Drug utilization evaluation of parenteral proton pump inhibitors

Current evidence supports parenteral infusion of proton pump inhibitors (PPI) after endoscopic treatment of bleeding peptic ulcers and such treatment seems reasonable where there is active bleeding or visible vessel on endoscopy. Parenteral boluses of PPI can be used in patients nil by mouth who cannot tolerate oral therapy. We sought to examine the appropriateness of parenteral PPI use. Drug utilisation evaluation was performed on 94 patients admitted to a 500 bed metropolitan hospital. 39 patients received continuous parenteral infusion of omeprazole (8 mg/ h) over a mean of 60 ± 29 h. 55 patients had parenteral boluses (40 mg bd) of omeprazole over a mean of 5 ± 4 days. Indications for PPI infusion (n = 39) were: major haemorrhage requiring transfusion (23), minor haemorrhage (8), dyspepsia (4) and others (4). 31 of the 39 patients on PPI infusion had upper gastrointestinal (GI) endoscopy. PPI infusion was commenced prior to endoscopy in 26 (84%) patients. 13 patients (33%) had active bleeding or visible non bleeding vessels at endoscopy. Only 11 patients (28%) had endoscopically treated peptic ulcers. Indications for parenteral PPI boluses (n = 55) included patients nil by mouth unable to take maintenance PPI orally (21), minor haemorrhage (8), peptic ulcer prophylaxis in seriously unwell (6), major haemorrhage (4), dyspepsia (2), postoprative period following peptic ulcer surgery (2) and others (12). Endoscopy was performed in 10 patients (18%) with only 1 endoscopically treated peptic ulcer. Our data suggest significant inappropriate use of parenteral PPI, which may be used for minor GI bleeding and dyspepsia and are typically commenced prior to endoscopy. These findings can explain the costly hospital expenditure on PPI.

Relationships between morphological types of plaque in Alzheimer’s disease as revealed in silver and immunostained preparations

The objective of this study was to determine the possible relationships between the morphological types of plaque revealed in silver and immunostained sections of Alzheimer’s disease (AD) tissue. The density of cored and uncored senile plaques in Glees and Marsland preparations, and of diffuse, primitive, classic and compact beta/A4 deposits in immunostained preparations were estimated. A principal components analysis (PCA) of the data suggested that three uncorrelated principal components accounted for 80% of the variation in lesion density in the tissues. This suggested that thee processes lead independently to the formation of: (1) the uncored Glees plaques; (2) the primitive beta/A4 deposits and most of the classic beta/A4 deposits and (3) the compact beta/A4 deposits and the remaining classic deposits. Hence, the uncored plaques revealed by the Glees stain and the primitive beta/A4 deposits represented distinct plaque populations. In addition, the classic beta/A4 deposits did not appear to represent a uniform plaque population but to originate from at least two pathological processes. The uncored Glees plaques appeared to the only plaque population closely related to the diffuse beta/A4 deposits.

Novel bioadhesive formulations for mucosal and parenteral delivery of vaccines

In this work we have established the efficient mucosal delivery of vaccines using absorption enhancers and chitosan. In addition, the use of chitosan was shown to enhance the action of other known adjuvants, such as CTB or Quil-A. Collectively, the results presented herein indicate that chitosan has excellent potential as a mucosal adjuvant. We have evaluated a number of absorption enhancers for their adjuvant activity in vivo. Polyornithine was shown to engender high scrum immune reasons to nasally delivered antigens, with higher molecular weight polyornithine facilitating the best results. We have demonstrated for the first time that vitamin E TPGS can act as mucosal adjuvant. Deoxycholic acid, cyclodextrins and acylcarnitines were also identified as effective mucosal adjuvants and showed enhanced immune responses to nasally delivered TT, DT and Yersinia pestis V and F1 antigens. Previously, none of these agents, common in their action as absorption enhancing agents, have been shown to have immunopotentiating activity for mucosal immunisation. We have successfully developed novel surface modified microspheres using chitosan as an emulsion stabiliser during the preparation of PLA microspheres. It was found that immune responses could be substantially increased, effectively exploiting the immunopenetrating characteristics of both chitosan and PLA microspheres in the same delivery vehicle. In the same study, comparison of intranasal and intramuscular routes of administration showed that with these formulations, the nasal route could be as effective as intramuscular delivery, highlighting the potential of mucosal administration for these particulate delivery systems. Chitosan was co-administered with polymer microspheres. It was demonstrated that this strategy facilitates markedly enhanced immune responses in both magnitude and duration following intramuscular administration. We conclude that this combination shows potential for single dose administration of vaccines. In another study, we have shown that the addition of chitosan to alum adsorbed TT was able to enhance immune responses. PLA micro/nanospheres were prepared and characterised with discreet particle size ranges. A smaller particle size was shown to facilitate higher scrum IgG responses following nasal administration. A lower antigen loading was additionally identified as being preferential for the induction of immune responses in combination with the smaller particle size. This may be due to the fact that the number of particles will be increased when antigen loading is low, which may in turn facilitate a more widespread uptake of particles. PLA lamellar particles were prepared and characterised. Adsorbed TT was evaluated for the potential to engender immune responses in vivo. These formulations were shown to generate effective immune responses following intramuscular administration. Positively charged polyethylcyanoacrylate and PLA nanoparticies were designed and characterised and their potential as delivery vehicles for DNA vaccines was investigated. Successful preparation of particles with narrow size distribution and positive surface charge (imparted by the inclusion of chitosan) was achieved. In the evaluation of antibody responses to DNA encoded antigen in the presence of alum administered intranasally, discrimination between the groups was only seen following intramuscular boosting with the corresponding protein. Our study showed that DNA vaccines in the presence of either alum or Quil-A may advantageously influence priming of the immune system by a mucosal route. The potential for the combination of adjuvants, Quil-A and chitosan, to enhance antibody responses to plasmid encoded antigen co-administered with the corresponding protein antigen was shown and this is worthy of further investigation. The findings here have identified novel adjuvants and approaches to vaccine delivery. In particular, chitosan or vitamin E TPGS are shown here to have considerable promise as non-toxic, safe mucosal adjuvants. In addition, biodegradable mucoadhesive delivery systems, surface modified with chitosan in a single step process, may have application for other uses such as drug and gene delivery.

