Search

Ming Chiang Lim,1,2 Ernieda Hatah,3 Kay Chee Lai,1 Asdayati Buang,1,4 Tze Juin Koay,1 Wendy Jia Yii Sim,1 Suet Chee Ng1 1Pharmacy Department, Hospital Banting, Selangor, 42700, Malaysia; 2Pharmacy Department, Hospital Sultan Haji Ahmad Shah, Temerloh, 28000, Malaysia; 3Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Kuala Lumpur, 50300, Malaysia; 4Pharmacy Department, Hospital Sultan Ismail Petra, Kelantan, 18000, MalaysiaCorrespondence: Ernieda Hatah, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, Jalan Raja Muda Abdul Aziz, Kuala Lumpur, 50300, Malaysia, Tel +603-9289 7328, Fax +603-2698 3271, Email ernieda@ukm.edu.myPurpose: Previous studies show that customer loyalty and purchase intentions were influenced by perceived product value, but little is known about the factors that influence patients’ perceptions of the value of their subsidized prescriptions, when purchasing of medications were not required, and how these factors influence their medication adherence. Hence, this study aims to investigate perceptions of patients receiving subsidized medications regarding the value of their medication.Patients and Methods: This qualitative study involved semi-structured, face-to-face interviews with patients diagnosed with type 2 diabetes mellitus at a government district hospital in Selangor state, Malaysia between June to September 2019. Using purposive sampling, patients were identified at an out-patient pharmacy during prescription refill. They were asked how they perceived the value of their medication. Interviews were audio recorded and then transcribed verbatim for thematic analysis.Results: A total of thirty patients were interviewed. Patients’ perceptions on the value of medications were influenced by several factors such as trust, how the medications impact on their physical and social well-beings, and the perceived sacrificed made when the medications were procured and used. Perceptions on medication values were influenced by the recommendation received from someone they trust such as their doctors or significant others. It was also influenced by their perceptions of how the medication helps to improve their disease symptoms and affect their religious and social activities. Other factors include the perceived worth of the sacrifices made to access and use the medication.Conclusion: Identifying factors that may influence patients’ perceived value of the medication may help improve healthcare practices.Keywords: value, medication, adherence, subsidies

Can phenomenological architecture be simply described as: Phenomenological Architecture = Phenomenology + Architecture? In the simplest terms, phenomenology is the interpretive study of human experience. Any object, event, situation or experience that a person can see, hear, tough, smell, taste, feel, intuit, know, understand, or live through is a legitimate subject or phenomenological investigation. Architecture is not only the physical form of the building we inhabit, but a place, memory and time in which we see, hear, touch, smell, taste, feel, intuit, know, understand and live. Therefore, architecture is a natural subject for phenomenological investigation. As individuals, we immerse ourselves in the spaces we inhabit and form our own individual and unique experiences. By immersing ourselves in the spaces we inhabit, we interact with the form, textures and smells of the building which we are in. Can an inert thing such as a building help support the development of human beings' experiences; therefore help with his or her understanding of the world that they are physically in? The concept of phenomenological architecture seeks to provide a balanced and holistic physical manifestation of explaining, describing and representing an architectural intention that places emphasis on the human experience. The human experience includes paying particular emphasis on some of the essentials which help develops an experience. Essentials such as bodily senses, memories, materiality and perception are examined. This therefore creates a focus by using architecture as a catalyst in creating human experiences. In conclusion, phenomenology added with architecture does not fully explain phenomenological architecture, but it is how architecture works and helps encourage phenomena and experiences which creates phenomenological architecture.

