Jennifer Schneider

Advances in oral nano-delivery systems for colon targeted drug delivery in inflammatory bowel disease: selective targeting to diseased versus healthy tissue.

UNLABELLED Colon targeted drug delivery is an active area of research for local diseases affecting the colon, as it improves the efficacy of therapeutics and enables localized treatment, which reduces systemic toxicity. Targeted delivery of therapeutics to the colon is particularly advantageous for the treatment of inflammatory bowel disease (IBD), which includes ulcerative colitis and Crohns disease. Advances in oral drug delivery design have significantly improved the bioavailability of drugs to the colon; however in order for a drug to have therapeutic efficacy during disease, considerations must be made for the altered physiology of the gastrointestinal (GI) tract that is associated with GI inflammation. Nanotechnology has been used in oral dosage formulation design as strategies to further enhance uptake into diseased tissue within the colon. This review will describe some of the physiological challenges faced by orally administered delivery systems in IBD, the important developments in orally administered nano-delivery systems for colon targeting, and the future advances of this research. FROM THE CLINICAL EDITOR Inflammatory Bowel Disease (IBD) poses a significant problem for a large number of patients worldwide. Current medical therapy mostly aims at suppressing the active inflammatory episodes. In this review article, the authors described and discussed the various approaches current nano-delivery systems can offer in overcoming the limitations of conventional drug formulations.

Targeting peripheral opioid receptors to promote analgesic and anti-inflammatory actions.

Mechanisms of endogenous pain control are significant. Increasing studies have clearly produced evidence for the clinical usefulness of opioids in peripheral analgesia. The immune system uses mechanisms of cell migration not only to fight pathogens but also to control pain and inflammation within injured tissue. It has been demonstrated that peripheral inflammatory pain can be effectively controlled by an interaction of immune cell-derived opioid peptides with opioid receptors on peripheral sensory nerve terminals. Experimental and clinical studies have clearly shown that activation of peripheral opioid receptors with exogenous opioid agonists and endogenous opioid peptides are able to produce significant analgesic and anti-inflammatory effects, without central opioid mediated side effects (e.g., respiratory depression, sedation, tolerance, dependence). This article will focus on the role of opioids in peripheral inflammatory conditions and the clinical implications of targeting peripheral opioid receptors.

Survey of diabetes risk assessment tools: concepts, structure and performance

The objective of this study is to review the effectiveness and limitations of existing diabetes risk screening tools to assess the need for further developing of such tools. An electronic search of the EMBASE, MEDLINE, and Cochrane library supplemented by a manual search was performed from 1995–2010. The search retrieved a total of 2168 articles reporting diabetes risk assessment tools which, after culling, produced 41 tools developed in 22 countries, with the majority (n = 26) developed in North America and Europe. All are short questionnaires of 2–16 questions incorporating common variables including age, gender, waist circumference, BMI, family history of diabetes, history of hypertension or antihypertensive medications. While scoring format and cut‐offs point are diverse between questionnaires, overall accuracy value range of 40‐97%, 24‐86% and 62‐87% were reported for sensitivity, specificity and receiver operating characteristic curve respectively. In summary, there is a trend of increasing availability of diabetes prediction tools with the existing risk assessment tools being generally a short questionnaire aiming for ease of use in clinical practice. The overall performance of existing tools showed moderate to high accuracy in their predictive performance. However, further detailed comparison of existing questionnaires is needed to evaluate whether they can serve adequately as diabetes risk assessment tool in clinical practice. Copyright

An examination of the cardiovascular effects of an 'Irukandji' jellyfish, Alatina nr mordens.

Irukandji syndrome is usually characterized by delayed severe abdominal, back and chest pain associated with autonomic effects including diaphoresis, hypertension and, in severe cases, myocardial injury and pulmonary oedema. It is most often associated with envenoming by the jellyfish Carukia barnesi, but a number of other jellyfish, including Alatina mordens, are now known to produce Irukandji syndrome. In the present study, nematocyst-derived venom from A. nr mordens (150-250 microg/kg, i.v.) produced a long-lasting pressor effect in anaesthetised rats. This pressor response (250 microg/kg, i.v.) was significantly inhibited by prior administration of the alpha-adrenoceptor antagonist prazosin (200 microg/kg, i.v.) but not by CSL box jellyfish antivenom (300 U/kg, i.v.). A. nr mordens venom 250 microg/kg (i.v.) caused marked increases in plasma adrenaline and noradrenaline concentrations following administration in anaesthetised rats. The venom did not contain appreciable amounts of either adrenaline or noradrenaline. A. nr mordens venom (25 microg/ml) produced a contractile response in rat electrically stimulated vas deferens which was markedly reduced in tissues pre-treated with reserpine (0.1mM) or guanethidine (0.1mM). Sodium dodecyl sulphate (SDS)-PAGE analysis showed that A. nr mordens venom is comprised of multiple protein bands ranging from 10 to 200 kDa. Western blot analysis using CSL box jellyfish antivenom indicated several antigenic proteins in A. nr mordens venom, however, it did not detect all proteins present in the venom. This study characterizes the in vitro and in vivo effects of A. nr mordens venom and indicates that the cardiovascular effects are at least partially mediated by endogenous catecholamine release.

