Application of a Mixture Experimental Design in the Optimization of a Self‐Emulsifying Formulation with a High Drug Load

Response surface methodology (RSM) was applied to optimize the self‐emulsifying drug delivery system (SEDDS) containing 25% (w/w) Drug A, a model drug with a high lipophilicity and low water solubility. The key objective of this study was to identify an optimal SEDDS formulation that: 1) possesses a minimum concentration of the surfactant and a maximum concentration of lipid and 2) generates a fine emulsion and eliminates large size droplets (≥ 1 µm) upon dilution with an aqueous medium. Three ingredient variables [PEG 400, Cremophor EL, and a mixture of glycerol dioleate (GDO), and glycerol monooleate (GMO)] were included in the experimental design, while keeping the other ingredients at a fixed level (25% Drug A, 6% ethanol, 3% propylene glycol, 4% water, and 2% tromethamine) in the SEDDS formulation. Dispersion performance of these formulations upon dilution with a simulated gastrointestinal fluid was measured, and the population of the large droplets was used as the primary response for statistical modeling. The results of this mixture study revealed significant interactions among the three ingredients, and their individual levels in the formulation collectively dictated the dispersion performance. The fitted response surface model predicted an optimal region of the SEDDS formulation compositions that generate fine emulsions and essentially eliminates large droplets upon dilution. The predicted optimal 25% Drug A–SEDDS formulations with the levels of Cremophor EL ranging from 40–44%, GDO/GMO ranging from 10–13%, and PEG 400 ranging from 2.7–9.0% were selected and prepared. The dispersion experiment results confirmed the prediction of this model and identified potential optimal formulations for further development. This work demonstrates that RSM is an efficient approach for optimization of the SEDDS formulation.     

Optimization of a Raman Microscopy Technique to Efficiently Detect Amorphous–Amorphous Phase Separation in Freeze‐Dried Protein Formulations

A confocal Raman microscopic technique was optimized to more efficiently detect amorphous–amorphous phase separation in freeze‐dried protein formulations. A Renishaw Raman inVia confocal microscope was used to collect 100–200 μm line maps (2 μm step size) of freeze‐dried protein–excipient formulations. At each point across the line map, the composition was evaluated from the intensity of the nonoverlapping peaks representative of each component. Collection aperture, scan time, and line map length significantly contributed to the phase‐separation analysis, whereas different sample preparation methods did not affect the analysis. Using the optimized parameters (i.e., large aperture 5 s scan time, 200 μm line map), phase separation was successfully detected in binary polymer formulations and was comparable to the previously developed Raman method. However, the previous method required 2.5 h/sample, whereas the optimized method only requires 0.5 h/sample. Phase separation was detected in the following protein–excipient formulations: lysozyme–trehalose (1:1), lysozyme–isomaltose (1:1), β‐lactoglobulin–dextran (1:1), β‐lactoglobulin–dextran (1:3), and β‐lactoglobulin–trehalose (1:1). Phase separation was not detected in lysozyme–sucrose (1:1) and β‐lactoglobulin–sucrose (1:1) formulations. The optimized method successfully detected phase separation in several protein formulations, where phase separation was previously suspected, and promised to be a useful tool for detection of phase separation in amorphous therapeutic formulations. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2749–2758, 2014     

