Design of new oxazaphosphorine anticancer drugs

The oxazaphosphorines including cyclophosphamide (CPA, Cytoxan, or Neosar), ifosfamide (IFO, Ifex) and trofosfamide (Ixoten) represent an important group of therapeutic agents due to their substantial antitumor and immunomodulating activity. However, several intrinsic limitations have been uncounted during the clinical use of these oxazaphosphorines, including substantial pharmacokinetic variability, resistance and severe host toxicity. To circumvent these problems, new oxazaphosphorines derivatives have been designed and evaluated with an attempt to improve the selectivity and response with reduced host toxicity. These include mafosfamide (NSC 345842), glufosfamide (D19575, β-Dglucosylisophosphoramide mustard), S-(-)-bromofosfamide (CBM-11), NSC 612567 (aldophosphamide perhydrothiazine) and NSC 613060 (aldophosphamide thiazolidine). Mafosfamide is an oxazaphosphorine analog that is a chemically stable 4-thioethane sulfonic acid salt of 4-hydroxy-CPA. Glufosfamide is IFO derivative in which the isophosphoramide mustard, the alkylating metabolite of IFO, is glycosidically linked to a β-D-glucose molecule. Phase II studies of glufosfamide in the treatment of pancreatic cancer, non-small cell lung cancer (NCSLC), and recurrent glioblastoma multiform (GBM) have recently completed and Phase III trials are ongoing, while Phase I studies of intrathecal mafosfamide have recently completed for the treatment of meningeal malignancy secondary to leukemia, lymphoma, or solid tumors. S-(-)- bromofosfamide is a bromine-substituted IFO analog being evaluated in a few Phase I clinical trials. The synthesis and development of novel oxazaphosphorine analogs with favourable pharmacokinetic and pharmacodynamic properties still constitutes a great challenge for medicinal chemists and cancer pharmacologists.

2001 Volvo Award winner in clinical studies : effects of a media campaign on back pain beliefs and its potential influence on management of low back pain in general practice

Study Design. Quasi-experimental, nonrandomized, nonequivalent, parallel group-controlled study involving before and after telephone surveys of the general population and postal surveys of general practitioners was conducted, with an adjacent state used as a control group.


Objectives. To evaluate the effectiveness of a population-based intervention designed to alter beliefs about back pain, influence medical management, and reduce disability and workers’ compensation–related costs.


Summary of Background Data. A multimedia campaign begun during 1997 in Victoria, Australia, positively advised patients with back pain to stay active and exercise, not to rest for prolonged periods, and to remain at work.


Methods. The campaign’s impact on population beliefs about back pain and fear-avoidance beliefs was measured in telephone surveys, and the effect of the campaign on the potential management of low back pain by general practitioners was assessed by eliciting their likely approach to two hypothetical scenarios in mailed surveys. Demographically identical population groups in Victoria and the control state, New South Wales, were surveyed at three times: before, during, and after intervention in Victoria.


Results. The studies were completed by 4730 individuals in the general population and 2556 general practitioners. There were large statistically significant improvements in back pain beliefs over time in Victoria (mean scores on the Back Beliefs Questionnaire, 26.5, 28.4, and 29.7), but not in New South Wales (26.3, 26.2, and 26.3, respectively). Among those who reported back pain during the previous year, fear-avoidance beliefs about physical activity improved significantly in Victoria (mean scores on the Fear-Avoidance Beliefs Questionnaire for physical activity, 14, 12.5, and 11.6), but not in New South Wales (13.3, 13.6, and 12.7, respectively). General practitioners in Victoria reported significant improvements over time in beliefs about back pain management, as compared with their interstate colleagues. There were statistically significant interactions between state and time for 7 of 10 responses on management of acute low back pain, and for 6 of 10 responses on management of subacute low back pain.


Conclusion. A population-based strategy of providing positive messages about back pain improves the beliefs of the general population and general practitioners about back pain and appears to influence medical management.