Mobile health (mHealth) applications (apps) have the potential to increase access to mental health care. In China, there is growing interest in mHealth apps for depression. Our objective was to systematically review research on mHealth for depression in China to identify benefits and challenges. A systematic literature search was conducted using Chinese and English databases in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Randomized and nonrandomized clinical studies on mHealth apps and depression in China were included. Study quality was assessed using the Cochrane Risk of Bias tool. Seven studies met the inclusion criteria with three randomized trials, two quasi-randomized trials, one clinical trial with an uncertain grouping method, and one study with a single-group design. All studies used the WeChat platform and included activities such as psychoeducation, self-management, supervised group chats, and/or remote contact with a healthcare team, in comparison to usual care. All studies reported significant and large benefits for outcomes, but the risk of bias was high. There are few rigorous evaluations of mHealth apps for depression in China, with all included studies involving WeChat programs and most using WeChat to extend nursing discharge care for inpatients with depression. While these studies showed significant improvement in health outcomes as compared to usual care, the results remain inconclusive because of the high risk of bias. mHealth holds promise for increasing access to mental health care in China, but issues such as efficacy, scalability, patient and clinician acceptability, and data privacy must be addressed.

Hepatocellular carcinoma (HCC) is the most common type of liver cancer. Its incidence is increasing, and is closely related to advanced liver disease. Interactions in the HCC microenvironment between tumor cells and the associated stroma actively regulate tumor initiation, progression, metastasis, and therapy response. In the present study, we used the OrganoPlate graft to establish a co-culture system consisting of dissociated HCC tumors (HCC 1-8) and cell lines, HCC derived fibroblasts and vasculature. Cultures were prepared and validated by assessing their response to Sorafenib and Lenvatinib (72 hours). Cultures had their viability (alamar blue assay), and chemokine/cytokine levels in the supernatant (Luminex) determined. In addition, the organization of the vasculature in the tumor compartment was studied through immunostainings, confocal imaging, and subsequent morphological analyses. HCC models were characterized by a range of specific markers, tumor (albumin), endothelial (CD31 and VE-Cadherin) and stromal (aSMA) cells. CD31 immunostained cultures were imaged, and morphology changes quantified. Sorafenib and Lenvatinib induced changes in the tumor vasculature area and organization. Hereby, we present vascularized patient-derived HCC models that include relevant cellular players of the HCC microenvironment. These co-cultures are highly suitable for studying specific cell types as well as patient-specific responses. We envision that this patient derived model will evolve to become a platform for understanding the interplay between angiogenesis, stroma and immune infiltrate in HCC. Citation Format: Orsola Mocellin, Abbie Robinson, Aleksandra Olczyk, Stephane Treillard, Thomas Olivier, Chee Ng, Jeroen Heijmans, Désiréé Goubert, Arthur Stok, Gilles van Tienderen, Monique Verstegen, Sebastian Trietsch, Henriëtte Lanz, Paul Vulto, Jos Joore, Karla S. Queiroz. Sorafenib and Lenvatinib induce vascular responses in patient derived HCC on-Chip models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5876.

ImportanceWomen have a lower incidence of atrial fibrillation (AF) compared with men in several studies, but it is unclear whether this sex difference is independent of sex differences in prevalent cardiovascular disease (CVD), body size, and other risk factors.ObjectiveTo examine sex differences in AF incidence and whether AF risk factors differ by sex in a contemporary cohort of men and women without prevalent CVD.Design, Setting, and ParticipantsThis was a prospective cohort analysis within the Vitamin D and Omega-3 Trial (VITAL) Rhythm Study, a randomized trial that examined the effect of vitamin D and ω-3 fatty acid supplementation on incident AF among men 50 years or older and women 55 years or older without a prior history of prevalent AF, CVD, or cancer at baseline. Data were analyzed from September 29, 2020, to June 29, 2021.ExposuresSex, height, weight, body mass index (BMI), body surface area (BSA), and other AF risk factors at study enrollment.Main Outcomes and MeasuresIncident AF confirmed by medical record review.ResultsA total of 25 119 individuals (mean [SD] age, 67.0 [7.1] years; 12 757 women [51%]) were included in this study. Over a median (IQR) follow-up of 5.3 (5.1-5.7) years, 900 confirmed incident AF events occurred among 12 362 men (495 events, 4.0%) and 12 757 women (405 events, 3.2%). After adjustment for age and treatment assignment, women were at lower risk for incident AF than men (hazard ratio [HR], 0.68; 95% CI, 0.59-0.77; P P P = .001), height and weight (HR 1.49, 95% CI, 1.21-1.82; P P = .009) were substituted for BMI in the multivariate model. In stratified models, risk factor associations with incident AF were similar for women and men.Conclusions and RelevanceIn this cohort study, findings suggest that after controlling for height and/or body size, women without CVD at baseline were at higher risk for AF than men, suggesting that sex differences in body size account for much of the protective association between female sex and AF. These data underscore the importance of AF prevention in women.