Subambient Behavior of Mannitol in Ethanol–Water Co-solvent System

Purpose  The purpose of this study is to characterize the freezing behavior of mannitol in ethanol–water co-solvent systems in comparison with the corresponding aqueous solution. Methods  Subambient differential scanning calorimetry (DSC) and microscopy techniques were used to investigate the freezing behavior of mannitol in aqueous solutions and in ethanol–water co-solvent systems. Results  The DSC thermogram of the frozen aqueous solution, which was warmed after cooling at 5.0°C/min, consisted of a glass transition, an endothermic transition, and a crystallization exotherm from mannitol, respectively. The thermograms of ethanol-containing solutions were different in view of including some thermal events attributable to ethanol hydrates. The glass transition of amorphous mannitol was also observed in the thermograms, but became unclear with increasing ethanol in the co-solvent system. The microscopy experiments enabled understanding of the subambient behavior of mannitol. Ethanol was largely removed by vacuum drying rather than freeze-drying. In addition, such manipulations as annealing during the freezing process and slower cooling (0.5°C/min) enhanced the crystallization of mannitol in the frozen system. Conclusions  In the presence of ethanol, crystallization of mannitol was inhibited under subambient conditions. Annealing or slower cooling promoted the crystallization of mannitol during the freezing process.     

Pro‐cognitive activity in rats of 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide,a positive allosteric modulator of the α7 nicotinic acetylcholine receptor

Background and Purpose

α7 nicotinic acetylcholine receptors (α7 nAChRs) may represent useful targets for cognitive improvement. The aim of this study is to compare the pro‐cognitive activity of selective α7‐nAChR ligands, including the partial agonists, DMXBA and A‐582941, as well as the positive allosteric modulator, 3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide (PAM‐2).

Experimental Approach

The attentional set‐shifting task (ASST) and the novel object recognition task (NORT) in rats, were used to evaluate the pro‐cognitive activity of each ligand [i.e., PAM‐2 (0.5, 1.0, and 2.0 mg·kg⁻¹), DMXBA and A‐582941 (0.3 and 1.0 mg·kg⁻¹)], in the absence and presence of methyllycaconitine (MLA), a selective competitive antagonist. To determine potential drug interactions, an inactive dose of PAM‐2 (0.5 mg·kg⁻¹) was co‐injected with inactive doses of either agonist ‐ DMXBA: 0.1 (NORT); 0.3 mg·kg⁻¹ (ASST) or A‐582941: 0.1 mg·kg⁻¹.

Key Results

PAM‐2, DMXBA, and A‐582941 improved cognition in a MLA‐dependent manner, indicating that the observed activities are mediated by α7 nAChRs. Interestingly, the co‐injection of inactive doses of PAM‐2 and DMXBA or A‐582941 also improved cognition, suggesting drug interactions. Moreover, PAM‐2 reversed the scopolamine‐induced NORT deficit. The electrophysiological results also support the view that PAM‐2 potentiates the α7 nAChR currents elicited by a fixed concentration (3 μM) of DMXBA with apparent EC₅₀ = 34 ± 3 μM and E_max = 225 ± 5 %.

Conclusions and Implications

Our results support the view that α7 nAChRs are involved in cognition processes and that PAM‐2 is a novel promising candidate for the treatment of cognitive disorders.

Abbreviations

α7 nAChR

nicotinic acetylcholine receptor with α7 subunit

AD

Alzheimer''s disease

apparent EC₅₀

enhancement potency

ASST

attentional set‐shifting task

CD

compound discrimination

DI

discrimination index

E

exploration time

ED

extra‐dimensional

E_max

ligand efficacy

ID

intra‐dimensional

ITI

inter‐trial interval

MLA

methyllycaconitine

NORT

novel object recognition task

n_H

Hill coefficient

PAM

positive allosteric modulator

PAM‐2

3‐furan‐2‐yl‐N‐p‐tolyl‐acrylamide

Rev

reversal of discrimination

SD

simple discrimination

T1

familiarisation trial

T2

retention trial

     

Real‐Time Monitoring of Changes of Adsorbed and Crystalline Water Contents in Tablet Formulation Powder Containing Theophylline Anhydrate at Various Temperatures During Agitated Granulation by Near‐Infrared Spectroscopy