Women exposed to intimate partner violence : expectations and experiences when they encounter health care professionals : a meta-analysis of qualitative studies

Background The appropriate response of health care professionals to intimate partner violence is still a matter of debate. This article reports a meta-analysis of qualitative studies that answers 2 questions: (1) How do women with histories of intimate partner violence perceive the responses of health care professionals? and (2) How do women with histories of intimate partner violence want their health care providers to respond to disclosures of abuse?

Methods Multiple databases were searched from their start to July 1, 2004. Searches were complemented with citation tracking and contact with researchers. Inclusion criteria included a qualitative design, women 15 years or older with experience of intimate partner violence, and English language. Two reviewers independently applied criteria and extracted data. Findings from the primary studies were combined using a qualitative meta-analysis.

Results Twenty-nine articles reporting 25 studies (847 participants) were included. The emerging constructs were largely consistent across studies and did not vary by study quality. We ordered constructs by the temporal structure of consultations with health care professionals: before the abuse is discussed, at disclosure, and the immediate and further responses of the health care professional. Key constructs included a wish from women for responses from health care professionals that were nonjudgmental, nondirective, and individually tailored, with an appreciation of the complexity of partner violence. Repeated inquiry about partner violence was seen as appropriate by women who were at later stages of an abusive relationship.

Conclusion Women’s perceptions of appropriate and inappropriate responses partly depended on the context of the consultation, their own readiness to address the issue, and the nature of the relationship between the woman and the health care professional.

Drug-herb interactions: eliminating toxicity with hard drug design.

By searching the literatures, it was found that a total of 32 drugs interacting with herbal medicines in humans. These drugs mainly include anticoagulants (warfarin, aspirin and phenprocoumon), sedatives and antidepressants (midazolam, alprazolam and amitriptyline), oral contraceptives, anti-HIV agents (indinavir, ritonavir and saquinavir), cardiovascular drug (digoxin), immunosuppressants (cyclosporine and tacrolimus) and anticancer drugs (imatinib and irinotecan). Most of them are substrates for cytochrome P450s (CYPs) and/or P-glycoprotein (PgP) and many of which have narrow therapeutic indices. However, several drugs including acetaminophen, carbamazepine, mycophenolic acid, and pravastatin did not interact with herbs. Both pharmacokinetic (e.g. induction of hepatic CYPs and intestinal PgP) and/or pharmacodynamic mechanisms (e.g. synergistic or antagonistic interaction on the same drug target) may be involved in drug-herb interactions, leading of altered drug clearance, response and toxicity. Toxicity arising from drug-herb interactions may be minor, moderate, or even fatal, depending on a number of factors associated with the patients, herbs and drugs. Predicting drug-herb interactions, timely identification of drugs that interact with herbs, and therapeutic drug monitoring may minimize toxic drug-herb interactions. It is likely to predict pharmacokinetic herb-drug interactions by following the pharmacokinetic principles and using proper models that are used for predicting drug-drug interactions. Identification of drugs that interact with herbs can be incorporated into the early stages of drug development. A fourth approach for circumventing toxicity arising from drug-herb interactions is proper design of drugs with minimal potential for herbal interaction. So-called ”hard drugs” that are not metabolized by CYPs and not transported by PgP are believed not to interact with herbs due to their unique pharmacokinetic properties. More studies are needed and new approached are required to minimize toxicity arising from drug-herb interactions.

Reliability of building embodied energy modelling: an analysis of 30 Melbourne case studies

Building design decisions are commonly based on issues pertaining to construction cost, and consideration of energy performance is made only within the context of the initial project budget. Even where energy is elevated to more importance, operating energy is seen as the focus and embodied energy is nearly always ignored. For the first time, a large sample of buildings has been assembled and analysed in a single study to improve the understanding of the relationship between energy and cost performance over their full life cycle. Thirty recently completed buildings in Melbourne, Australia have been studied to explore the accuracy of initial embodied energy prediction based on capital cost at various levels of model detail. The embodied energy of projects, elemental groups, elements and selected items of work are correlated against capital cost and the strength of the relationship is computed. The relationship between initial embodied energy and capital cost generally declines as the predictive model assumes more detail, although elemental modelling may provide the best solution on balance.