IMPORTANCE: Atrial fibrillation (AF) is the most common heart rhythm disturbance, continues to increase in incidence, and results in significant morbidity and mortality. The marine omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and vitamin D have been reported to have both benefits and risks with respect to incident AF, but large-scale, long-term randomized trial data are lacking. OBJECTIVE: To test the effects of long-term administration of marine omega-3 fatty acids and vitamin D on incident AF. DESIGN, SETTING, AND PARTICIPANTS: An ancillary study of a 2 × 2 factorial randomized clinical trial involving 25 119 women and men aged 50 years or older without prior cardiovascular disease, cancer, or AF. Participants were recruited directly by mail between November 2011 and March 2014 from all 50 US states and were followed up until December 31, 2017. INTERVENTIONS: Participants were randomized to receive EPA-DHA (460 mg/d of EPA and 380 mg/d of DHA) and vitamin D(3) (2000 IU/d) (n = 6272 analyzed); EPA-DHA and placebo (n = 6270 analyzed); vitamin D(3) and placebo (n = 6281 analyzed); or 2 placebos (n = 6296 analyzed). MAIN OUTCOMES AND MEASURES: The primary outcome was incident AF confirmed by medical record review. RESULTS: Among the 25 119 participants who were randomized and included in the analysis (mean age, 66.7 years; 50.8% women), 24 127 (96.1%) completed the trial. Over a median 5.3 years of treatment and follow-up, the primary end point of incident AF occurred in 900 participants (3.6% of study population). For the EPA-DHA vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.24; P = .19). For the vitamin D(3) vs placebo comparison, incident AF events occurred in 469 (3.7%) vs 431 (3.4%) participants, respectively (hazard ratio, 1.09; 95% CI, 0.96-1.25; P = .19). There was no evidence for interaction between the 2 study agents (P = .39). CONCLUSIONS AND RELEVANCE: Among adults aged 50 years or older, treatment with EPA-DHA or vitamin D(3), compared with placebo, resulted in no significant difference in the risk of incident AF over a median follow-up of more than 5 years. The findings do not support the use of either agent for the primary prevention of incident AF. TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT02178410; NCT01169259

Distant metastases change the prognosis of patients with nasopharyngeal carcinoma (NPC) which most commonly metastasizes to the bone. 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) is reported as useful in imaging NPC metastases. Our study assesses the incidence and distribution of bone metastases detected by 18F-FDG PET/CT in NPC. 717 18F-FDG PET/CT scan reports of histologically proven NPC patients imaged in Singapore General Hospital, Singapore, between 2003 and 2009 were reviewed for the total number of metastases (scanned from vertex to mid-thigh) and analyzed for distribution. Of the 709 FDG avid metastases in these reports, 357/709 (50.35%) were locoregional nodal metastasis and 352/709 (49.65%) were distant metastases of which 192/709 (27.08%) of total metastases and 54.54% of distant metastases (192/352) were in the bones. The majority of the bone lesions 125/192 (65.1%) were in the axial skeleton with 109/192 (56.77%) in the lower skeleton (thoracolumbar spine, sacrum, and pelvis). The incidence of bone metastases in our study (27.08%) was higher than that reported in other studies, for example, 15% by Liu et al. and 11% (230 patients) by Caglar et al. Bone metastases have been reported in the femurs and the feet and as such some metastases may have been outside the field of view of the scans. In our study, 27% of FDG avid NPC metastases are in the bones.

