Buccal absorption of enalapril and lisinopril

Objective: The buccal absorption of captopril does not exhibit the classical pH/partition hypothesis, suggesting that mechanisms other than passive diffusion are involved in its absorption; animal studies have suggested that a peptide carrier-mediated transport system may be responsible for its absorption. The present study evaluated the effects of pH on octanol partitioning, and on the buccal absorption of enalapril and lisinopril, using in vitro techniques and buccal partitioning in human volunteer subjects.

Design of composite asymmetric cellular beams and beams with large web openings

The design of composite asymmetric cellular beams is not fully covered by existing guidance but is an area of important practical application. Asymmetry in the shape of the cross-section of cellular beams causes development of additional bending moments in the web-posts between closely placed openings. Furthermore, the development of local composite action influences the distribution of forces in the web-flange Tees. The design method presented in this paper takes account of high degrees of asymmetry in the cross-section and also the influence of elongated or rectangular openings.

Transforming the Irish Presidency: Activist Presidents and Gender Politics, 1990-2011

The election of two energetic women in succession to the office of President of Ireland challenged the notion that the presidency was a long-service reward for retiring politicians. Mary Robinson and Mary McAleese broke the male domination of the office, interpreted its functions in a more dynamic manner, and utilised the ‘soft power’ of the presidency with skill. Yet, as individuals they were very different in political focus, experience and ideological disposition. This article charts their respective backgrounds and discusses the context in which each woman came to the presidency. It explores their vision for the office. Focusing on the potential for harnessing the soft power of the presidency, it argues that Robinson adopted a classical representative view of the office, whereas McAleese chose a facilitatory style of leadership. The article concludes that in their different ways, Robinson and McAleese contributed to reshaping the office, utilising its symbolic potential and soft power to make it a more meaningful and fit-for-purpose political institution for the twenty-first century. © 2012 Political Studies Association of Ireland.

Domain configuration of permalloy ellipses in a rotating magnetic field

The domain configuration of micron-sized permalloy ellipses was studied under the influence of an in-plane rotating magnetic field using magnetic force microscopy. The field amplitude was chosen such that when the field is applied parallel to the long axis of the ellipses they are saturated, but when the field is perpendicular to the long axis they exhibit multi-domain states. The rotation angle for nucleation and annihilation of domains was determined for different magnitudes of the applied magnetic field and for two different lateral sizes of ellipses, 6 Am x 2 Am and 3 Am x 1 Am. It was found that both nucleation and annihilation occur over a range of angles for both lateral sizes of ellipses. Saturated states are stable for a wider range of angles for larger values of the applied field.

Physicians' and Nurses' Perceived Usefulness and Acceptability of a Family Information Booklet about Comfort Care in Advanced Dementia

Background: Families of patients with advanced dementia need to be informed about the course of the dementia and comfort care. Conditional for health care providers educating families is their knowledge and comfort in family education. Methods: Perceived usefulness and acceptability of a Canadian family booklet explaining possible complications and comfort care in dementia was assessed by physicians and nurses caring for dementia patients in 14 nursing homes in Lombardy, Italy and 21 in the Netherlands. The practitioners received a questionnaire and translated versions adapted to local practice where needed. In 10 of 21 Dutch homes, physicians evaluated only the original Canadian version in English. A 15-item scale assessed the booklet's acceptability, for example, to inform families, or for educational purposes. Perceived usefulness referred to proportion of families of dementia patients for whom the booklet would be useful. A total of 168 evaluations were available for multivariable regression analyses. Results: The practitioners anticipated that the booklet would be useful for most families. Evaluation of the Dutch translation of the booklet was similar to the English version. Country (Netherlands) and profession (nurses) were independently associated with better acceptability. Usefulness was perceived as better by Italian respondents and nurses, but only in analyses unadjusted for the higher educational needs of these respondents. Conclusion: Overall, the concept of written information on comfort care was appreciated by practitioners of European countries differing in attitudes toward end-of-life care. A booklet may help practitioners, and in particular nurses, in providing comfort care for dementia patients and their families. © Copyright 2011, Mary Ann Liebert, Inc. 2011.