Role of multi-tenure reserve networks in improving reserve design and connectivity

Multi-tenure reserve networks aim to connect areas managed for biodiversity conservation across public and private land. This paper seeks to determine to what extent multi-tenure reserve networks improve the reserve design and connectivity of the public protected area estate, using three networks in southeastern Australia as case studies. Network configuration varied considerably and those networks with generally larger parcels tended to be better connected. On average, public land components were larger than private land components in all networks. Two networks had 18 components physically adjoining other network components while another had only 6 components adjoining. Importantly for two of the networks, the average distance between the nearest neighbouring component was significantly less than average distances between public protected areas in the subregion. Thus these multi-tenure reserve networks acted to enhance the existing public protected area estate by increasing the potential linkages in the landscape and therefore the viability of individual public protected areas.

The effects of a simplified tai-chi exercise program (STEP) on the physical health of older adults living in long-term care facilities : a single group design with multiple time points

Background
Studies support the positive effects that Tai Chi has on the physical health of older adults. However, many older adults residing in long-term care facilities feel too weak to practice traditional Tai Chi, and a more simplified style is preferred.
Objective
To test the effects of a newly-developed, Simplified Tai-Chi Exercise Program (STEP) on the physical health of older adults who resided in long-term care facilities.
Design
A single group design with multiple time points: three pre-tests, one month apart; four post-tests at one month, two months, three months, and six months after intervention started.
Settings
Two 300–400 bed veteran homes in Taiwan.
Participants
The 51 male older adults were recruited through convenience sampling, and 41 of them completed six-month study. Inclusion criteria included: (1) aged 65 and over; (2) no previous training in Tai Chi; (3) cognitively alert and had a score of at least eight on the Short Portable Mental Status Questionnaire; (4) able to walk without assistance; and (5) had a Barthel Index score of 61 or higher. Participants who had dementia, were wheel-chair bound, or had severe or acute cardiovascular, musculoskeletal, or pulmonary illnesses were excluded.
Methods
The STEP was implemented three times a week, 50 min per session for six months. The outcome measures included cardio-respiratory function, blood pressure, balance, hand-grip strength, lower body flexibility, and physical health actualization.
Results
A drop in systolic blood pressure (p=.017) and diastolic blood pressure (p<.001) was detected six months after intervention started. Increase in hand-grip strength from pre to post intervention was found (left hand: p<.001; right hand: p=.035). Participants also had better lower body flexibility after practicing STEP (p=.038).
Conclusions
Findings suggest that the STEP be incorporated as a floor activity in long-term care facilities to promote physical health of older adults.

Design-related bias in hospital fall risk screening tool predictive accuracy evaluations: systematic review and meta-analysis.

Introduction: Fall risk screening tools are frequently used as a part of falls prevention programs in hospitals. Design-related bias in evaluations of tool predictive accuracy could lead to overoptimistic results, which would then contribute to program failure in practice.

Methods: A systematic review was undertaken. Two blind reviewers assessed the methodology of relevant publications into a four-point classification system adapted from multiple sources. The association between study design classification and reported results was examined using linear regression with clustering based on screening tool and robust variance estimates with point estimates of Youden Index (= sensitivity + specificity - 1) as the dependent variable. Meta-analysis was then performed pooling data from prospective studies.

Results: Thirty-five publications met inclusion criteria, containing 51 evaluations of fall risk screening tools. Twenty evaluations were classified as retrospective validation evaluations, 11 as prospective (temporal) validation evaluations, and 20 as prospective (external) validation evaluations. Retrospective evaluations had significantly higher Youden Indices (point estimate [95% confidence interval]: 0.22 [0.11, 0.33]). Pooled Youden Indices from prospective evaluations demonstrated the STRATIFY, Morse Falls Scale, and nursing staff clinical judgment to have comparable accuracy.