Summary Introduction The only investigation to determine if a whole body FDG PET/CT scan is helpful in the evaluation of NPC is a study from Stanford. In this study, 26 patients with whole body PET/CT, were evaluated for lesions below adrenals and showed that 7.7% of distant metastases were below adrenals. Our study comparing distant metastases below diaphragm with Stanford study to evaluate the need for whole body PET/CT. Material and methods Reports of NPC patients in Singapore General Hospital were reviewed. The lesions were analyzed for total number and number below diaphragm. The lesions below the diaphragm were further analyzed if they were solitary or involved multiple areas and if any additional lesions were above diaphragm. Results 717 reports were included in final analysis. The number of FDG avid lesions in these reports was 709. Distant metastases represented 352 of the 709 lesions. The number of lesions below diaphragm was 152, of the lesions below diaphragm only 16 of lesions have no co-existing distant metastases above diaphragm. From these lesions, there were only 12 solitary lesions. The other 4 has concurrent metastases but all localized below diaphragm. Conclusion Compared to Stanford study, number of reports is more representative in this study and the yield is much lower (7.7% versus 2.26%). From the results of our study we can consider limiting the scan area from vertex to below diaphragm. However, the symptoms and clinical presentation of the patient will further direct the requesting physician in the area to be imaged.

Culinary and medicinal mushrooms have been appreciated since prehistoric times as valuable resources for food and medicine. Edible mushrooms represent an untapped source of nutraceuticals and valuable palatable food. Long considered tonics, they are now treasured as functional foods that can improve human health and quality of life. Numerous studies have provided insights into the neuroprotective effects of edible mushrooms, which are attributed to their antioxidant, antineuroinflammatory, and cholinesterase inhibitory properties, and their ability to prevent neuronal death. Here we review the recent literature on the role of culinary and medicinal mushrooms in the management of neurodegenerative diseases and neurotrauma. We highlight some of the molecular mechanisms for how these alternative medicines provide health benefits that could help us to harness their neuroprotective effects.

In most research, Oswald ripening and/or oriented aggregation processes are used to describe the Ceria (CeO2) nano particles crystals growth mechanism pathway. However, these analysis on the crystals structures and morphologies are done after the hydrothermal reaction, making it challenging to assign the growth pathways of the nano crystals. In this work, we studied the detailed in-situ structural analysis on the growth mechanisms pathways of hydrothermal synthesized CeO2 nanocrystals through the use of electron tomography. Based on the findings, oriented aggregation process plays the primarily role as the mechanism for CeO2 nanocrystals growth in hydrothermal reactions, while Oswald ripening process plays a secondary role in hydrothermal reactions. The study provides a representative pathway for the initial nucleation and growth of CeO2 for hydrothermal process in different synthesis conditions.

Objectives: Stage Two of the Asia-Pacific Community Mental Health Development Project was established to document successful partnership models in community mental health care in the region. This paper summarizes the best-practice examples and principles of partnerships in community mental health across 17 Asia-Pacific countries. Conclusions: A series of consensus workshops between countries identified best-practice exemplars that promote or advance community mental health care in collaboration with a range of community stakeholders. These prototypes highlighted a broad range of partnerships across government, non-government and community agencies, as well as service users and family carers. From practice-based evidence, a set of 10 key principles was developed that can be applied in building partnerships for community mental health care consistent with the local cultures, communities and systems in the region. Such practical guidance can be useful to minimize fragmentation of community resources and promote effective partnerships to extend community mental health services in the region.

The growth mechanism of CeO2 nanocrystals prepared by the hydrothermal method has been studied in this article. The synthesis of CeO2 nanocrystals follows two stages, the initial nucleation of CeO2 nuclei and the subsequent ripening of nuclei in the hydrothermal process. The nucleation involves the precipitation of Ce3+ cations by OH– ions to form Ce(OH)3 nanoparticles and the transition from Ce(OH)3 to 2–3 nm CeO2 nuclei through an oxidation and rapid dehydration process. In the hydrothermal process, the oriented attachment of nuclei through a lattice matched surface and subsequent Ostwald ripening results in the growth of CeO2 nanocrystals. The dominant mechanism for the ripening of nuclei in hydrothermal reactions is the oriented attachment. The addition of polyvinylpyrrolidone surfactant and adjustment of solution acidity can promote the dispersion of the nuclei and enhance the effective collision among them in the hydrothermal stage, resulting in the oriented aggregation of particles and further grow...