Multi-detection method for five common microalgal toxins based on the use of microspheres coupled to a flow-cytometry system

Freshwater and brackish microalgal toxins, such as microcystins, cylindrospermopsins, paralytic toxins, anatoxins or other neurotoxins are produced during the overgrowth of certain phytoplankton and benthic cyanobacteria, which includes either prokaryotic or eukaryotic microalgae. Although, further studies are necessary to define the biological role of these toxins, at least some of them are known to be poisonous to humans and wildlife due to their occurrence in these aquatic systems. The World Health Organization (WHO) has established as provisional recommended limit 1 μg of microcystin-LR per liter of drinking water. In this work we present a microsphere-based multi-detection method for five classes of freshwater and brackish toxins: microcystin-LR (MC-LR), cylindrospermopsin (CYN), anatoxin-a (ANA-a), saxitoxin (STX) and domoic acid (DA). Five inhibition assays were developed using different binding proteins and microsphere classes coupled to a flow-cytometry Luminex system. Then, assays were combined in one method for the simultaneous detection of the toxins. The IC₅₀'s using this method were 1.9 ± 0.1 μg L⁻¹ MC-LR, 1.3 ± 0.1 μg L⁻¹ CYN, 61 ± 4 μg L⁻¹ ANA-a, 5.4 ± 0.4 μg L⁻¹ STX and 4.9 ± 0.9 μg L⁻¹ DA. Lyophilized cyanobacterial culture samples were extracted using a simple procedure and analyzed by the Luminex method and by UPLC–IT-TOF-MS. Similar quantification was obtained by both methods for all toxins except for ANA-a, whereby the estimated content was lower when using UPLC–IT-TOF-MS. Therefore, this newly developed multiplexed detection method provides a rapid, simple, semi-quantitative screening tool for the simultaneous detection of five environmentally important freshwater and brackish toxins, in buffer and cyanobacterial extracts.

Hydrogel-Forming Microneedles Prepared from ‘‘Super Swelling’’ Polymers Combined with Lyophilised Wafers for Transdermal Drug Delivery

We describe, for the first time, hydrogel-forming microneedle arrays prepared from "super swelling" polymeric compositions. We produced a microneedle formulation with enhanced swelling capabilities from aqueous blends containing 20% w/w Gantrez S-97, 7.5% w/w PEG 10,000 and 3% w/w Na2CO3 and utilised a drug reservoir of a lyophilised wafer-like design. These microneedle-lyophilised wafer compositions were robust and effectively penetrated skin, swelling extensively, but being removed intact. In in vitro delivery experiments across excised neonatal porcine skin, approximately 44 mg of the model high dose small molecule drug ibuprofen sodium was delivered in 24 h, equating to 37% of the loading in the lyophilised reservoir. The super swelling microneedles delivered approximately 1.24 mg of the model protein ovalbumin over 24 h, equivalent to a delivery efficiency of approximately 49%. The integrated microneedle-lyophilised wafer delivery system produced a progressive increase in plasma concentrations of ibuprofen sodium in rats over 6 h, with a maximal concentration of approximately 179 µg/ml achieved in this time. The plasma concentration had fallen to 71±6.7 µg/ml by 24 h. Ovalbumin levels peaked in rat plasma after only 1 hour at 42.36±17.01 ng/ml. Ovalbumin plasma levels then remained almost constant up to 6 h, dropping somewhat at 24 h, when 23.61±4.84 ng/ml was detected. This work represents a significant advancement on conventional microneedle systems, which are presently only suitable for bolus delivery of very potent drugs and vaccines. Once fully developed, such technology may greatly expand the range of drugs that can be delivered transdermally, to the benefit of patients and industry. Accordingly, we are currently progressing towards clinical evaluations with a range of candidate molecules.

Tiotropium Respimat® in cystic fibrosis: Phase 3 and Pooled phase 2/3 randomized trials

Background: Tiotropium Respimat® improved lung function in a phase 2 trial in patients with cystic fibrosis (CF). We investigated its efficacy and safety in a phase 3 trial, including a pre-specified pooled analysis of the phase 2 and 3 trials. 

Methods: 12-week, randomized, double-blind, placebo-controlled trial of tiotropium Respimat® 5. μg once daily in patients with CF (N = 463). 

Results: Co-primary efficacy endpoints showed no statistical difference between tiotropium and placebo: percent-predicted forced expiratory volume in 1s (FEV₁) area under the curve from 0-4h (AUC_0-4h) (95% CI): 1.64% (0.27,3.55; p=0.092); percent-predicted trough FEV₁ (95% CI) 1.40% (0.50,3.30; p=0.15). Adverse events were similar between groups. Pooled phase 2/3 trial results showed a treatment difference in favor of tiotropium: percent-predicted FEV₁ AUC_0-4h (95% CI): 2.62% (1.34,3.90). 

Conclusion: Tiotropium was well tolerated in patients with CF; lung function improvements compared with placebo were not statistically significant in the phase 3 trial. Clinical trials: These studies are registered with clinical trial identifier numbers NCT00737100 and NCT01179347NCT00737100NCT01179347. These studies are also registered with the EudraCT number: 2008-001156-43 and 2010-019802-17.