Real‐time monitoring of adsorbed water content (FW) and hydrate formation of theophylline anhydrate (THA) in tablet formulation during agitated granulation was investigated by near‐infrared (NIR) spectroscopy. As the wet‐granulation process of THA tablet formulation involves change in pseudo‐polymorphs between THA and theophylline monohydrate (THM), the pharmaceutical properties of THA tablet depend on the degree of hydration during granulation. After mixing of the powder materials (4 g) containing THA, and excipients and the addition of 600 μL of binding water, the powder was kneaded at 27°C, 40°C, and 50°C and then dried. The mixing, granulating, and drying processes were monitored using NIR. The calibration models to predict THM and total water contents during granulation in THA tablet formulation were obtained by partial least‐squares regression. The FW in the formulation was determined by subtracting THM from the water content. The results of the THA formulation powder bed during granulation by NIR monitoring indicated that the transformation pathway of the THA powder was THA ⇒ THM ⇒ THA at 27°C and 40°C, but that at 50°C was THA ⇒ THA ⇒ THA. The pharmaceutical properties, such as tablet porosity, hardness, tablet disintegration time, and dissolution rate of the final THA tablet products, were affected by the degree of crystalline transformation during granulation. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2924–2936, 2014     

Intravesical delivery of 5‐aminolevulinic acid from water‐in‐oil nano/submicron‐emulsion systems

The present work reports on the development of water‐in‐oil (w/o) emulsions for the intravesical administration of 5‐aminolevulinic acid (ALA). The physicochemical properties of droplet size, zeta potential, and viscosity of the emulsions are characterized and the ability of the emulsions to release ALA following in vitro application is tested. The delivery systems are administered intravesically for 1 and 3 h in rats to examine the drug accumulation in bladder tissue. The mean size and zeta potential of the emulsions are 50–200 nm and ?3 to ?14 mV, respectively. The loading of ALA into the emulsions resulted in a slower and sustained release. The release extent was found to be inversely related to the droplet size of the emulsions. The emulsions did not increase the drug permeation into tissues during short exposure duration (1 h). When the dwell time was extended to 3 h, the systems showed a 2.7‐fold increase in the ALA concentration in the bladder wall. Images of confocal laser scanning microscopy demonstrated a higher and deeper fluorescence signal, with emulsion administration, as compared to the aqueous control. Intravesical emulsion delivery provides a significant advantage for drugs targeting bladder tissues. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 2375–2385, 2010     

Formulation and in vitro/in vivo correlation of a drug‐in‐adhesive transdermal patch containing azasetron

The aim of the present study was to develop a transdermal drug delivery system for azasetron and evaluate the correlation between in vitro and in vivo release. The effects of different adhesives, permeation enhancers, and loadings of azasetron used in patches on the penetration of azasetron through rabbit skin were investigated using two‐chamber diffusion cells in vitro. For in vivo studies, azasetron pharmacokinetic parameters in Bama miniature pigs were determined according to a noncompartment model method after topical application of transdermal patches and intravenous administration of azasetron injections. The best permeation profile was obtained with the formulation containing DURO‐TAK 87‐9301 as adhesive, 5% of isopropyl myristate as penetration enhancer, and 5% of azasetron. The optimal patch formulation exhibited sustained release profiles in vivo for 216 h. The in vivo absorption curve in Bama miniature pigs obtained by deconvolution approach using WinNonlin® program was correlated well with the in vitro permeation curve of the azasetron patch. These findings indicated that the developed patch for azasetron is promising for the treatment of delayed chemotherapy‐induced nausea and vomiting, and the in vitro skin permeation experiments could be useful to predict the in vivo performance of transdermal azasetron patches. © 2012 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 101:4540–4548, 2012     

Preparation and Evaluation of High Dispersion Stable Nanocrystal Formulation of Poorly Water‐Soluble Compounds by Using Povacoat