Purpose: This study aimed to assess the safety and feasibility of administering volociximab, a chimeric monoclonal antibody that specifically binds to α5β1 integrin, and to determine the pharmacokinetics, pharmacodynamics, and preliminary evidence of antitumor activity. Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of volociximab i.v. administered over 60 minutes. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human antichimeric antibody formation, and determine the saturation of α5β1 sites on peripheral blood monocytes. Results: Twenty-one patients received 223 infusions of volociximab at doses ranging from 0.5 to 15 mg/kg i.v. on days 1, 15, 22, 29, and 36; and weekly thereafter. Treatment was well tolerated, and dose-limiting toxicity was not identified over the range examined. Mild (grade 1 or 2), reversible fatigue was the principal toxicity of volociximab at the highest dose levels of 10 and 15 mg/kg. Nausea, fever, anorexia, headache, vomiting, and myalgias were mild and infrequent, and there was no hematologic toxicity. Volociximab had biexponential distribution; clearance was inversely related to increasing dose, and the half-life at 15 mg/kg was estimated as being 30 days. Three patients tested positive for anti-volociximab antibodies. Saturation of monocyte α5β1 integrin sites was dose-dependent up to 15 mg/kg. There was one minor response (renal, 7 months) and one durable stable disease (melanoma, 14 months). Conclusions: Volociximab can be safely administered at 15 mg/kg i.v. per week. The absence of severe toxicities and preliminary activity at the highest dose level warrants further disease-directed studies.

We have developed quantitative structure-pharmacokinetic parameters relationship (QSPKR) models using k-nearest-neighbor (k-NN) and partial least-square (PLS) methods to predict the volume of distribution at steady state (Vss) and clearance (CL) of 44 antimicrobial agents in humans. The performance of QSPKR was determined by the values of the internal leave-one-out, crossvalidated coefficient of determination q(2) for the training set and external predictive r(2) for the test set. The best simulated annealing (SA)-kNN model was highly predictive for Vss and provided q(2) and r(2) values of 0.93 and 0.80, respectively. For all compounds, the model produced average fold error values for Vss of 1.00 and for 93% of the compounds provided predictions that were within a twofold error of actual values. The best SA-kNN model for prediction of CL yielded q(2) and r(2) values of 0.77 and 0.94, respectively, and had an average fold rror of 1.05. Use of PLS methods resulted in inferior QSPKR models. The SA-kNN QSPKR approach has utility in drug discovery and development in the identification of compounds that possess appropriate pharmacokinetic characteristics in humans, and will assist in the selection of a suitable starting dose for Phase I, first-time-in-man studies.

The secretory transport of the H(2)-antagonists, ranitidine and famotidine, across Caco-2 cell monolayers was found to be a saturable process. Both drugs exhibited greater permeability in the basolateral (BL) to apical (AP) direction than in the AP to BL direction, indicating apically directed secretion; BL to AP transport was inhibited by P-glycoprotein (P-gp) inhibitors verapamil and cyclosporin A. The cellular uptake of ranitidine across the BL membrane was saturable and temperature dependent, indicative of carrier-mediated transport. The K(m) and V(max) for the uptake process were estimated to be 66.9 mM and 20.9 nmol/mg of protein/min, respectively. The uptake of [(14)C]ranitidine across the BL membrane was inhibited by unlabeled ranitidine and structurally diverse organic cations. The tetraethylammonium (TEA)-sensitive organic cation transporters are not involved in the uptake of ranitidine and famotidine across the BL membrane of Caco-2. This conclusion was based on the evidence that functionally active TEA-sensitive organic cation transporters did not exist in the BL membranes of the Caco-2 cells, whereas the functionally active TEA-sensitive organic cation transporter(s) in LLC-PK(1) cells did not contribute to the transport of ranitidine or famotidine across the cell monolayers. Thus, we conclude that the secretory transport of ranitidine and famotidine across Caco-2 cell monolayers is mediated by 1) a carrier in the BL membrane that is distinct from the TEA-sensitive organic cation transporter(s) and 2) P-gp in the apical membrane.