Effect of radium-223 dichloride on symptomatic skeletal events in patients with castration-resistant prostate cancer and bone metastases: results from a phase 3, double-blind, randomised trial

BACKGROUND: Bone metastases frequently cause skeletal events in patients with metastatic castration-resistant prostate cancer. Radium-223 dichloride (radium-223) selectively targets bone metastases with high-energy, short-range α-particles. We assessed the effect of radium-223 compared with placebo in patients with castration-resistant prostate cancer and bone metastases.

METHODS: In this phase 3, double-blind, randomised ALSYMPCA trial, we enrolled patients who had symptomatic castration-resistant prostate cancer with two or more bone metastases and no known visceral metastases, who were receiving best standard of care, and had previously either received or were unsuitable for docetaxel. Patients were stratified by previous docetaxel use, baseline total alkaline phosphatase level, and current bisphosphonate use, then randomly assigned (2:1) to receive either six intravenous injections of radium-223 (50 kBq/kg) or matching placebo; one injection was given every 4 weeks. Randomisation was done with an interactive voice response system, taking into account trial stratification factors. Participants and investigators were masked to treatment assignment. The primary endpoint was overall survival, which has been reported previously. Here we report on time to first symptomatic skeletal event, defined as the use of external beam radiation to relieve bone pain, or occurrence of a new symptomatic pathological fracture (vertebral or non-verterbal), or occurence of spinal cord compression, or tumour-related orthopeadic surgical intervention. All events were required to be clinically apparent and were not assessed by periodic radiological review. Statistical analyses of symptomatic skeletal events were based on the intention-to-treat population. The study has been completed and is registered with ClinicalTrials.gov, number NCT00699751.

FINDINGS: Between June 12, 2008, and Feb 1, 2011, 921 patients were enrolled, of whom 614 (67%) were randomly assigned to receive radium-223 and 307 (33%) placebo. Symptomatic skeletal events occurred in 202 (33%) of 614 patients in the radium-223 group and 116 (38%) of 307 patients in the placebo group. Time to first symptomatic skeletal event was longer with radium-223 than with placebo (median 15·6 months [95% CI 13·5-18·0] vs 9·8 months [7·3-23·7]; hazard ratio [HR]=0·66, 95% CI 0·52-0·83; p=0·00037). The risks of external beam radiation therapy for bone pain (HR 0·67, 95% CI 0·53-0·85) and spinal cord compression (HR=0·52, 95% CI 0·29-0·93) were reduced with radium-233 compared with placebo. Radium-223 treatment did not seem to significantly reduce the risk of symptomatic pathological bone fracture (HR 0·62, 95% CI 0·35-1·09), or the need for tumour-related orthopaedic surgical intervention (HR 0·72, 95% CI 0·28-1·82).

INTERPRETATION: Radium-223 should be considered as a treatment option for patients with castration-resistant prostate cancer and symptomatic bone metastases.

FUNDING: Algeta and Bayer HealthCare Pharmaceuticals.

Key Generation from Wireless Channels: A Review

Key generation from the randomness of wireless channels is a promising alternative to public key cryptography for the establishment of cryptographic keys between any two users. This paper reviews the current techniques for wireless key generation. The principles, performance metrics and key generation procedure are comprehensively surveyed. Methods for optimizing the performance of key generation are also discussed. Key generation applications in various environments are then introduced along with the challenges of applying the approach in each scenario. The paper concludes with some suggestions for future studies.

Lake Kumphawapi revisited – The complex climatic and environmental record of a tropical wetland in NE Thailand

Kumphawapi, which is Thailand’s largest natural freshwater lake, contains a >10,000-year-long climatic and environmental archive. New data sets (stratigraphy, chronology, hydrogen isotopes, plant macrofossil and charcoal records) for two sedimentary sequences are here combined with earlier multi-proxy studies to provide a comprehensive reconstruction of past climatic and environmental changes for Northeast Thailand. Gradually higher moisture availability due to a strengthening of the summer monsoon led to the formation of a large shallow lake in the Kumphawapi basin between >10,700 and c. 7000 cal. BP. The marked increase in moisture availability and lower evaporation between c. 7000 and 6400 cal. BP favoured the growth and expansion of vegetation in and around the shallow lake. The increase in biomass led to gradual overgrowing and infilling, to an apparent lake level lowering and to the development of a wetland. Multiple hiatuses are apparent in all investigated sequences between c. 6500 and 1400 cal. BP and are explained by periodic desiccation events of the wetland and erosion due to the subsequent lake level rise. The rise in lake level, which started c. 2000 cal. BP and reached shallower parts c. 1400 cal. BP, is attributed to an increase in effective moisture availability. The timing of hydroclimatic conditions during the past 2000 years cannot be resolved because of chronological limitations.