Matthew J. Ingram

Renin- angiotensin- system gene polymorphisms and depression

Given the abundance of the renin-angiotensin system (RAS) components in the brain, their importance in behavior and cognition, and the data that implicates them in the etiology and treatment of depression, it is possible that those RAS gene polymorphisms associated with increased RAS activity may also be associated with depression. The frequencies of common polymorphisms of genes encoding for components of the RAS, namely angiotensinogen (M235T), angiotensin converting enzyme (ACE) (insertion, I; deletion, D), angiotensin receptor type I (A1166C), and angiotensin receptor type II (C3123A) were determined in DNA extracted from buccal cells from a Lebanese population of 132 depressed patients and their first-degree relative case-controls. The angiotensin receptor type 1 (A1166C) CC genotype was significantly associated with depression (p=0.036). None of the other common RAS-associated polymorphisms were significantly associated. The results support the hypothesis that increased RAS activity may increase relative risk of depression in that the angiotensin receptor type 1 (A1166C) CC genotype is associated with increased responsiveness to angiotensin II.

Design, synthesis and characterization of captopril prodrugs for enhanced percutaneous absorption

Most drugs are designed primarily for oral administration, but the activity and stability profiles desirable for this route often make them unsuitable for transdermal delivery. We were therefore interested in designing analogues of captopril, a model drug with poor percutaneous penetration, for which the sustained steady‐state blood plasma level associated with transdermal delivery (and which is unattainable orally) would be particularly beneficial. Quantitative structure—permeability relationships (QSPRs) predicted that ester and thiol prodrug derivatives of captopril would have lower maximal transdermal flux (Jm) than the parent drug, since the increases in permeability coefficient (kp) of prodrugs would be outweighed by the reductions in aqueous solubility. Therefore, the aim of this study was to synthesize a series of prodrugs of captopril and to determine if a QSPR model could be used to design therapeutically viable prodrugs. Molecules with the highest predicted kp values were synthesized and characterized, and Jm measured in Franz diffusion cells from saturated aqueous donor across porcine skin (fresh and frozen). In‐vitro metabolism was also measured. Captopril and the prodrugs crossed the skin relatively freely, with Jm being highest for ethyl to butyl esters. Substantial first‐order metabolism of the prodrugs was observed, suggesting that their enhanced percutaneous absorption was complemented by their metabolic performance. The results suggested that QSPR models provided excellent enhancements in drug delivery. This was not seen at higher lipophilicities, suggesting that issues of solubility need to be considered in conjunction with any such use of a QSPR model.

Chitosan microparticles for the controlled delivery of fluoride

OBJECTIVES To manufacture and characterise chitosan/fluoride microparticles prepared by spray drying and assess their utility as controlled release vehicles for fluoride. METHODS Microparticles were manufactured from dispersions containing 1.0% and 2.0% (w/v) chitosan and 0.20% or 0.40% (w/v) NaF in the absence/presence of glutaraldehyde. Particle size distributions were determined using laser diffraction; fluoride loading and release were determined by ion-selective electrode. Release profiles were studied in isotonic media (pH 5.5) over 360 min; microparticles exhibiting greatest cumulative fluoride release were further evaluated at pH 4.0 and 7.0. Particle morphology was investigated using environmental scanning electron microscopy. Bioadhesion parameters were determined with a texture-probe analyser. RESULTS Microparticles exhibited low polydispersity and volume mean diameters (VMDs) <6 μm. VMDs increased on doubling the chitosan/fluoride concentrations but were largely independent of glutaraldehyde concentration. Recovered yields were inversely proportional to dispersion viscosity due to compromised fluid atomisation; adding NaF reduced viscosity and improved yields. Best-case entrapment efficiency and NaF loading were 84.1% and 14%, respectively. Release profiles were biphasic, releasing 40-60% of the total fluoride during the first 600 s, followed by a prolonged release phase extending out to 6h. Incorporation of 0.40% NaF to the 2.0% chitosan dispersion yielded microparticles with reduced bioadhesive parameters (F(max) and WOA) versus the chitosan-only control whilst retaining significant bioadhesive potential. CONCLUSIONS Bioadhesive chitosan/fluoride microparticles manufactured using a spray-drying protocol have been extensively characterised and further opportunity for optimisation identified. These microparticles may provide a means of increasing fluoride uptake from oral care products to provide increased protection against caries, however further work is required to demonstrate this principle in vivo. CLINICAL SIGNIFICANCE Spray-drying is a low-cost route for the manufacture of bioadhesive chitosan/fluoride microparticles which can be exploited as controlled fluoride release agents to aid fluoride retention in the oral cavity. The potential exists to optimise release profiles to suit the delivery format thereby maximising the cariostatic benefits.