This article reviews recent literature published over the period March 2012-August 2013 on antidepressant pharmacogenetics, with a focus on clinical translation and methodological challenges.Recently, various polymorphisms associated with differential antidepressant efficacy, tolerability, and safety have emerged in association studies, but mixed findings, limited effect sizes, and poor control of confounders have prevented findings translating to practice. Although promising steps have been made, empirically robust clinically translatable pharmacogenetic tests are not yet established. The complex neurobiology of major depressive disorder (MDD) together with the evolving understanding of genetic processes present research challenges for clinical translation.Early reports of clinical utility are published. The current evidence base for antidepressant pharmacogenetics is, however, not yet empirically robust enough to inform routine prescribing guidelines. Over the coming years, genetically guided versus unguided trials will help determine if antidepressant pharmacogenetics merits more widespread application.

The objective of this study is to investigate the influence of the 5-HTTLPR (serotonin transporter-linked promoter region), cytochrome P450 2C19, and cytochrome P450 2D6 polymorphisms on escitalopram (ESC) and venlafaxine (VEN) responses in major depressive disorder.A prospective multi-site study of 106 patients (Caucasian and Han Chinese ethnicities) with major depressive disorder treated with either ESC or VEN was conducted. The 17-item Hamilton Depression scale (HDRS), Clinical Global Impression Scale, and an adverse events scale (UKU) were assessed over 8 weeks, blind to genotype.At the 8-week end point, a significant HDRS reduction for both ESC and VEN occurred (p 0.0001). The 5-HTTLPR l/l genotype was associated with significantly greater score reductions on the HDRS compared with s/s carriers (p = 0.016) among Caucasian subjects receiving ESC (n = 47). Response rates were significantly higher for l/l (92%) compared with l/s (61%) and s/s (46%) variants (p = 0.042). For every l allele a participant carried, there was a 3.33 (95% confidence interval 1.25, 8.84; p = 0.02) times greater odds of ESC response. No significant associations between any of the genotypes and adverse effects were found.Ethnicity may have differential effects on the 5-HTTLPR genotype-efficacy relationship. Results suggest that l/l allele for 5-HTTLPR is associated with a robust treatment response to ESC in Caucasian subjects only.

P-glycoprotein Polymorphisms Predict Antidepressant Dose to Remit. Original hypothesis and empirical study by: Dr Ajeet Bhagat Singh (DOB 24-01-1973) 'Singh Patent 1' Patent Application Number: 2012201179 Abstract The P-glycoprotein (Pgp) transporter is a key component of the blood brain barrier (BBB). Many antidepressants are subject to Pgp efflux. Functional polymorphisms of the gene encoding Pgp may influence CNS bioavailability of antidepressants subject to efflux. Single nucleotide polymorphisms (SNPs) at rs1045642 (C3435T) of the Pgp gene have been associated with efflux pump efficiency. This may help explain inter-individual variation in antidepressant dose needed to remit. In this study 113 patients with DSM-IV major depressive disorder (MDD) and of either Caucasian or Chinese heritage where treated with escitalopram (ESCIT) or venlafaxine (VEN) in a naturalistic setting over 8 weeks. 17-item Hamilton Depression Rating Scale (HDRS) scale was assessed serially and blind to genotype. SNP rs1045642(C3435T) of the Pgp gene along with two SNPs previously reported to be in linkage disequilibrium (LD) with it (rs2032582 and rsl 128503) where genotyped. Hepatic P450 2D6 and 2C19 metaboliser status and 5-HTTLPR genotype were controlled for along with demographic and clinical factors. 12.5% of VEN treated subjects with CC allele at rs1045642(C3435T) remitted compared to 73.3% for TT subjects odds ratio (OR) = 6.69 (p=0.006). This was significant with Bonferroni correction. ESCIT average dose needed to remit was 24mg for subjects carrying the TC allele and only 11mg for subjects carrying the TT allele (p = 0.0001) at rs1045642(C3435T). These are these first known data indicating antidepressant dose needed to remit can be predicted by a Pgp SNP. This has potential clinical implications for initial dose selection and sooner remission from MDD.

