Effect of intragranular porosity on compression behaviour of and drug release from reservoir pellets

In this study, reservoir pellets were prepared and their compression behaviour as well as the importance of their porosity for compression-induced changes in drug release was investigated. Pellets of three different porosities, consisting of microcrystalline cellulose and salicylic acid, were prepared by extrusion–spheronisation and spray-coated with ethyl cellulose (ethanol solution). Lubricated reservoir pellets were compressed and retrieved by deaggregation of the tablets. The retrieved pellets were analysed regarding porosity, thickness, surface area, shape and drug release. It was found that the coating did not significantly affect their compression behaviour. Compaction of pellets of high original porosity considerably affected densification and degree of deformation, whereas the effect on drug release was minor. For low porosity pellets the influence of compaction on drug release was appreciable, but only slight regarding densification and degree of deformation. In conclusion, the porosity of pellets is a potential factor that the formulator can use to optimize drug release and one that can affect the robustness of a formulation during manufacture. Moreover, the coating may be able to adapt to the densification and deformation of the pellets.     

Peptide-targeted PEG-liposomes in anti-angiogenic therapy

Peptides with the RGD amino acid sequence show affinity for the alpha(v)beta(3) integrin, an integrin which is over-expressed on angiogenic endothelium and involved in cell adhesion. A peptide with the sequence ATWLPPR has been demonstrated to show affinity for the vascular endothelial growth factor (VEGF) receptor, a receptor involved in the proliferation of endothelial cells. By coupling these peptides to liposomes, these liposomes can serve as a site-specific drug delivery system to tumor endothelial cells in order to inhibit angiogenesis. In the present study we demonstrate that the coupling of cyclic RGD-peptides or ATWLPPR-peptides to the surface of PEG-liposomes results in binding of these liposomes to endothelial cells in vitro. Subsequent studies with RGD-peptide targeted liposomes in vivo also demonstrate specific binding to the tumor endothelium.     

Metabolism of salbutamol differs between asthmatic patients and healthy volunteers

Patients with asthma are a target group for medication with beta2-agonists, often in combination with corticosteroids. Salbutamol is commonly marketed as racemate. R-Salbutamol carries beta2-agonistic property whereas S-salbutamol does not. The racemate undergoes stereoselective sulphatisation by sulfotransferases mainly in the gut and liver, so that S-salbutamol rests for a longer time in the body and reaches higher plasma levels than R-salbutamol. Ten patients with mild stable asthma and at present without cortisone medication were given racemic salbutamol as ventoline 4 mg orally. Plasma and urine levels were estimated until 24 hr after ingestion. For comparison healthy volunteers were treated in the same way. The group of asthma patients was then treated with budesonide inhalations 800 microg daily for one week and the initial programme resumed. Non-cortisone-treated asthmatic patients displayed higher levels of both R- and S-salbutamol in plasma than did healthy volunteers after one single ingestion of racemic salbutamol (CMAX both comparisons P<0.05). Plasma levels of salbutamol isomers in cortisone-treated asthmatic patients resembled the levels in volunteers. The most plausible explanation for the discrepancy in values between asthmatic patients and volunteers is a defective metabolic function by asthmatic patients possibly enzymatic in origin.     

Socio-economic differences in health risk behaviour and attitudes towards health risk behaviour among Slovak adolescents

Objectives  

Socio-economic differences in the frequency of smoking, alcohol consumption, drug use, physical exercise, and attitudes toward smoking were explored in an sample of Slovak adolescents (1 370 boys, 1 246 girls, mean age 15 years).     

Hostility and the educational gradient in health. The mediating role of health-related behaviours

BACKGROUND: The aim was to study hostility as a factor intermediate in the association between educational level and health. METHODS: 1997 cross-sectional data from the Dutch GLOBE study (1675 men and 1819 women) was used. The analyses distinguishes between direct effects of hostility on health, and indirect effects, which are through health-related behaviours. The latter indicates that hostile people may be at risk of adverse health, because they engage in unhealthy behaviours. Data were analysed with logistic regression techniques. RESULTS: Among men and women, the odds of less than good health was higher in lower educational groups. A substantial part of the educational gradient in health could be ascribed to the intermediate effects of hostility. Among both men and women, the direct effects of hostility were more important than indirect effects. CONCLUSION: Results suggest that interventions should be aimed at the prevention of the development of hostility. Additionally, interventions aimed at the reduction of health damaging behaviours among adults may lead to a reduction of socio-economic inequalities in health.     

