the importance of genome-wide surveys for assessing strain diversity. Not only has the microarray provided an alternative to the phylogeny-derived pattern for virus evolution, it has also begun to provide some clues to the genes that may be responsible for the different phenotypes displayed by these viruses. [ABSTRACT FROM AUTHOR]

On behalf of the Nova Scotia Seniors' Pharmacare Program, the Drug Evaluation Alliance of Nova Scotia developed a multicomponent intervention plan to facilitate the removal of chlorpropamide as an insured benefit. Chlorpropamide has caused serious hypoglycemia in seniors to a greater extent than some other agents. Pharmacy administrative claims were used to compute monthly use rates for insulin and each oral antihyperglycemic drug from January 1, 2000-December 30, 2002, in an intervention cohort (patients receiving chlorpropamide) and a control cohort (patients receiving an antihyperglycemic agent other than chlorpropamide). Initially, 630 patients were receiving chlorpropamide therapy. By the time chlorpropamide was deinsured, only 10% of the treatment cohort continued receiving chlorpropamide; shortly after deinsurance, no beneficiaries continued receiving the drug. The antihyperglycemics with the greatest increase in prescription were glyburide and gliclazide. The deinsuring of chlorpropamide and the educational strategies that accompanied it resulted in the selection of more appropriate antihyperglycemics for Nova Scotia seniors. [ABSTRACT FROM AUTHOR]

Voriconazole is a potent new triazole with broad-spectrum antifungal activity against clinically significant and emerging pathogens. The present study evaluated the safety, toleration, and pharmacokinetics of oral voriconazole after single and multiple dosing. Sixty-four healthy subjects were randomized to receive treatment and 56 completed the study. Groups of eight subjects each received voriconazole doses of 2 mg kg−1 twice daily, 4 mg kg−1 once daily, 2 mg kg−1 three times daily, or 3 mg kg−1 twice daily. Eleven subjects received 1.5 mg kg−1 three times daily, and 21 subjects were administered placebo. Voriconazole exhibited nonlinear (dose- and time-dependent) pharmacokinetics. This deviation from linear pharmacokinetics was confirmed by linearity ratios of > 1 and decreasing kel values on multiple dosing, with a consequent increase in the terminal phase t1/2. There was also notable intersubject variability in Cmax and AUCτ. The absorption of voriconazole was rapid (mean tmax= 0.9–1.7 h) after single and multiple dosing and the decline in plasma concentration–time curves after tmax was generally biphasic. By day 12, the Cmax, AUCτ, tmax, and t1/2 values for the 3 mg kg−1 twice-daily group were 2356 ng ml−1, 11 170 ng·h ml−1, 1.1 h, and 6.4 h, respectively. The observed accumulation of voriconazole after multiple dosing was greater than predicted from single-dose data. Accumulation ratios for Cmax and AUCτ, which were 1.97 and 3.55, respectively, for the group given voriconazole 3 mg kg−1 twice daily, varied between treatment groups and appeared to be influenced by total daily dose and the frequency and duration of dosing. Visual inspection of Cmin values together with statistical analyses of Cmax and AUCτ values suggest that steady-state levels were achieved by the fifth to sixth day of multiple dosing. Plasma concentrations of voriconazole were well above the minimum inhibitory concentrations (MICs) for Aspergillus spp., Candida spp., and for most emerging fungal pathogens ( Cmin > 0.8 µg ml−1). Voriconazole was well tolerated: most treatment-related adverse events (abnormal vision, headache, dizziness) were mild and resolved within an hour of dosing. The oral dosing regimen selected for subsequent Phase II/III clinical trials on the basis of these results was 200 mg twice daily, equivalent to 3 mg kg−1 twice daily. [ABSTRACT FROM AUTHOR]

Four separate studies were conducted to examine the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of eletriptan, a 5-HT1B/1Dreceptor agonist being developed for the treatment of migraines, after oral and intravenous administration. Fifty-five males received oral (1.5-30 mg or 30-120 mg) or intravenous (1.67-50μg/kg or 50-102μg/kg) eletriptan in four double-and single-blind, placebo-controlled, ascending-dose crossover studies. The maximum plasma concentration (Cmax) and area under the concentration curve (AUC) appeared linear over all dose ranges, with an apparent terminal half-life of 4 to 5 hours. Clearance and volume of distribution remained constant with dose. The time to first occurrence of Cmax(tmax) for oral eletriptan was approximately 1 hour and was unaffected by dose. Comparison of AUC values suggested an absolute bioavailability of approximately 50%. A linear PK/PD model, fitted to the data, predicted small, transient elevations in diastolic blood pressure following eletriptan doses≥ 60 mg. These effects were considered unlikely to be clinically significant. Eletriptan was well tolerated, and treatment-related adverse events were mild to moderate and transient. These PK properties should result in eletriptan having a rapid onset and sustained duration of action in terms of migraine efficacy. [ABSTRACT FROM PUBLISHER]

Focuses on the neoplatonist philosopher Marsilio Ficino's interpretation of philosopher Plato's works. Author's views on the intelligible ideas which concern a Platonist; Discussion on Plato's work 'Statesman'; Author's comments on Ficino's interpretation of Plato's work 'Phaedrus.'

Aims To investigate the pharmacokinetics and pharmacodynamics of dofetilide 1 mg twice daily continuously for 24 days compared with intermittent single dose treatments. Methods A randomized, single-blinded, placebo-controlled, parallel-group, multiple-dose study design was utilized. Healthy male volunteer subjects were randomized into three groups. Group 1 received dofetilide 1.0 mg twice daily for 23 days and once on day 24. Group 2 received matching placebo capsules under the same regimen as group 1. Group 3 received a single dose of dofetilide 1.0 mg on days 1, 5, 10, 17, and 24 with identical placebo capsules administered at all other times to match the dosing pattern of the other groups. Results Continuous administration of dofetilide resulted in the achievement of steady-state concentrations by day 5. Pharmacokinetic parameters following intermittent treatment showed no accumulation. Maximum daily QTc interval (mean± s.e. mean) increased in response to continuous twice-daily dofetilide from baseline (373 ± 5) to day 2 (453 ± 9) but thereafter decreased slightly, but not beyond day 5, by which time the mean maximum QTc was 440 ± 7 ms. In contrast, single doses of dofetilide in the intermittently treated group led to reproducible increases in QTc. Thus mean (± s.e. mean) maximum QTc increased from a baseline of 387 ± 7–467 ± 14, 467 ± 18, 469 ± 14 and 458 ± 10 ms on days 5, 10, 17 and 24, respectively. In view of the pharmacokinetic accumulation on continuous dosing, the attenuation of responsiveness is best represented by the slope of the QTc vs plasma concentration relationship. In the continuously treated group, an initial decrease in the value of the mean slope between day 1 (14.2 ± 1.7 ms/ng ml-1) and day 5 (9.1 ± 0.8 ms/ng ml-1) did not progress beyond day 5. The mean difference in slopes (95% CI) between the intermittent and continuously treated groups were... [ABSTRACT FROM AUTHOR]

Discusses the pharmacokinetics and pharmacodynamics of oral antiarrhythmic drug dofetilide after twice daily and three times daily dosing. Rise in plasma dofetilde concentrations; Relationship between plasma dofetilide concentration and the prolongation of the QT interval; Metabolism of dofetilide.