The primary science objective of the Coronal Suprathermal Particle Explorer (C-SPEX) is to investigate the spatial and temporal variations of coronal suprathermal particle populations that are seeds for acceleration to solar energetic particles (SEPs). It is understood that such seed particle populations vary with coronal structures and can change responding to solar flare and coronal mass ejection (CME) events. Models have shown that higher densities of suprathermal protons can result in higher rates of acceleration to high energies. Understanding the variations in the suprathermal seed particle population is thus crucial for understanding the variations in SEPs. However, direct measurements are still lacking. C-SPEX will measure the variation in the suprathermal protons across various coronal magnetic structures, before/after the passage of CME shocks, in the post-CME current sheets, and before/after major solar flares. Understanding the causes for variation in the suprathermal seed particle population and its effect on the variation in SEPs will also help build the predictive capability of SEPs that reach Earth. The CSPEX measurements will be obtained from instrumentation on the International Space Station (ISS) employing well-established UV coronal spectroscopy techniques.

HAE1, a high-affinity anti-IgE monoclonal antibody, is discussed here as a case study in the use of quantitative pharmacology in the development of a second-generation molecule. In vitro, preclinical, and clinical data from the first-generation molecule, omalizumab, were heavily leveraged in the HAE1 program. A preliminary mechanism-based pharmacokinetic/pharmacodynamic (PK/PD) model for HAE1 was developed using an existing model for omalizumab, together with in vitro binding data for HAE1 and omalizumab. When phase I data were available, the model was refined by simultaneously modeling PK/PD data from omalizumab studies with the available HAE1 phase I data. The HAE1 clinical program was based on knowledge of the quantitative relationship between a pharmacodynamic biomarker, suppression of free IgE, and clinical response (e.g., lower exacerbation rates) obtained in pivotal studies with omalizumab. A clinical trial simulation platform was developed to predict free IgE levels and clinical responses following attainment of a target free IgE level (/=10 IU/ml). The simulation platform enabled selection of four doses for the phase II dose-ranging trial by two independent methods: dose-response non-linear fitting and linear mixed modeling. Agreement between the two methods provided confidence in the doses selected. Modeling and simulation played a large role in supporting acceleration of the HAE1 program by enabling data-driven decision-making, often based on confirmation of projections and/or learning from incoming new data.

An overview is provided of the present population analysis methods and an assessment of which software packages are most appropriate for various PK/PD modeling problems. Four PK/PD example problems were solved using the programs NONMEM VI beta version, PDx-MCPEM, S-ADAPT, MONOLIX, and WinBUGS, informally assessed for reasonable accuracy and stability in analyzing these problems. Also, for each program we describe their general interface, ease of use, and abilities. We conclude with discussing which algorithms and software are most suitable for which types of PK/PD problems. NONMEM FO method is accurate and fast with 2-compartment models, if intra-individual and interindividual variances are small. The NONMEM FOCE method is slower than FO, but gives accurate population values regardless of size of intra- and interindividual errors. However, if data are very sparse, the NONMEM FOCE method can lead to inaccurate values, while the Laplace method can provide more accurate results. The exact EM methods (performed using S-ADAPT, PDx-MCPEM, and MONOLIX) have greater stability in analyzing complex PK/PD models, and can provide accurate results with sparse or rich data. MCPEM methods perform more slowly than NONMEM FOCE for simple models, but perform more quickly and stably than NONMEM FOCE for complex models. WinBUGS provides accurate assessments of the population parameters, standard errors and 95% confidence intervals for all examples. Like the MCPEM methods, WinBUGS's efficiency increases relative to NONMEM when solving the complex PK/PD models.

