The feasibility of a school-based VI polysaccharide vaccine mass immunization campaign in Hue City, central Vietnam: streamlining a typhoid fever preventive strategy

We report the coverage, safety, and logistics of a school-based typhoid fever immunization campaign that took place in Hue City, central Vietnam; a typhoid fever endemic area. A cluster-randomized evaluation-blinded controlled trial was designed where 68 schools (cluster) were randomly allocated the single dose Vi polysaccharide vaccine (Typherix) or the active control hepatitis A vaccine (Havrix). A safety surveillance system was implemented. A total of 32,267 children were immunized with a coverage of 57.5%. Strong predictors for vaccination were attending primary schools, peri-urban location of the school, and low family income. Human resources were mainly schoolteachers and the campaign was completed in about 1 month. Most adverse events reported were mild. Safe injection and safe sharp-waste disposal practices were followed. A typhoid fever school-based immunization campaign was safe and logistically possible. Coverage was moderate and can be interpreted as the minimum that could have been achievable because individual written informed consent procedures were sought for the first time in Hue City and the trial nature of the campaign. The lessons learned, together with cost-effectiveness results to be obtained by the end of follow-up period, will hopefully accelerate the introduction of Vi typhoid fever vaccine in Vietnam.     

In-vitro and in-vivo evaluation of enteric-coated starch-based pellets prepared via extrusion/spheronisation

Pellet cores containing modified starch (high-amylose, crystalline and resistant starch) as the main excipient were enteric-coated with an Eudragit L30 D-55 based dispersion. The polymer weight gain was from 15% to 30% (w/w). Pellet cores were prepared using piroxicam (2.5% w/w, poor water solubility) and anhydrous theophylline (2.5% and 25% w/w, coarse and micronised powder, medium water solubility) as model drugs. Next to the water solubility, particle size and concentration of the model drugs, the influence of sorbitol (0% and 10%, w/w) and drying method (oven and fluid-bed) on pellet yield, size (Feret mean diameter), sphericity (aspect ratio, AR and two-dimensional shape factor, e(R)), friability, surface morphology and drug release were evaluated. Binder (HPMC) and granulation liquid (water) concentration were optimised to obtain maximum yield (size fraction between 900 and 1400 microm) and acceptable sphericity (AR<1.2). Pellet friability was <0.01% for all formulations, while the mean pellet diameter was lower for pellets with sorbitol and the ones dried in an oven. Mercury intrusion porosimetry combined with scanning electron microscopy revealed an influence of drying method and sorbitol level on the surface structure: the surface of fluid-bed dried pellets without sorbitol and with 2.5% of model drug was cracked, which correlated with a Hg-intrusion peak at the 6-80 microm pore size range. Due to improved mechanical properties of the wet mass, sorbitol addition smoothened the pellets as the main peak of Hg-intrusion shifted to a smaller pore size range. Using a higher drug concentration and micronised theophylline shifted the main peak of Hg-intrusion further towards the smaller pore size range. Oven-dried pellets showed no Hg-intrusion and no cracks were observed. When applying the highest coating thickness (30% weight gain), all theophylline pellet formulations were successfully coated (<10% drug release after 2h in acid dissolution medium), while pellets with the lowest coating thickness (15% weight gain) released from 5% to about 30% theophylline. The extent of drug release depended on the pellet composition and drying method as these factors determined the surface properties. Piroxicam release in acid medium was less than 1% irrespective of the surface characteristics, due to its poor water solubility. In basic medium (phosphate buffer, pH 6.8) all pellets released the drug in less than 45 min. The bioavailability of coated and uncoated piroxicam pellets was determined after oral administration to six dogs. Values of AUC(0-->72h), C(max) and t(max) after oral administration of piroxicam pellets to dogs were not significantly different from the values obtained for immediate release capsules (P>0.05).     

Bioavailability of starch based hot stage extrusion formulations.

The aim of the study was to develop a starch based hot stage extrusion formulation for controlled drug delivery and to evaluate its in vivo behavior. The extrusion mixture consisted of 53% corn starch as the matrix forming agent, 15% sorbitol as a plasticizer, 30% theophylline monohydrate as the model drug and 2% glyceryl monostearate as a lubricant. The extrudates were produced by means of a corotating twin screw extruder of APV Baker equipped with a twin screw powder feeder and a 3-mm cylindrical die. During extrusion 20% water (based on the wet mass) was added to the powder mixture. The extrudates were dried in an oven at 60 degrees C during 48 h, cut and filled out in hard gelatine capsules, in a way that the content of two capsules corresponded with a dose of 300 mg anhydrous theophylline. The dissolution profile of the experimental dosage form was retarded with a drug release of around 80% in 8 h. The in vivo behavior of the experimental formulation was evaluated in a randomized crossover design study (n=8) with a commercially available multiple unit sustained release product as the reference formulation. The plasma samples were analyzed by a validated HPLC-UV method with solid phase extraction for the sample preparation. It was clear that the experimental formulation exhibited sustained release behavior, but that it performed less well than the multiple unit dosage form.     