In this study, we reported the application of Povacoat®, a hydrophilic polyvinylalcohol copolymer, as a dispersion stabilizer of nanoparticles of poorly water‐soluble compounds. In addition, the influence of aggregation of the nanoparticles on their solubility and oral absorption was studied. Griseofulvin (GF) was used as a model compound with poor water solubility and was milled to nanoparticles by wet bead milling. The dispersion stability of GF milled with Povacoat® or the generally used polymers (polyvinylalcohol, hydroxypropylcellulose SSL, and polyvinylpyrrolidone K30) was compared. Milled GF suspended in Povacoat® aqueous solution with D‐mannitol, added to improve the disintegration rate of freeze‐dried GF, exhibited high dispersion stability without aggregation (D90 = ca. 0.220 μm), whereas milled GF suspended in aqueous solutions of the other polymers aggregated (D90 > 5 μm). Milled GF with Povacoat® showed improved aqueous solubility and bioavailability compared with the other polymers. The aggregation of nanoparticles had significant impact on the solubility and bioavailability of GF. Povacoat® also prevented the aggregation of the various milled poorly water‐soluble compounds (hydrochlorothiazide and tolbutamide, etc.) more effectively than the other polymers. These results showed that Povacoat® could have wide applicability to the development of nanoformulations of poorly water‐soluble compounds. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3772–3781, 2014     

Genotyping of the arylamine N‐acetyltransferase polymorphism in the prediction of idiosyncratic reactions to trimethoprim‐sulfamethoxazole in infants.

The pathogenesis of hypersensitivity to trimethoprimsulfamethoxazole (TMPSMX) is supposed to be associated with the slow acetylation phenotype. This pharmacogenetic defect is associated with the mutations of the arylamine Nacetyltransferase (NAT2) encoding gene. The aim of the study was to compare the usefulness of the acetylation phenotype and NAT2 coding genotype in the prediction of idiosyncratic reaction to Cotrimoxazole in infants. The study was carried out in the group of 20 infants, aged 212 months (mean age 6.3 months) treated with Cotrimoxazole, administered at 100 mg/kg b.w./24 h doses. In seven children (35%) no adverse effects of the treatment have been observed, whereas in 13 (65%) children various adverse effects occurred as a result of the therapy, such as rash (4 children), granulocytopenia with anemization (5 children) or liver impairment (4 children). The acetylation phenotype of each child was determined on the basis of urine of Nacetyl isoniazid/isoniazid ratio, after ingestion of isoniazid as a model drug. Furthermore we used polymerase chain reaction (PCR) followed by the analysis of restriction fragments length polymorphism (RFLP) technique to identify the known mutant alleles of the NAT2 gene. It has been presumed that the genotype determining fast acetylation contains at least one of wildtype allele. No correlation has been found between the observed adverse effects of Cotrimoxazole and age, gender and acetylation phenotype. However, it has been demonstrated that the risk of adverse effects of Cotrimoxazole is considerably higher in children with mutations of the NAT2 encoding gene. The comparison of the results from PCRRFLP genotyping with phenotyping suggested that in infants, the NAT2 genotype rather than phenotype provides the basis for the detection of hypersensitivity to TMPSMX.     

Assessing the Impact of Polymers on the pH‐Induced Precipitation Behavior of Poorly Water Soluble Compounds using Synchrotron Wide Angle X‐Ray Scattering

The aim of this study was to investigate the pH‐induced precipitation behavior of four ionizable compounds (papaverine, dipyridamole, glyburide, and warfarin) in the absence and presence of polymers. Polymers selected included nonionic, anionic, and cationic polymers. Precipitates were analyzed immediately after formation using high‐energy radiation wide‐angle X‐ray scattering analysis and polarized light microscopy. Papaverine immediately crystallized to the original solid‐state form upon creation of a highly supersaturated solution and polymers were unable to prevent crystallization. Dipyridamole also crystallized rapidly, forming a metastable polymorph that was stabilized by several of the cellulosic polymers. For glyburide and warfarin, although the compounds readily crystallized in the absence of the polymers, several of the polymers were able to prevent crystallization for more than 6 h. In general, measurements of solution concentration immediately following precipitation corroborated the solid‐state analysis results, with the solution phase for the noncrystalline precipitates having a concentration considerably higher than that of the equilibrium solubility value, whereas for the crystalline precipitates, values were closer to the equilibrium solubility. Thus, precipitation to a noncrystalline solid was found to be promoted by the presence of some polymers, resulting in the formation of a supersaturated solution. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2724–2735, 2014     