Robust spatially resolved pressure measurements using MRI with novel buoyant advection-free preparations of stable microbubbles in polysaccharide gels

MRI of fluids containing lipid coated microbubbles has been shown to be an effective toot for measuring the local fluid pressure. However, the intrinsically buoyant nature of these microbubbles precludes lengthy measurements due to their vertical migration under gravity and pressure-induced coalescence. A novel preparation is presented which is shown to minimize both these effects for at least 25 min. By using a 2% polysaccharide gel base with a small concentration of glycerol and 1,2-distearoyl-sn-glycero-3-phosphocholine coated gas microbubbles, MR measurements are made for pressures between 0.95 and 1.44 bar. The signal drifts due to migration and amalgamation are shown to be minimized for such an experiment whilst yielding very high NMR sensitivities up to 38% signal change per bar.

Pharmaceutical service to ophthalmology patients: studies on cefuroxime preparations

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Proplyene glycol intake from medications used on paediatric intensive care

here is an increasing number of reports of propylene glycol (PG) toxicity in the literature, regardless of its inclusion on the Generally Recognized as Safe List (GRAS).1 PG is an excipient used in many medications as a solvent for water-insoluble drugs. Polypharmacy may increase PG exposure in vulnerable PICU patients who may accumulate PG due to compromised liver and renal function. The study aim was to quantify PG intake in PICU patients and attitudes of clinicians towards PG. Method A snapshot of 50 PICU patients oral or intravenous medication intake was collected. Other data collected included age, weight, diagnosis, lactate levels and renal function. Manufacturers were contacted for PG content and then converted to mg/kg. Excipients in formulations that compete with the PG metabolism pathway were recorded. The Intensivists' opinions on PG intake was sought via e-survey. Results The 50 patients were prescribed 62 drugs and 83 formulations, 43/83 (52%) were parenteral formulations. Median weight of the patients was 5.5 kg (range 2–50 kg), ages ranged from 1 day to 13 years of age. Eleven of the patients were classed as renally impaired (defined as 1.5 times the baseline creatinine). Sixteen formulations contained PG, 2/16 were parenteral, 6/16 unlicensed preparations. Thirty-eight patients received at least one prescription containing PG and 29/38 of these patients were receiving formulations that contained excipients that may have competed with the metabolic pathways of PG. PG intake ranged from 0.002 mg/kg/day to 250 mg/kg/day. Total intake was inconclusive for 2 patients due to a of lack of availability of information from the manufacturer; these formulations were licensed but used in for off-label indications. Five commonly used formulations contributed to higher intakes of PG, namely co-trimoxazole, dexamethasone, potassium chloride, dipyridamole and phenobarbitone. Lactate levels were difficult to interpret due to the underlying conditions of the patients. One of the sixteen intensivist was aware of PG content in drugs, 16/16 would actively change therapy if intake was above European Medicines Agency recommendations. Conclusions Certain formulations used on PICU can considerably increase PG exposure to patients. Due to a lack of awareness of PG content, these should be highlighted to the clinician to assist with making informed decisions regarding risks versus benefits in continuing that drug, route of administration or formulation.