Formulation and characterization of a captopril ethyl ester drug-in-adhesive-type patch for percutaneous absorption

Background: The ethyl ester of captopril has been shown to exhibit enhanced permeation across human skin compared to the parent drug. A drug-in-adhesive patch formulation of a captopril ethyl ester was therefore developed for optimum drug release. Method: A wide range of transdermal patches were prepared using two commercially available bioadhesive polymers. Investigational screening was conducted on the patches using microscopy, texture profile analysis, and infrared spectroscopy. Drug release profiles of suitable patches were obtained using both polydimethylsiloxane (Silastic™) and porcine skin in vitro. Results: Diffusion results across Silastic™ showed a gradual plateau in flux with increased drug loading that may be attributable to intramolecular interactions while flux across porcine skin was seen to increase with increasing patch thickness and attained a therapeutic level. Conclusions: This study demonstrated that adhesion and drug loading are significant factors in optimizing a topical patch formulation for the delivery of a captopril prodrug.

The effect of language background on teaching and learning in the master of pharmacy degree

biomedical teaching. The effect of first language on scientific comprehension was assessed on full-time, undergraduate Master of Pharmacy students from all four years of study at the University of Brighton. This was achieved by the use of a language quiz, which was scored for comprehension of parts of scientific words. Students with English as their native language scored significantly higher than others (medians 45, 20%, respectively; p < 0.001). Scores of native English speakers improved with age and year of study, but these trends were not seen for others. Students who had studied Latin obtained significantly higher test scores (medians 60, 45%; p = 0.006). Students whose parental language was English or European scored significantly better than others (medians 9,7,5 out of 20%; p < 0.001).

Synthesis and hydrolytic behaviour of glycerol‐1,2‐diibuprofenate‐3‐nitrate, a putative pro‐drug of ibuprofen and glycerol‐1‐nitrate

Nitroxylated derivatives of non‐steroidal anti‐inflammatory drugs appear to offer protection against the gastrotoxicity normally associated with non‐steroidal anti‐inflammatory drugs, ostensibly via local production of nitric oxide. A diester of ibuprofen and glycerol‐1‐mononitrate has been prepared via the condensation of ibuprofen with 3‐bromopropan‐1,2‐diol, followed by silver‐(I)‐nitrate‐mediated nitroxylation. The release of ibuprofen from this diester has been studied in a simulated gastric fluid model with direct analysis by reverse‐phase HPLC, using an acetonitrile‐water (80%:20%) mobile phase containing trifluoroacetic acid (0.005%). n‐Propyl ibuprofen was found to undergo pH‐dependent hydrolysis, ranging from negligible hydrolysis at pH 5 to 52% hydrolysis at pH 3, over a 2‐h period in this model. The ibuprofen‐glycerol mononitrate diester was subjected to the most vigorous model hydrolytic conditions and was found to undergo 50% hydrolysis during the study period. This study shows that pro‐drugs of ibuprofen and glycerol mononitrate can be obtained, and can undergo degradation to the parent drugs under conditions simulating those likely to be encountered in the stomach.

Pharmacy student perceptions of educational media tools

User perception is an important consideration when assessing the educational value of multimedia resources. A media tool may be proven educationally, but if the users (normally the students) perceive it as anything less than helpful, they are unlikely to obtain maximum utility from it. The aim of this study is to assess the perceived educational value of multimedia tools currently available to MPharm students (i.e. DVD, CD-ROM, handouts/practical schedules and internet resources, including streaming video media) and the factors that influenced students’ perception. MPharm students from all four cohorts of the Brighton MPharm degree pathway participated in this study. Respondents identified handouts and schedules for workshops and laboratory classes as the most useful resource, followed by internet-based resources and DVD/CD-ROM resources. Printed resources were perceived as more reliable and trustworthy compared to multimedia resources. DVD-based resources were perceived to captivate attention and maintain focus more than other resources and respondents favoured a combination of printed and electronic resources to be available. Generally, although electronic resources (particularly those which are internet-based) were positively perceived, the use of printed media, such as laboratory schedules and lecture notes, was preferred in conjunction with multimedia resources.

