Developing oral formulations for protein and peptide drugs

The vast majority of protein/peptide drugs are not available orally. Their oral delivery is hindered by intestinal instability and limited permeability. The aim of this project was to gain an understanding of the stability of a large protein, lactase, a small protein, insulin, and a newly discovered peptide throughout the intestinal tract. This was used for the rational design of their oral formulations. Lactase was completely denatured at gastric pH within 10 minutes but was stable with intestinal enzymes. Encapsulation in enteric Eudragit L100 microparticles using a method previously used to encapsulate low molecular weight drugs produced small particles with a high yield and encapsulation efficiency, >90%. They restricted lactase release in acid but did not protect it from denaturation. Porosity and particle morphology investigations using an SEM with a new type of detector revealed surface structures which disappeared upon dispersal in acid and an inner porous structure which may allow acid entry and lactase denaturation. Co-encapsulation of an antacid preserved almost 10% of lactase activity in acid, superior to existing oral lactase supplements. Insulin was not hydrolysed at gastric pH but was immediately and completely digested by gastrointestinal enzymes. To protect it from pepsin insulin was encapsulated in Eudragit L100 microparticles. The particles produced were 70%. After incubation with pepsin they protected 80% of encapsulated insulin. A small peptide, peptide 1 was gradually degraded in the intestinal fluids. To provide protection and increase its permeability peptide 1 was encapsulated in PLGA nanoparticles but 15% of the encapsulated peptide was immediately released in vitro. Encapsulation of the nanoparticles in Eudragit L100 microparticles successfully prevented any burst release in acid. This should minimise gastric digestion of peptide 1 and concentrate nanoparticle release in the small intestine providing a higher probability of permeation

Management of acute intracerebral haemorrhage – an update

Managing acute intracerebral haemorrhage is a challenging task for physicians. Evidence shows that outcome can be improved with admission to an acute stroke unit and active care, including urgent reversal of anticoagulant effects and, potentially, intensive blood pressure reduction. Nevertheless, many management issues remain controversial, including the use of haemostatic therapy, selection of patients for neurosurgery and neurocritical care, the extent of investigations for underlying causes and the benefit versus risk of restarting antithrombotic therapy after an episode of intracerebral haemorrhage

South African health care providers’ recognition of the links between alcohol and HIV in their daily practice: a pilot study.

This pilot study assessed the extent to which health care providers in HIV care and treatment, substance abuse intervention and employee assistance programmes (EAPs) consider and inform their clients about the role of alcohol use/abuse in HIV transmission, HIV disease progression and adherence to antiretroviral therapy (ART). A web- and telephone-based survey was conducted among 84 of the aforementioned programmes. Albeit not routinely, respondents from most organisations reported addressing the issues of alcohol in HIV transmission, disease progression and ART adherence among their clients. Contrary to expectations, many programmes do consider the links between alcohol and HIV and AIDS in their operations, but seem to lack adequate resources, information and skills to intervene in a comprehensive way. Key Words: Alcohol, HIV/AIDS, South Africa, health care providers, antiretroviral therapy, adherenc

Discrete structures in continuum descriptions of defective crystals

I discuss various mathematical constructions that combine together to provide a natural setting for discrete and continuum geometric models of defective crystals. In particular I provide a quite general list of `plastic strain variables', which quantifies inelastic behaviour, and exhibit rigorous connections between discrete and continuous mathematical structures associated with crystalline materials that have a correspond-ingly general constitutive specification