Discussion: Practitioners should exercise caution in comparing validity of fall risk assessment tools where the evaluation has been limited to retrospective classifications of methodology. Heterogeneity between studies indicates that the Morse Falls Scale and STRATIFY may still be useful in particular settings, but that widespread adoption of either is unlikely to generate benefits significantly greater than that of nursing staff clinical judgment.

Getting old and heading south: the academic success of Southerner learners in design cohorts

This paper investigates the relationship between learning style, as determined by Kolb's Learning Style Inventory, age and one measure of academic performance in design assignments for two cohorts of first- and third-year architecture students. The paper focuses on the results of a cross-curriculum learning style survey conducted as part of a project aimed at resolving the learning difficulties of students collaborating in multi-disciplinary and multi-cultural team assignments. The research was conducted to determine how learning style differences in heterogeneous teams might be addressed through pedagogy. In light of evidence in student cohorts of learning style changes towards the learning styles of design teachers as students progress through their studies, this paper demonstrates how these changes reflect a statistically significant relationship between learning styles and academic performance in design assignments.

Longitudinal studies into science learning - methodological issues

The Gold Standard for education research promotes randomized controlled trials (RCTs) that can produce generalizable knowledge claims across similar problems and situations. Unfortunately, the Gold Standard does not fully recognize the need for developmental research to better understand the problem space, formulate theory and approaches to teaching and learning, and formulate and pursue associated research questions. This developmental research has been a precursor to the development of interventions together with the necessary instrumentation and technologies required to fully investigate these through the more formal evaluative processes imagined by the Gold Standard. This chapter focuses on longitudinal studies that cover a continuum from such developmental research to research that uses control-experimental features to evaluate interventions. These studies attend to a set of issues dealing with  developmental progressions and learning trajectories that require  investigation over an extended period of time. It will be argued that
these longitudinal studies of a variety of methodological types represent quality research in that rigorous design and implementation produce  evidence-based claims. The chapter examines the nature of the relationship between evidence and claims in these studies, to show the possibility of building in control features every bit as strong as those in classic Gold Standard designs. Further, it will be argued that, given the complexity of learning pathways, a simplistic interpretation of RCTs conducted over the shorter term can be misleading in terms of both internal and external validity claims.

Are aspects of study design associated with the reported prevalence of female sexual difficulties?

Objective: To investigate associations between the prevalence of sexual  difficulties reported in published studies and design features of those studies to determine if differences in design contribute to variation in prevalence estimates.
Design: Systematic review, multivariate analysis.
Setting: Studies published internationally in English.
Patient(s): Not applicable.
Intervention(s): None.
Main Outcome Measure(s): Prevalence estimates of difficulty with desire, arousal, orgasm, and sexual pain reported in published studies.
Result(s): Our systematic literature search identified 1,380 publications. Fifty-five studies met our inclusion criteria (reporting prevalence, sample size and response rate, sample size greater than 100, not clinic based). Reported prevalence of sexual difficulty varied across studies (up to tenfold). Eleven aspects of research conduct in these studies were included in our multivariate analysis as explanatory variables. Five aspects of study design and conduct (data collection procedures, inclusion criteria, duration of sexual difficulty recorded, sample size, and response rate) were associated with the reported prevalence of at least one type of sexual difficulty independently of likely predictors of true variation in prevalence: study location, study year, and age range of participants.
Conclusion(s): This review provides evidence that study design may influence reported prevalence estimates of female sexual difficulties and contribute to the wide variation in published estimates.