Metabolism of captopril carboxyl ester derivatives for percutaneous absorption

OBJECTIVES To determine the metabolism of captopril n-carboxyl derivatives and how this may impact on their use as transdermal prodrugs. The pharmacological activity of the ester derivatives was also characterised in order to compare the angiotensin converting enzyme inhibitory potency of the derivatives compared with the parent drug, captopril. METHODS The metabolism rates of the ester derivatives were determined in vitro (using porcine liver esterase and porcine ear skin) and in silico (using molecular modelling to investigate the potential to predict metabolism). KEY FINDINGS Relatively slow pseudo first-order metabolism of the prodrugs was observed, with the ethyl ester displaying the highest rate of metabolism. A strong relationship was established between in-vitro methods, while in-silico methods support the use of in-vitro methods and highlight the potential of in-silico techniques to predict metabolism. All the prodrugs behaved as angiotensin converting enzyme inhibitors, with the methyl ester displaying optimum inhibition. CONCLUSIONS In-vitro porcine liver esterase metabolism rates inform in-vitro skin rates well, and in-silico interaction energies relate well to both. Thus, in-silico methods may be developed that include interaction energies to predict metabolism rates.

The Role of Handouts in the M.Pharm Degree Pathway—Differentiating between the Inquisitive and the Acquisitive

Handouts are an established and recognised way for teaching staff to facilitate learning within higher education, by supplementing traditional didactic Learn- ing and Teaching (L&T) methods. Traditionally, teaching in UK Schools of Pharmacy has often relied upon the use of handouts as part of the L&T strategy. However, their use is inconsistent, and dependent upon the teaching style of the educator. To our knowledge, a systematic analysis of their impact on the student learning experience has not been conducted with respect to their use in the Master of Pharmacy (M.Pharm) degree programme. In this article, we survey the attitudes of undergraduate M.Pharm students with respect to the use of handouts and the effect on their learning at two UK schools of pharmacy and compare the results with an Australian (University of Queensland) school of veterinary science. We report that most students’ stated preference is for comprehensive learning support in the form of handouts. This is at slight variance with one of our previous works which, although reported a similar result, also reported that there is in some cases an inversely proportional relationship between the number of handouts given to students and the value they place upon them, as well as that students place greater value on material that they have downloaded them- selves by means of an intranet or Managed Learning Environment. Two hundred and eighty five School of Pharmacy and Biomolecular Sciences, University of Brighton students (Levels 1–4) and 19 staff responded to questionnaire and 150 School of Pharmacy and Biomolecular Sciences, University of Portsmouth students responded. Reporting from the view that handouts can be a coherent and effective educational strategy to promote lifelong learning, we compare attitudes of the staff and students of the schools and whether or not these influence the manner in which students and staff approach their subjects. We report significant differences in the way five major questions were answered between each school. Comparisons of the responses from the different schools indicated that students from different universities and from both countries have different beliefs regarding handout usage. Eighty-three percent of Brighton students requested comprehensive handouts as an integral component of the lectures, compared to 56% of Queensland students, and 53% of Portsmouth students. Whilst staff favour the limited use of handouts as supplements to lecture materials and tended to agree on most responses, with only 32% of Brighton staff and 34% of Queensland staff agreeing that students should receive comprehensive handouts. More staff than students also agreed that handouts discourage further reading in a subject. Other factors that were significantly related to student responses were gender, year of study, choice of pre-registration field, the presence or absence of a part-time job and whether or not the student was studying in their native country.

A potential anti-implantation and spermicidal strategy: Putative derivatives of nonoxynol-9 and anti-inflammatory agents and their spermicidal activity

Objectives We report the synthesis of novel ester derivatives of nonoxynol-9, an approved spermicidal agent, using the non-steroidal inflammatory drugs (NSAIDs) ibuprofen and indomethacin. Indomethacin has previously been shown to inhibit the implantation of the fertilised ovum into the uterus wall of pregnant rats. It is proposed that nonoxynol-9, in combination with a non-selective NSAID may exhibit both anti-implantation and spermicidal properties. Methods Both novel derivatives and nonoxynol-9 were then tested on boar spermatozoa in order to establish if spermicidal activity was retained following the esterification. Results The results showed that both the ibuprofen and indomethacin derivatives enabled complete cell death of boar spermatozoa at a concentration of 100 µg ml−1, which is comparable to nonoxynol-9 at the same concentration. Conclusions These results indicate that NSAID derivatives of nonoxynol-9 retain the activity of the parent molecule and may have other advantages associated with the molecular incorporation of the NSAID moieties and their anti-implantation activity.