Polymeric multilayer capsules delivering biotherapeutics

Polymeric multilayer capsules have emerged as a novel drug delivery platform. These capsules are fabricated through layer-by-layer sequential deposition of polymers onto a sacrificial core template followed by the decomposition of this core yielding hollow capsules. The resulting nanometer thin membrane is permselective, allowing diffusion of water and ions but excluding larger molecules. Moreover, the sequential fabrication procedure allows a precise fine-tuning of the capsules’ physicochemical and biological properties. These properties have put polymeric multilayer capsules under major attention in the field of drug delivery. In this review we focus on polymeric multilayer capsule mediated delivery of biotechnological macromolecular drugs such as peptides, proteins and nucleic acids.     

Sustained-release and swelling characteristics of xanthan gum/ethylcellulose-based injection moulded matrix tablets: in vitro and in vivo evaluation

Sustained-release matrix tablets were developed by injection moulding using metoprolol tartrate (MPT) and ethylcellulose (EC) as sustained-release agent. Dibutyl sebacate was selected as plasticiser. The influence of matrix composition, plasticiser concentration, and drug load on drug release was evaluated. The influence of plasticiser addition was assessed on processability and drug release: Dibutyl sebacate was added to a dichloromethane/EC solution and subsequently spray-dried, or was mixed as a liquid with EC powder. Hydrated tablets were evaluated by frequency sweep and creep rheological tests to correlate the results with drug release. Xanthan gum (XG) was added to the formulation because drug release was too slow (< 50%, 24 h) from EC/MPT matrices (70%/30%, w/w). Increasing XG concentrations provided faster MPT release rates characterised by zero-order release kinetics, no burst release was observed. Lower plasticiser concentrations and higher drug loads increased drug release substantially. The plasticiser addition method did not affect drug release. Matrix composition, drug load, and plasticiser level affected the rheological properties of the swollen matrix tablets. X-ray diffraction demonstrated the formation of solid dispersions. Formulations composed of XG/EC (ratio 1:1.5) and 30% (w/w) MPT had a low relative bioavailability compared with the commercial product Lopressor®, which significantly improved at higher MPT concentration (50%, w/w).     

Brain metastases from renal cell carcinoma. Should we change the current standard?

Renal cell carcinoma (RCC) is one of the most common sources of brain metastases, with an incidence that varies widely from 4% to 48% according to different studies. In addition, asymptomatic metastases occur in up to 33% of patients with metastatic RCC, further complicating the decision-making process in this poor prognosis population. The purpose of this review is to cover in depth the present state of knowledge on the diagnosis and management of patients with brain metastases from RCC, in order to assess whether the current standard should be challenged. The existing systems to predict response and survival will be reviewed, as well as the available therapeutic options regarding local treatment and systemic therapy, all within the context of updated data from clinical trials. In this regard, the role of novel targeted agents for the treatment of brain metastases from RCC, such as the multi-targeted receptor tyrosine kinase inhibitors sunitinib and sorafenib, will be updated and discussed.     

Metastatic lymph node ratio versus number of metastatic lymph nodes as a prognostic factor in gastric cancer

Objective

Knowledge of prognostic factors in gastric cancer is essential to decide on single patient management. We aim to establish the value of lymph node ratio compared to lymph node involvement in the prediction of gastric cancer survival and treatment approach.

Methods

Charts of ninety-six consecutive patients undergoing gastrectomy for resectable gastric cancer were reviewed between January 1996 and December 2005. Receiver operating characteristic (ROC) curves were plotted to verify the accuracy of metastatic lymph node ratio (MLNR) and number of metastatic lymph node (NMLN) cut-off values for survival prediction. Patients were divided into two groups according to ROC curve cut-offs and accuracy in prognosis was reviewed.

Results

ROC curves showed that 5 metastatic nodes and a node ratio value of 20% had the best survival prognostic correlation. The median survival of patients with MLNR and NMLN were similar according to cut-off determinations (≤5/>5 metastatic nodes and ≤20/>20% lymph node ratio). Five-year survival rates were 70.9% vs 17.1% and 72.4% vs 15.6%, respectively (p < 0.001). Positive correlation coefficient was found between the number of excised nodes and the number of metastatic nodes.