Ionic Strength Affects Tertiary Structure and Aggregation Propensity of a Monoclonal Antibody Adsorbed to Silicone Oil–Water Interfaces

Therapeutic proteins formulated in prefilled syringes lubricated with silicone oil come in contact with silicone oil–water interfaces for their entire shelf lives. Thus, the interactions between protein and silicone oil were studied to determine the effect of silicone oil on a monoclonal antibody's stability, both at the interface and in the bulk solution. The influence of ionic strength on these interactions was also investigated through the addition of various monovalent and divalent salts to sample formulations. The tertiary structure of the antibody was perturbed when it adsorbed to the silicone oil–water interface in solutions at low ionic strength. However, the tertiary structure of the antibody at the interface was not perturbed when the ionic strength of the formulation was increased. Even at low ionic strength, the secondary structure of the antibody adsorbed to the silicone oil–water interface was retained, suggesting that at low ionic strength, the adsorbed antibody assumes a molten globule-like conformation. This partially unfolded species was aggregation-prone, especially during agitation. Silicone oil-induced aggregation of the antibody was inhibited at higher ionic strength.     

Near‐Infrared Imaging for High‐Throughput Screening of Moisture Induced Changes in Freeze‐Dried Formulations

Evaluation of freeze‐dried biopharmaceutical formulations requires careful analysis of multiple quality attributes. The aim of this study was to evaluate the use of near‐infrared (NIR) imaging for fast analysis of water content and related physical properties in freeze‐dried formulations. Model formulations were freeze‐dried in well plates. Samples were imaged with a NIR hyperspectral camera after freeze‐drying and upon storage. On the basis of Karl Fischer titration reference values, a univariate quantification model was constructed and used to visualize the distribution of water within freeze‐dried samples. Differences observed between samples stored at 11% and 43% relative humidity (RH) were found to be related to the amount of amorphous component in the sample. When stored at 43% RH, the moisture content in samples with high sucrose content increased within 2 days and some degree of localized drying was observed within the samples after 3 days of storage. Further investigations with X‐ray powder diffraction confirmed this local drying to be related to crystallization of sucrose. The combination of fast analysis of water content and spatial solid‐state information makes NIR imaging a powerful tool for formulation development of freeze‐dried samples. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2839–2846, 2014     

Thermodynamics of Water–Solid Interactions in Crystalline and Amorphous Pharmaceutical Materials

Pharmaceutical materials, crystalline and amorphous, sorb water from the atmosphere, which affects critical factors in the development of drugs, such as the selection of drug substance crystal form, compatibility with excipients, dosage form selection, packaging, and product shelf-life. It is common practice to quantify the amount of water that a material sorbs at a given relative humidity (RH), but the results alone provide minimal to no physicochemical insight into water–solid interactions, without which pharmaceutical scientists cannot develop an understanding of their materials, so as to anticipate and circumvent potential problems. This research was conducted to advance the science of pharmaceutical materials by examining the thermodynamics of solids with sorbed water. The compounds studied include nonhygroscopic drugs, a channel hydrate drug, a stoichiometric hydrate excipient, and an amorphous excipient. The water sorption isotherms were measured over a range of temperature to extract the partial molar enthalpy and entropy of sorbed water as well as the same quantities for some of the solids. It was found that water–solid interactions spanned a range of energy and entropy as a function of RH, which was unique to the solid, and which could be valuable in identifying batch-to-batch differences and effects of processing in material performance. © 2013 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:2772–2783, 2014     

Optimization of chemically defined cell culture media – Replacing fetal bovine serum in mammalian in vitro methods

