Cracking the junction: update on the progress of gastrointestinal absorption enhancement in the delivery of poorly absorbed drugs

There are many challenges to the oral delivery of peptide-based drugs. In addition to overcoming issues relating to the metabolic stability of peptides and maximizing adherence and penetration through the mucus layer, new formulations to enhance absorption across the intestinal epithelium are required for effective delivery. The tight junctions between epithelial cells usually permit the flux of small hydrophilic drugs, while restricting the movement of larger hydrophilic drugs. Efforts to reversibly open tight junctions with paracellular permeability enhancers (PPE) have been shown to promote the absorption of larger molecules, including protein therapeutics. This review describes the proteins that comprise the tight junction and outlines various methods that have been explored to enhance class III solute absorption across this barrier, with particular attention to efforts to enhance oral peptide delivery. In particular, peptide-based PPEs are highlighted. Being proteins themselves, they potentially share physicochemical properties, diffusional characteristics, and stability issues with the therapeutic proteins being delivered. By understanding the mechanisms by which these PPEs act, analogues and peptidomimetics can be designed in order to safely enhance the delivery of biotech cargoes via the oral route.     

Prevalence of risk factors for cardiovascular disease in Canadians 55 to 74 years of age: results from the Canadian Heart Health Surveys, 1986-1992

BACKGROUND: By 2016, the proportion of Canadians older than 65 years of age will increase to 16%, and there will be an increase in the absolute number of cases of cardiovascular disease in older Canadians. The Canadian Heart Health Surveys database provides information about this population upon which health policy related to cardiovascular disease can be based. This paper presents for the first time population-based data on the risk factors for cardiovascular disease in older Canadians. METHODS: Canadians from all 10 provinces participated in surveys of cardiovascular risk factors; health insurance registries were used as sampling frames. In each province, probability samples of 2200 adults 18 to 74 years old not living in institutions, on reserves or in military camps were asked to participate in interviews and to undergo testing at clinics for major risk factors for cardiovascular disease. RESULTS: A total of 2739 men (response rate 70%) and 2617 women (response rate 66%) aged 55 to 74 years participated in the survey and also provided follow-up clinical measurements at the clinic. Overall, 52% of participants were hypertensive, 26% had isolated systolic hypertension, and 30% had a total blood cholesterol level of 6.2 mmol/L or greater. Rates of current smoking were lower in women than men (17% v. 22%). Overall, 87% of men and 78% of women who were current smokers smoked at least 10 cigarettes per day. Only slightly more than half of participants exercised at least once a week for at least 15 minutes, and almost half had a body mass index of 27 or greater. In only 4% was no major risk factor for cardiovascular disease detected. INTERPRETATION: Significant numbers of older Canadians have one or more major risk factors for cardiovascular disease. Many of these risk factors are amenable to modification.     

Creativity, identity and healing: participants' accounts of music therapy in cancer care

This article reports on findings from a study of the accounts of people participating in music therapy as part of a programme of complementary and alternative medicine (CAM) in supportive cancer care. The article outlines the perceived effects of music therapy, which shares many characteristics with CAM therapies as well as offering a distinct contribution as a creative therapy. Hence in this article we draw on theories and writings from the sociology of CAM as well as those relating to music, healing and aesthetics in order to explore participants' accounts. The importance of identity and the role of creativity in processes of individuation are key themes emerging from the analysis. While music and creativity are often seen uncritically as resources for health and well-being, we draw attention to the challenges and complexity of diverse responses to music, framed by personal biographies that are in turn often situated within socially constructed notions of aesthetics. We argue that in research on music therapy, as well as other CAM therapies, issues of identity can be key to an understanding of questions of therapeutic impact.     

Physical and chemical characterization of asphalt (bitumen) paving exposures

The purpose of this research was to characterize the physical and chemical properties of asphalt (bitumen) fume and vapor in hot mix asphalt roadway paving operations. Area and personal air samples were taken using real-time equipment and extractive sampling and analytical methods to determine worker asphalt exposure, as well as to characterize the properties of the particulate and vapor phase components. Analysis of personal inhalation and dermal samples by gas chromatography/mass spectroscopy showed that the polycyclic aromatic hydrocarbon profile is dominated by compounds with molecular weights below 228, and that substituted and heterocyclic polycyclic aromatic hydrocarbons comprised approximately 71% of the detectable mass concentration (vapor and particulate combined). Principal components analysis shows that the polycyclic aromatic hydrocarbons with molecular weights greater than 190 are the driving force behind the polycyclic aromatic compound exposures measured for the dermal and particulate phases; there was no clear trend for the vapor phase Most of the aerosol particles are fine (mass median aerodynamic diameter 1.02 microm; count median diameter 0.24 microm).     

Modelling patient duration of stay to facilitate resource management of geriatric hospitals

A fundamental aspect of health care management is the effective allocation of resources. This is of particular importance in geriatric hospitals where elderly patients tend to have more complex needs. Hospital managers would benefit immensely if they had advance knowledge of patient duration of stay in hospital. Managers could assess the costs of patient care and make allowances for these in their budget. In this paper, we tackle this important problem via a model which predicts the duration of stay distribution of patients in hospital. The approach uses phase-type distributions conditioned on a Bayesian belief network.     