Conclusion

Number of metastatic lymph nodes showed greater accuracy than lymph node ratio for survival prediction in gastric cancer.     

Taste-masked quinine sulphate pellets: bio-availability in adults and steady-state plasma concentrations in children with uncomplicated Plasmodium falciparum malaria

BACKGROUND: Quinine sulphate (QS), like most other antimalarials, is in tablet form designed for adults. In children, treatment is based on breaking the tablets to adapt the dose to the child's bodyweight. However, poor breakability owing to the tablet design or the absence of a score line can lead to inaccurate dosage. Furthermore, QS is very bitter which reduces its acceptability to children. QS taste-masked pellets have been developed which offer more flexibility in adapting dosage to a child's weight. AIMS: To evaluate the oral bio-availability of QS taste-masked pellets in healthy adult volunteers and to determine steady-state plasma concentrations in children aged <5 years with uncomplicated Plasmodium falciparum malaria. METHODS: Healthy adult volunteers at Kigali University Hospital received a single dose of 600 mg QS as taste-masked pellets or as commercially available tablets. A total of 56 children <5 years with uncomplicated P. falciparum malaria were recruited among patients attending Butare University Hospital and nearby health centres and treated with QS taste-masked pellets, 10-12.5 mg/kg every 8 h for 7 days. Quinine steady-state plasma concentrations were assessed on the 4th day of treatment. RESULTS: Following administration of taste-masked pellets to healthy adult volunteers, peak plasma concentration (C(max)) and area-under-the-curve (AUC) (C(max) 4.7 microg x ml(-1), AUC(0-24) 63.5 microg x h x ml(-1)) were significantly higher (p<0.05) than for tablets (C(max) 3.7 microg x ml(-1), AUC(0-24) 52.4 microg x h x ml(-1)), but still within the limits reported for quinine. The steady-state concentrations in children were in the therapeutic range for quinine. All the children recovered and completed the 14-day follow-up. CONCLUSION: QS taste-masked pellets offered the possibility to easily adjust the dose to the bodyweight of the child and can be used as an alternative to dividing tablets.     

The value of 16-slice multidetector computed tomographic angiography in preoperative appraisal of vascular anatomy in potential living renal donors

Background

Comprehensive preoperative appraisal of potential living renal donors is the key for selecting a proper donor and a suitable kidney.

Objective

To prospectively assess the diagnostic value of 16-slice multidetector computed tomography (MDCT) in preoperative appraisal of vascular anatomy in potential living renal donors.

Materials and methods

Preoperative angiography using a 16-slice MDCT scanner was performed in 68 consecutive potential living renal donors. The MDCT angiography included unenhanced and contrast-enhanced multiphasic scans. The MDCT images were reviewed for the number and branching pattern of the renal arteries and for the number and presence of major or minor variants of the renal veins. The results were compared with the actual anatomy at the open donor nephrectomy as the diagnostic standard of reference.

Results

The sensitivity and the specificity of MDCT angiography for the detection of various anatomic variants of renal arteries as well as renal venous anomalies were 100%. The anatomic variants of renal arteries included accessory arteries (n = 7) and early arterial branching (n = 10). Whereas, the detected venous anomalies were of major category of the circumaortic left renal vein anomaly (n = 2). No minor renal venous anomaly was identified in any subject.

Conclusion

16-Slice MDCT angiography is highly accurate for preoperative assessment of diverse anomalies of the renal vascular anatomy in potential living renal donors; in consequence, it markedly affects the surgical planning.     

Medication administration via enteral feeding tube: a survey of pharmacists’ knowledge

Background Medication administration to patients with an enteral feeding tube (EFT) is complex and prone to errors. Community pharmacists may be ideally placed to provide training and advice on this topic in individual patients as well as in institutions supplied by the pharmacy. Objective To assess community pharmacists’ knowledge on guideline recommendations regarding medication preparation and administration through EFT. Method Knowledge of guideline recommendations was assessed using a 15-item self-administered online questionnaire (April–June 2014). Questions reflected key aspects of guideline recommendations on medication administration via EFT. All graduated community pharmacists from the Dutch-speaking part of Belgium were eligible for participation. Results A total of 105 community pharmacists completed the questionnaire. Median self-perceived knowledge of medication administration via EFT was 2 (on a 0–10 scale). On average 5.2 (SD 2.6) out of the 15 questions were answered correctly. Strikingly, the ability to select suspensions in a list of liquid medications and knowledge on crushability of solid dosage forms were low. Conclusion Our findings demonstrate that pharmacists’ knowledge on correct medication administration via EFT is too limited to be able to provide good advice to EFT patients or their caregivers. Tailored training on this topic is needed.