Pre- and postprandial changes in plasma hormone and metabolite levels and hepatic deiodinase activities in meal-fed broiler chickens

The present study aimed to study the effects of food deprivation and subsequent postprandial changes in plasma somatotrophic and thyrotrophic hormone levels and focused on the inter-relationships between these hormonal axes and representative metabolites of the intermediary metabolism of meal-fed broiler chickens. Male broiler chickens (2 weeks old) were fed a meal of 40-45 g/bird per d for two consecutive weeks (food-restricted (FR) treatment). The daily allowance was consumed in about 30 min. At 4 weeks of age, FR chickens were killed at several time intervals (ten per sampling time) in relation to the daily food allowance: before feeding (about 23.5 h of food deprivation), and at 10, 20, 30 (end of feeding), 40, 50, 60, 90, 120 and 200 min after initiation of feeding. Birds fed ad libitum served as controls (ad-libitum (AL) treatment). Liver tissue was collected for deiodinase type I and type III activity measurements and blood samples for analysis of growth hormone (GH), insulin-like growth factor (IGF)-I, thyroxine (T4), 3,3',5-triiodothyronine (T3), glucose, non-esterified fatty acids (NEFA), uric acid, triacylglycerol (TG) and lactate levels. Food deprivation caused a shift from lipogenesis to lipolysis and increased fatty acid turnover, a reduction in protein anabolism and reduced metabolic rate. Food intake was followed immediately by a pronounced increase in metabolic rate, initially mainly based on anaerobic mechanisms. Refeeding gradually reversed the fasting-induced alterations in plasma hormone and metabolite levels, but the time course of changes differed between metabolites, which clearly preceded those of the hormones investigated. The order of responsiveness after food provision were glucose>uric acid>or=NEFA>lactate>TG for the plasma metabolites and for hormones. Based on these different postprandial time courses, several functional relationships are proposed. Glucose is believed to be the primary trigger for the normalisation of the effects of fasting on these plasma variables by restoring hepatic GH receptor capacity, as well as decreasing deiodinase type III activity.     

Pain catastrophizing and kinesiophobia: predictors of chronic low back pain

By using a population-based cohort of the general Dutch population, the authors studied whether an excessively negative orientation toward pain (pain catastrophizing) and fear of movement/(re)injury (kinesiophobia) are important in the etiology of chronic low back pain and associated disability, as clinical studies have suggested. A total of 1,845 of the 2,338 inhabitants (without severe disease) aged 25-64 years who participated in a 1998 population-based questionnaire survey on musculoskeletal pain were sent a second questionnaire after 6 months; 1,571 (85 percent) participated. For subjects with low back pain at baseline, a high level of pain catastrophizing predicted low back pain at follow-up (odds ratio (OR) = 1.7, 95% confidence interval (CI): 1.0, 2.8) and chronic low back pain (OR = 1.7, 95% CI: 1.0, 2.3), in particular severe low back pain (OR = 3.0, 95% CI: 1.7, 5.2) and low back pain with disability (OR = 3.0, 95% CI: 1.7, 5.4). A high level of kinesiophobia showed similar associations. The significant associations remained after adjustment for pain duration, pain severity, or disability at baseline. For those without low back pain at baseline, a high level of pain catastrophizing or kinesiophobia predicted low back pain with disability during follow-up. These cognitive and emotional factors should be considered when prevention programs are developed for chronic low back pain and related disability.     

Selective inhibition of COX-2 by a standardized CO2 extract of Humulus lupulus in vitro and its activity in a mouse model of zymosan-induced arthritis