Signal transduction pathways and tyrosine hydroxylase regulation in the adrenal medulla following glucoprivation: An in vivo analysis

The regulation of tyrosine hydroxylase (TH, the rate limiting enzyme involved in catecholamine synthesis) is critical for the acute and sustained release of catecholamines from adrenal medullary chromaffin cells, however the mechanisms involved have only ever been investigated under in vitro/in situ conditions. Here we explored the effects on, TH phosphorylation and synthesis, and upstream signalling pathways, in the adrenal medulla evoked by the glucoprivic stimulus, 2-deoxy-d-glucose (2DG) administered intraperitoneally to conscious rats. Our results show that 2DG evoked expected increases in plasma adrenaline and glucose at 20 and 60min. We demonstrated that protein kinase A (PKA) and cyclin dependent kinases (CDK) were activated 20min following 2DG, whereas mitogen activated protein kinase (MAPK) was activated later and PKC was not significantly activated. We demonstrated that phosphorylation of Ser40TH peaked after 20min whereas phosphorylation of Ser31TH was still increasing at 60min. Serine 19 was not phosphorylated in this time frame. TH phosphorylation also occurred on newly synthesized protein 24h after 2DG. Thus 2DG increases secretion of adrenaline into the plasma and the consequent rise in glucose levels. In the adrenal medulla 2DG activates PKA, CDK and MAPK, and evokes phosphorylation of Ser40 and Ser31 in the short term and induces TH synthesis in the longer term all of which most likely contribute to increased capacity for the synthesis of adrenaline.

Expression of Tyrosine Hydroxylase Increases the Resistance of Human Neuroblastoma Cells to Oxidative Insults

In this study, we demonstrate that human neuroblastoma SH-SY5Y cells transfected with human tyrosine hydroxylase isoform 1 (SH + TH cells) were substantially more resistant to cell death induced by hydrogen peroxide and 6-hydroxydopamine when compared to wild-type SH-SY5Y cells (SH cells). SH + TH cells exhibit increased levels of dopamine (DA) compared to SH cells. Incubation with hydrogen peroxide or 6-hydroxydopamine (10-100microM) for 24 h caused a significant reduction in cell viability and increased apoptosis in both cell types. However, these effects were significantly reduced in the SH + TH cells when compared to the SH cells. The SH + TH cells showed an improved ability to detoxify peroxide, which correlated with an increase in glutathione peroxidase and glutathione reductase activities, while catalase activity was unchanged. Our data suggest that a preconditioning-like mechanism linked to higher DA levels increased the resistance of SH + TH cells against oxidative insults, which is at least in part related to an augmentation in the activity of glutathione-related antioxidant enzymes.

Stability of Midazolam and Fentanyl in Infusion Solutions

The administration of drugs by subcutaneous infusion is routinely practiced in palliative medicine for the management of patients who are no longer able to take oral medication. It is not uncommon for two or more drugs to be combined in subcutaneous infusion solutions. The combination of an opioid and a short-acting benzodiazepine is frequently required. Unfortunately, the stability of benzodiazepines and newer opioids, such as fentanyl, has not been determined. This study examined the stability of solutions containing either fentanyl alone or fentanyl and midazolam in combination. Eight different solutions were assessed for up to 7 days following preparation. The solutions were prepared in polypropylene syringes using 0.9% saline as a diluent. Duplicate syringes were stored at approximately 5 degrees C, 22 degrees C, and 38 degrees C. High performance liquid chromatography was the analytical technique used to measure fentanyl and midazolam. Initial concentrations ranges were 13.2-38.9 micrograms/mL for fentanyl and 282-959 micrograms/mL for midazolam. It was found that fentanyl (+/- midazolam) was very stable (> 95%) when stored at temperatures ranging from 5 degrees C to 38 degrees C for at least 1 week. Midazolam (+ fentanyl) was not as stable as fentanyl under the same storage conditions and underwent time-dependent decomposition of up to 12.1% (observed at 7 days when stored at 38 degrees C). When stored at 22 degrees C and 38 degrees C, more than 90% of initial midazolam concentrations were retained for 4 days following preparation and for 7 days when stored at 5 degrees C. The clinical implications of these results are that, on the basis of physicochemical stability, subcutaneous infusion solutions containing fentanyl and midazolam may be prepared at intervals of 4 days (or 7 days if stored under refrigerated conditions).

Bedside Perspectives On The Use Of Opioids: Transferring Results Of Clinical Research Into Practice

1. Transference of research findings to clinical practice has been a challenge for those managing chronic pain. Generally, pain is not well controlled in hospitals and steps need to be taken to make pain control more effective.

Pharmacokinetics in neonatal prescribing: evidence base, paradigms and the future

Paediatric patients, particularly preterm neonates, present many pharmacological challenges. Due to the difficulty in conducting clinical trials in these populations dosing information is often extrapolated from adult populations. As the processes of absorption, distribution, metabolism and excretion of drugs change throughout growth and development extrapolation presents risk of over or underestimating the doses required. Information about the development these processes, particularly drug metabolism pathways, is still limited with weight based dose adjustment presenting the best method of estimating pharmacokinetic changes due to growth and development. New innovations in pharmacokinetic research, such as population pharmacokinetic modelling, present unique opportunities to conduct clinical trials in these populations improving the safety and effectiveness of the drugs used. More research is required into this area to ensure the best outcomes for our most vulnerable patients.

Determination of morphine in plasma by high-performance liquid chromatography with fluorescence detection

In order to study the pharmacokinetics of morphine in cancer patients, we developed a simple method for determination of morphine by HPLC with fluorescence detection. This method requires only 0,5 ml of plasma and has a detection limit of 2.5 ng/ml