The role of cultural capital towards the development of a sustainable business model for design firm internationalization

This paper reports the results of three case studies of firms involved with design for the built environment who have been working in international markets for more than two decades. The first two firms are architectural practices and the third is a construction firm which designs and constructs. Their markets are diverse and their strategies have evolved over the two decades. There are numerous differences between countries including cultural, social, project governance structures, regulatory, procurement strategies, terminology, codes, etc. What is it that makes these firms able to develop sustainable business models in internationalisation? A grounded theory approach was used to examine the three case studies and develop a reflexive capability model drawing from the sociological theory of reflexivity to interpret the characteristics of the firms' ability to be able to adapt different international conditions. Twenty-two interviews were conducted across the three firms. Results indicated that sustainable business models rely upon the management of social, cultural and intellectual capital. The strategic management of capital leads to the development of increasing reflexive capability within the processes related to internationalisation. Reflexive capability is a characteristic of the three successful case study firms internationalising and working within global models of practice. This paper focuses on the role of cultural capital in a reflexive capability model for sustainable internationalisation.

Common structural basis for central nervous system drug design

The main theme of this thesis is that there is a common structural basis for drugs acting on the central nervous system (CNS), and that this concept may be used to design new CNS-active drugs which have greater specificity and hence less side-effects. To develop these ideas, the biological basis of how drugs modify CMS neurotransmission is described, and illustrated using dopaminergic pathways. An account is then given of the use of physicochemical concepts in contemporary drug design. The complete conformational analysis of several antipsychotic drugs is used to illustrate some of these techniques in the development of a model for antipsychotic drug action. After reviewing current structure-activity studies in several classes of CNS drugs (antipsychotics, anti-depressants, stimulants, hal1ucinogens, anticonvulsants and analgesics), a hypothesis for a common structural basis of CNS drug action is proposed- This is based on a topographical comparison of the X-ray structures of eight representative CNS-active drugs, and consists of three parts: 1.there is a common structural basis for the activity of many different CNS-active drug classes; 2. an aromatic ring and a nitrogen atom are the primary binding groups whose topographical arrangement is fundamental to the activity of these drug classes; 3. the nature and placement of secondary binding determines different classes of CNS drug activity. A four-Point model for this common structural basis is then defined using 14- CNS-active drug structures that include the original eight used in proposing the hypothesis. The coordinates of this model are: R1 (0. 3.5, 0), R2 (0, -3.5, O), N (4.8. -0.3, 1.4), and R3 (6.3, 1.3, 0), where R1 and R2 represent the point locations of a hydrophobic interaction of the common aromatic ring with a receptor, and R3 locates the receptor point for a hydrogen bond involving the common nitrogen, N. Extended structures were used to define the receptor points R1, R2 and R3, and the complete conformational space of each of the 14 molecules was considered. It is then shoun that the model may be used to predict whether a given structure is likely to show CNS activity: a search over 1,000 entries in the current Merck Index shows a high probability (82%) of CNS activity in compounds fitting the structural model. Analysis of CNS neurotransmitters and neuropeptides shows that these fit the common model well. Based on the available evidence supporting chemical evolution, protein evolution, and the evolution of neurotransmitter functions, it is surmised that the aromatic ring/nitrogen atom pharmacophore proposed in the common model supports the idea of the evolution of CNS receptors and their neurotransmitters, possibly from an aromatic amine or acety1cho1ine acting as a primaeval communicating molecule. The third point in the hypothesis trilogy is then addressed. The extensive conformation-activity analyses that have resulted in well-defined models for five separate CNS drug classes are used to map out the locations of secondary binding groups relative to the common model for anti-psychotics, antidepressants, analgesics, anticholinergics, and anticonvulsants. With this information, and knowledge derived from receptor-binding data, it is postulated that drugs having specified activity could be designed. In order to generate novel structures having a high probability of CNS-activity, a process of drug design is described in which known CNS structures are superimposed topographically using the common model as a template. Atoms regarded as superfluous may be selectively deleted and the required secondary binding groups added in predicted locations to give novel structures. It is concluded that this process provides the basis for the rational design of new lead compounds which could further be optimized for potent and specific CNS activity.