A simple mooring modification reduces impacts on seagrass meadows

AbstractMoorings can have a detrimental impact on seagrass, fragmenting the meadows, resulting in the habitat degradation. To reduce contact of the moorings with the seabed we attached small floats along the chain of a traditional swing mooring and monitored the ecological impacts of this modified mooring, with reference to a standard swing mooring, in a seagrass meadow under high tidal influence. After three years, seagrass density surrounding the modified mooring was over twice as high as that of the standard mooring, with blade length surrounding the modified mooring also found to exceed that of the standard mooring. Seagrass-associated epifaunal species richness was twice as high surrounding the modified mooring compared to the standard mooring. Sediment composition was considerably finer at the modified mooring, indicative of increased disturbance surrounding the standard mooring. A simple modification to existing swing moorings can mitigate some of the impacts of moorings on seagrass meadows, whilst accommodating for tidal fluctuations. The scale of the differences observed between the mooring types demonstrates the susceptibility of seagrass meadows to damage from swing moorings. Given the ecological importance of these habitats, it is crucial that action is taken to reduce further degradation, such as that demonstrated here.</jats:p

A population-based study of reduced sleep duration and hypertension : the strongest association may be in premenopausal women

Objectives: Recent evidence indicates that reduced sleep duration may be associated with an increased risk of hypertension with possibly stronger effects among women than men. We therefore examined cross-sectional sex-specific associations of sleep duration with hypertension in a large population-based sample from the Western New York Health Study (1996<2001). Methods: Participants were 3027 white men (43.5%) and women (56.5%) without prevalent cardiovascular disease (median age 56 years). Hypertension was defined as blood pressure at least 140 or at least 90&mmHg or regular use of antihypertensive medication. Multivariate logistic regression analyses were performed to estimate odds ratios (ORs) of hypertension comparing less than 6&h of sleep per night versus the reference category (&6&h) while accounting for a number of potential confounders. Results: In multivariate analyses, less than 6&h of sleep was associated with a significant increased risk of hypertension compared to sleeping at least 6&h per night, only among women [OR&=&1.66 (1.09 to 2.53)]. No significant association was found among men [OR&=&0.93 (0.62 to 1.41)]. In subgroup analyses by menopausal status, the effect was stronger among premenopausal women [OR&=&3.25 (1.37 to 7.76)] than among postmenopausal women [OR&=&1.49 (0.92 to 2.41)]. Conclusion: Reduced sleep duration, by increasing the risk of hypertension, may produce detrimental cardiovascular effects among women. The association is independent of socioeconomic status, traditional cardiovascular risk factors, and psychiatric comorbidities, and is stronger among premenopausal women. Prospective and mechanistic evidence is necessary to support causality

The biomechanics of amnion rupture: an X-ray diffraction study

Pre-term birth is the leading cause of perinatal and neonatal mortality, 40% of which are attributed to the pre-term premature rupture of amnion. Rupture of amnion is thought to be associated with a corresponding decrease in the extracellular collagen content and/or increase in collagenase activity. However, there is very little information concerning the detailed organisation of fibrillar collagen in amnion and how this might influence rupture. Here we identify a loss of lattice like arrangement in collagen organisation from areas near to the rupture site, and present a 9% increase in fibril spacing and a 50% decrease in fibrillar organisation using quantitative measurements gained by transmission electron microscopy and the novel application of synchrotron X-ray diffraction. These data provide an accurate insight into the biomechanical process of amnion rupture and highlight X-ray diffraction as a new and powerful tool in our understanding of this process

Q methodology and a Delphi poll: a useful approach to researching a narrative approach to therapy

Q methodology and a Delphi poll combined qualitative and quantitative methods to explore definitions of White and Epston's (1990) narrative approach to therapy among a group of UK practitioners. A Delphi poll was used to generate statements about narrative therapy. The piloting of statements by the Delphi panel identified agreement about theoretical ideas underpinning narrative therapy and certain key practices. A wider group of practitioners ranked the statements in a Q sort and made qualitative comments about their sorting. Quantitative methods (principal components analysis) were used to extract eight accounts of narrative therapy, five of which are qualitatively analysed in this paper. Agreement and differences were identified across a range of issues, including the social construction of narratives, privileging a political stance or narrative techniques and the relationship with other therapies, specifically systemic psychotherapy. Q methodology, combined with the Delphi poll, was a unique and innovative feature of this study