muM17 is an anti-mouse CD11a monoclonal antibody (mAb) developed as a surrogate molecule for assessing potential reproductive toxicities of efalizumab, an anti-human CD11a mAb approved for treatment of chronic moderate to severe plaque psoriasis. This article shows the use of a mechanism-based PK/PD model for muM17 to further support the determination of dose equivalency of muM17 in the mouse and efalizumab in humans based on CD11a expression on T-lymphocytes (PD). Patients in clinical studies received 1 mg/kg/week efalizumab subcutaneously for 12 weeks. In the mouse model, a single IV dose of 1 or 10 mg/kg or a single SC dose of 3, 5, or 10 mg/kg muM17 was administered. Drug concentrations and PD were quantitated using ELISA and flow cytometry (FACS) analyses, respectively. The PK/PD model of muM17 in mice was developed and was validated using sparse data from a separate multiple dose PK/PD study. The model was next used to simulate PD profiles with multiple dosing regimens mimicking those of the clinical dose of efalizumab. The model showed that 3 mg/kg/week SC administration of muM17 in mice is the minimum dose that can produce PD effects similar to those produced following 1 mg/kg/week SC of efalizumab in humans.

Quantitative structure-activity relationship (QSAR) computational methods were performed to characterize structural requirements and molecular features for rMrp2-mediated methotrexate (MTX) transport. The compounds used in this analysis included MTX and 24 MTX analogues, with activity assessed by measuring inhibition of (3)H-DNP-SG ((3)H-S-(2,4)-dinitrophenyl glutathione) uptake in rat canalicular membrane vesicles. 2D-QSAR modeling using simulated annealing partial least squares (SA-PLS) method identified octanol/water partition coefficient, hydrophobicity, and negative charge as three important factors for MTX and MTX analogue affinity to rMrp2. Further analysis using 3D-QSAR method identified a pharmacophore model consisting of two hydrophobes, two aromatic rings, and a negative ionizable group as the critical molecular features that predict binding affinity of these compounds to rMRP2. The addition of a benzoyl ornithine group at a 9.3A distance and 136.5 degrees vector from the negative ionizable structure of MTX resulted in a 40-fold more potent inhibition of DNP-SG transport, suggesting that this chemical modification, while not essential for activity, contributes to the transport of MTX analogue by rMrp2. These observations provide important insights to the rationale development of analogues of MTX for the treatment of neoplastic and immunological diseases that may be devoid of hepatotoxicity or lack drug resistance.

We have developed quantitative structure-pharmacokinetic parameters relationship (QSPKR) models using k-nearest-neighbor (k-NN) and partial least-square (PLS) methods to predict the volume of distribution at steady state (Vss) and clearance (CL) of 44 antimicrobial agents in humans. The performance of QSPKR was determined by the values of the internal leave-one-out, crossvalidated coefficient of determination q(2) for the training set and external predictive r(2) for the test set. The best simulated annealing (SA)-kNN model was highly predictive for Vss and provided q(2) and r(2) values of 0.93 and 0.80, respectively. For all compounds, the model produced average fold error values for Vss of 1.00 and for 93% of the compounds provided predictions that were within a twofold error of actual values. The best SA-kNN model for prediction of CL yielded q(2) and r(2) values of 0.77 and 0.94, respectively, and had an average fold rror of 1.05. Use of PLS methods resulted in inferior QSPKR models. The SA-kNN QSPKR approach has utility in drug discovery and development in the identification of compounds that possess appropriate pharmacokinetic characteristics in humans, and will assist in the selection of a suitable starting dose for Phase I, first-time-in-man studies.

We examine the ability of a dynamic asset-pricing model to explain the returns on G7-country stock market indices. We extend Campbell's (1996) asset-pricing model to investigate international equity returns. We also utilize and evaluate recent evidence on the predictability of stock returns. We find some evidence for the role of hedging demands in explaining stock returns and compare the predictions of the dynamic model to those from the static CAPM. Both models fail in their predictions of average returns on portfolios of high book-to-market stocks across countries.

not Available.