Quality assurance is becoming increasingly important. Good laboratory practice (GLP) and good manufacturing practice (GMP) are now established standards. The biomedical field aims at an increasing reliance on the use of in vitro methods. Cell and tissue culture methods are generally fast, cheap, reproducible and reduce the use of experimental animals. Good cell culture practice (GCCP) is an attempt to develop a common standard for in vitro methods. The implementation of the use of chemically defined media is part of the GCCP. This will decrease the dependence on animal serum, a supplement with an undefined and variable composition. Defined media supplements are commercially available for some cell types. However, information on the formulation by the companies is often limited and such supplements can therefore not be regarded as completely defined. The development of defined media is difficult and often takes place in isolation. A workshop was organised in 2009 in Copenhagen to discuss strategies to improve the development and use of serum-free defined media. In this report, the results from the meeting are discussed and the formulation of a basic serum-free medium is suggested. Furthermore, recommendations are provided to improve information exchange on newly developed serum-free media.     

Cost‐effectiveness analysis of tropisetron vs. chlorpromazine‐dexamethasone in the control of acute emesis induced by highly emetogenic chemotherapy in children

Objective. To perform a costeffectiveness analysis (CEA) between a standard antiemetic regimen chlorpromazine + dexamethasone (CPMDEX) and a 5HT3 receptor antagonist tropisetron (TROP) in the control of acute emesis induced by highly emetogenic chemotherapy in children, considering two analytic perspectives: hospital and patients. Methods. The CEA was performed by constructing a decision tree, for both analytic perspectives, of the possible outcomes of treatment with TROP (single 0.2 mg/kg i.v.) or CPM (515 mg i.v. infusion for 3 doses) plus DEX (2 mg/m2 i.v. bolus i.v. × 2). The patients were stratified by age in two groups (212 and 1317). To estimate the probability of each endpoint at the decision tree we have taken as a base a trial developed in the Department of Pediatrics. Direct medical cost of primary therapy, failure, complications and side effects were included in the cost calculations. Results. From patients' analytic perspective, TROP was more costeffective than CPMDEX for both groups of patients. Discrepancy between both analytic perspectives in 1317 yearold patient's group was resolved in favour of the option chosen from the patients' analytic perspective (TROP). Sensitivity analysis showed the reliability of the results. Conclusions. 1. TROP was more costeffective than CPMDEX. 2. Taking into account the patients' analytic perspective is essential when we compare antiemetics pharmacoeconomically. 3. It seems necessary to increase the effectiveness of TROP in pediatric patients receiving highly emetogenic chemotherapy with strategies such as the addition of a steroid.     

Regulator of G‐protein signalling 5 protects against atherosclerosis in apolipoprotein E‐deficient mice

Background and Purpose

Atherosclerosis is a chronic inflammatory disease, in which ‘vulnerable plaques’ have been recognized as the underlying risk factor for coronary disease. Regulator of G‐protein signalling (RGS) 5 controls endothelial cell function and inflammation. In this study, we explored the effect of RGS5 on atherosclerosis and the potential underlying mechanisms.

Experimental Approach

RGS5^−/− apolipoprotein E (ApoE)^−/− and ApoE ^−/− littermates were fed a high‐fat diet for 28 weeks. Total aorta surface and lipid accumulation were measured by Oil Red O staining and haematoxylin–eosin staining was used to analyse the morphology of atherosclerotic lesions. Inflammatory cell infiltration and general inflammatory mediators were examined by immunofluorescence staining. Apoptotic endothelial cells and macrophages were assayed with TUNEL. Expression of RGS5and adhesion molecules, and ERK1/2 phosphorylation were evaluated by co‐staining with CD31. Expression of mRNA and protein were determined by quantitative real‐time PCR and Western blotting respectively.