A standardized CO(2) extract from Humulus lupulus L. (hop extract) was investigated for its selective COX-1/2 inhibitory properties. An in vitro model of inflammation using lipopolysaccharide (LPS)-stimulated human peripheral blood mononuclear cells (PBMC) was used as a model to investigate the effect of hop extract on PGE(2) production. COX-1/2 selective inhibition by the hop extract was investigated in a COX-1 whole blood assay (WBA) and a COX-2 WBA. To evaluate the in vivo activity of hop extract, it was administered orally to C57BL/6 mice in which inflammation of the right joint was induced by injecting zymosan intra-articularly. Ex vivo PGE(2) production of LPS-stimulated blood cells was determined. Also, the effect of hop extract on healthy and arthritic cartilage was investigated as well as effects on inflammatory joint swelling. Hop extract inhibited PGE(2) production by LPS-stimulated PBMC without compromising the metabolic activity of these cells. Furthermore, hop extract showed a decline in PGE(2) production in the COX-2 whole blood assay (WBA) with an IC(50) of 20.4 microg/mL, while in the COX-1 WBA no inhibition of PGE(2) production was observed. This indicates a COX-2 selective inhibition. The COX-1 inhibitor SC-560 inhibited PGE(2) production in the COX-1 WBA but not in the COX-2 WBA. At 2 microM, celecoxib inhibited PGE(2) production in the COX-2 WBA by 92 % and in the COX-1 WBA by 50 %. When hop extract was administered orally to C57BL/6 mice in which joint inflammation was induced with zymosan, PGE(2) production in ex vivo LPS-stimulated whole blood was significantly decreased by 24 %, suggesting that hop extract becomes bioavailable. Furthermore, oral administration of hop extract showed no negative or positive effects on healthy cartilage proteoglycan synthesis, or on zymosan-induced arthritic cartilage proteoglycan synthesis. However, no effect of oral administration of 1.25 mg hop extract daily was observed on joint swelling. In conclusion, this standardized CO(2) extract of Humulus lupulus could be a useful agent for intervention strategies targeting inflammatory disorders and/or inflammatory pain.     

Production of prostaglandin e(2) by iridial melanocytes exposed to latanoprost acid, a prostaglandin F(2 alpha) analogue.

Several prostaglandin analogues used for glaucoma treatment cause increased pigmentation of the iris. The purpose of the present study was investigate whether latanoprost, a PGF(2 alpha) analogue, has any effect on the production of endogenous prostaglandins in iridial melanocytes, which could be important in the mechanism leading to increased pigmentation. Bovine and human iridial melanocytes in culture were used for the experiments. Production of endogenous prostaglandins was measured by enzyme immunoassay, and the melanin content was measured spectrophotometrically. In bovine iridial melanocytes, latanoprost acid caused a significant increase of the PGE(2) production, which could be blocked by indomethacin and NS398, indicating an involvement of cyclo-oxygenase 2. In order to study the selectivity of the phenomenon other endogenous substances/drugs were tested, e.g., acetylcholine, carbachol, noradrenaline, neuropeptide Y, substance P and alpha-MSH, but none was found to have any significant effect. Human iridial melanocytes also responded to latanoprost acid with increased production of PGE(2) and in 1 out of 5 individuals increased melanogenesis coincided with increased PGE(2) production. In bovine iridial melanocytes, latanoprost acid did not stimulate melanogenesis. These results indicate that latanoprost acid cause enhanced formation of endogenous prostaglandins that may have auto- and/or paracrine effects in the melanocytes, possibly associated with melanogenesis.     

The Methodological Quality of Economic Evaluations of Guideline Implementation into Clinical Practice: A Systematic Review of Empiric Studies

OBJECTIVES: Despite the emphasis on efficiency of health-care services delivery, there is an imperfect evidence base to inform decisions about whether and how to develop and implement guidelines into clinical practice. In general, studies evaluating the economics of guideline implementation lack methodological rigor. We conducted a systematic review of empiric studies to assess advances in the economic evaluations of guideline implementation. METHODS: The Cochrane Effective Professional and Organisational Change Group specialized register and the MEDLINE database were searched for English publications between January 1998 and July 2004 that reported objective effect measures and implementation costs. We extracted data on study characteristics, quality of study design, and economic methodology. It was assessed whether the economic evaluations followed methodological guidance. RESULTS: We included 24 economic evaluations, involving 21 controlled trials and three interrupted time series designs. The studies involved varying settings, targeted professionals, targeted behaviors, clinical guidelines, and implementation strategies. Overall, it was difficult to determine the quality of study designs owing to poor reporting. In addition, most economic evaluations were methodologically flawed: studies did not follow guidelines for evaluation design, data collection, and data analysis. CONCLUSIONS: The increasing importance of the value for money of providing health care seems to be reflected by an increase in empiric economic evaluations of guideline implementation. Because of the heterogeneity and poor methodological quality of these studies, however, the resulting evidence is still of limited use in decision-making. There seems to be a need for more methodological guidance, especially in terms of data collection and data synthesis, to appropriately evaluate the economics of developing and implementing guidelines into clinical practice.