Estimating the costs for a group of geriatric patients using the Coxian phase-type distribution

The length of stay in hospital of geriatric patients may be modelled using the Coxian phase-type distribution. This paper examines previous methods which have been used to model health-care costs and presents a new methodology to estimate the costs for a cohort of patients for their duration of stay in hospital, assuming there are no further admissions. The model, applied to 1392 patients admitted into the geriatric ward of a local hospital in Northern Ireland, between 2002 and 2003, should be beneficial to hospital managers, as future decisions and policy changes could be tested on the model to investigate their influence on costs before the decisions were carried out on a real ward.     

Dietary behaviour and health in Northern Ireland: an exploration of biochemical and haematological associations.

STUDY OBJECTIVE--The aim was to determine the relationships between dietary behaviour and biochemical and haematological measures. DESIGN--This was a cross sectional population study. SETTING--The study took place in the general community within Northern Ireland. SUBJECTS--522 randomly selected adults aged 18-64 years took part (65% of the eligible sample). MEASUREMENTS AND MAIN RESULTS--Four dietary behaviours were identified using principal components analysis from 7 d weighed dietary records described in terms of mean intake of 41 food groups. Haematological and biochemical analyses were carried out on non-fasting blood samples. Social, personal, and lifestyle information was ascertained through interviewer administered questionnaires. Partial correlations controlled for age and smoking behaviour were calculated. There were significant negative associations between iron status measures and the "traditional" behaviour, while the "meat and two veg" behaviour showed positive associations. There were positive associations between the "cosmopolitan" and "convenience" behaviours and folate status in women. White cell count and platelet levels in women were negatively associated with the "traditional" and "cosmopolitan" behaviours. Total cholesterol levels showed significant negative associations with the "cosmopolitan" behaviour in women and HDL cholesterol levels were positively associated with the "cosmopolitan", "convenience" and "meat and two veg" behaviours. CONCLUSIONS--Through a multivariate approach to dietary assessment it is possible to identify food combinations that cluster and interact to influence biochemical and haematological indices of health status.     

Kr-81m ventilation imaging: clinical utility in suspected pulmonary embolism

The results of Kr-81m/Tc-99m ventilation-perfusion (VP) lung scintigraphy were correlated with the results of pulmonary angiography for 74 patients suspected of having pulmonary embolism (PE). Among patients having a diagnostic scan, the sensitivity and specificity of scintigraphy were 91% and 94%, respectively. Also, 157 consecutive cases of Kr-81m/Tc-99m VP lung scintigraphy were reviewed, and the frequency of an indeterminate scan was found to be 22%. A similar frequency was found for VP scintigraphy with xenon-133. Of eight patients who had indeterminate scans due to the presence of a single VP mismatch, four were demonstrated to have PE by angiography. Kr-81m is an excellent agent for VP scanning in cases of suspected PE, offering accuracy in diagnosis as well as favorable physical properties.     

Pharmacokinetics and electrocardiographic pharmacodynamics of artemether-lumefantrine (Riamet) with concomitant administration of ketoconazole in healthy subjects

AIMS: To evaluate whether the potent CYP3A4 inhibitor ketoconazole has any influence on the pharmacokinetic and electrocardiographic parameters of the antimalarial co-artemether (artemether-lumefantrine) in healthy subjects. METHODS: Sixteen subjects were randomized in an open-label, two period crossover design study. Subjects received a single dose of co-artemether (day 1) either alone or in combination with multiple oral doses of ketoconazole (400 mg on day 1 followed by 200 mg o.d. for 4 additional days). Serial blood samples were taken and assayed for artemether and its main active metabolite dihydroartemisinin (DHA), and lumefantrine. RESULTS: The pharmacokinetics of artemether, its metabolite DHA, and lumefantrine were influenced by the presence of ketoconazole. AUC(0, infinity ) was increased from 320 to 740 ng ml-1 h (ratio 2.4, 90% CI 2.00, 2.86) for artemether, from 331 to 501 ng ml-1 h (ratio 1.7, 90% CI 1.40, 1.98) for DHA, and from 207 to 333 micro g ml-1 h (ratio 1.7, 90% CI 1.23, 2.21) for lumefantrine in the presence of ketoconazole. Cmax also increased in similar proportions for the three compounds (ratio 2.2 (90% CI 1.78, 2.83), 1.4 (90% CI 1.12, 1.74), and 1.3 (90% CI 0.96, 1.64), respectively). The terminal elimination half-life was increased for artemether (2.5 vs 1.9 h, 90% CI 1.12, 1.72) and DHA (3.1 vs 2.1 h, 90% CI 0.02, 3.36), but remained unchanged for lumefantrine (88 vs 95 h, 90% CI 0.81, 1.04). These increases in exposure to the antimalarial combination were much smaller than observed with food intake (up to 16 fold), and were not associated with increased side-effects or changes in electrocardiographic parameters. The study medications were well tolerated. CONCLUSIONS: The concurrent administration of ketoconazole with co-artemether led to modest increases in artemether, DHA, and lumefantrine exposure in healthy subjects. Dose adjustment of co-artemether is probably unnecessary in falciparum malaria patients when administered in association with ketoconazole or other potent CYP3A4 inhibitors.