Key Results

Atherosclerotic phenotypes were significantly accelerated in RGS5^−/− ApoE ^−/− mice, as indicated by increased inflammatory mediator expression and apoptosis of endothelial cells and macrophages. RGS5 deficiency enhanced instability of vulnerable plaques by increasing infiltration of macrophages in parallel with the accumulation of lipids, and decreased smooth muscle cell and collagen content. Mechanistically, increased activation of NF‐κB and MAPK/ERK 1/2 could be responsible for the accelerated development of atherosclerosis in RGS5‐deficient mice.

Conclusions and Implications

RGS5 deletion accelerated development of atherosclerosis and decreased the stability of atherosclerotic plaques partly through activating NF‐κB and the MEK‐ERK1/2 signalling pathways.

Linked Articles

This article is part of a themed section on Chinese Innovation in Cardiovascular Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-23

Abbreviations

ApoE

apolipoprotein E

CHD

coronary heart disease

H&E

haematoxylin‐eosin

ICAM‐1

intercellular adhesion molecue‐1

LDL

low‐density lipoprotein

MEK

MAPK/ERK kinase

RGS

regulator of G‐protein signalling

SMC

smooth muscle cell

VCAM‐1

vascular cell adhesion molecule‐1

Tables of Links

Evaluation of vancomycin use in a large university‐affiliated hospital in eastern France in 1999

Objective: In 1999, we conducted a retrospective drug utilization review to determine the volume and pattern of vancomycin use in a universityaffiliated hospital in eastern France. Methods: Total vancomycin use was determined and expressed as vancomycin courses per 100 admitted patients and defined daily doses (DDD) of vancomycin per 100 patientdays. The indication for vancomycin use was classified as appropriate or inappropriate according to the guidelines issues by the HICPAC. Results: A total of 311 vancomycin courses were given, as 2098 DDD, giving crude incidences of 1.17 courses per 100 admitted patients and of 1.19 defined daily doses per 100 patientdays. The frequency of appropriate courses was 66.7%. Of the 63 inappropriate courses of vancomycin, 39.7% and 28.6% were empiric therapy for nosocomial and communityacquired infections, respectively, 20.6% and 6.3% were specific therapy for nosocomial and communityacquired infections, respectively, and 4.7% were prophylactic. Conclusions: This study shows that vancomycin use in our hospital resulted in a lower selection pressure than has been reported for US universityaffiliated hospitals and that comprehensive programs to improve use of vancomycin are needed in our institution.     

Patients'' opinions of CFC‐free inhaler changeover in primary care

Objective: To determine patient's opinions regarding the changeover from CFC containing to CFCfree salbutamol. Design: Patients receiving metered dose salbutamol inhaler therapy were identified and verbal consent was obtained before a semistructured interview was performed.Setting An outpatient respiratory clinic within a busy teaching hospita. Main outcome measures: Knowledge of CFCfree inhaler therapy and acceptance of change. Results: A total of 28 patients were identified of whom only eight (29%) had been changed to a CFCfree product. Six of these (75%) had received counselling from their GP or pharmacist regarding the change. Differences were reported by all of the patients who had been changed to a CFCfree inhaler with comments including difference in taste (6 patients), difference in feel (6), less effective (1) and more effective (1). Three patients preferred the CFCfree inhaler to their previous therapy. Although 13 out of the 20 patients who had not received a CFCfree inhaler stated they were happy with the potential changeover, 10 (80%) has concerns relating to effectiveness. Conclusion: The majority of patients still receiving CFC inhalers were aware that the production of CFCcontaining products had been restricted although they were unaware of the imminent changes that would take place regarding their inhaler therapy. However, the small sample size recruited in this study may mean that the results are unrepresentative of the CFCfree implementation process in the Grampian Health Board area as a whole. Nonetheless, in view of the differences experienced by patients who received CFCfree inhalers and the concerns stated about potential lack of efficacy by patients about to be changed over, it is essential that healthcare professionals provide advice on CFCfree inhalers to all patients.