Effect of chemical conjugation of L-leucine to chitosan on the dispersibility and drug release of a dry powder inhaler nanoparticle formulation

Purpose: This study investigated the effect of chemical conjugation of the amino acid L-leucine to the polysaccharide chitosan on the dispersibility and drug release pattern of a polymeric nanoparticle (NP)-based controlled release dry powder inhaler (DPI) formulation. Methods: A chemical conjugate of L-leucine with chitosan was synthesized and characterized by Infrared (IR) Spectroscopy, Nuclear Magnetic Resonance (NMR) Spectroscopy, Elemental Analysis and X-ray Photoelectron Spectroscopy (XPS). Nanoparticles of both chitosan and its conjugate were prepared by a water-in-oil emulsification – glutaraldehyde cross-linking method using the antihypertensive agent, diltiazem (Dz) hydrochloride as the model drug. The surface morphology and particle size distribution of the nanoparticles were determined by Scanning Electron Microscopy (SEM) and Dynamic Light Scattering (DLS). The dispersibility of the nanoparticle formulation was analysed by a Twin Stage Impinger (TSI) with a Rotahaler as the DPI device. Deposition of the particles in the different stages was determined by gravimetry and the amount of drug released was analysed by UV spectrophotometry. The release profile of the drug was studied in phosphate buffered saline at 37 ⁰C and analyzed by UV spectrophotometry. Results: The TSI study revealed that the fine particle fractions (FPF), as determined gravimetrically, for empty and drug-loaded conjugate nanoparticles were significantly higher than for the corresponding chitosan nanoparticles (24±1.2% and 21±0.7% vs 19±1.2% and 15±1.5% respectively; n=3, p<0.05). The FPF of drug-loaded chitosan and conjugate nanoparticles, in terms of the amount of drug determined spectrophotometrically, had similar values (21±0.7% vs 16±1.6%). After an initial burst, both chitosan and conjugate nanoparticles showed controlled release that lasted about 8 to 10 days, but conjugate nanoparticles showed twice as much total drug release compared to chitosan nanoparticles (~50% vs ~25%). Conjugate nanoparticles also showed significantly higher dug loading and entrapment efficiency than chitosan nanoparticles (conjugate: 20±1% & 46±1%, chitosan: 16±1% & 38±1%, n=3, p<0.05). Conclusion: Although L-leucine conjugation to chitosan increased dispersibility of formulated nanoparticles, the FPF values are still far from optimum. The particles showed a high level of initial burst release (chitosan, 16% and conjugate, 31%) that also will need further optimization.

Failure to administer a drug and causation

Case note on King v Western Sydney Local Health Network In King v Western Sydney Local Health Network [2013] NSWCA 162 the appellant sought damages for the severe physical and intellectual disability she suffered as a result of foetal varicella syndrome (FVS) caused by her mother contracting varicella (chickenpox) in the second trimester of her pregnancy. The mother had been exposed to the virus and sought advice from a doctor at Blacktown Hospital as she had not had the virus herself and therefore did not possess immunity. In such circumstances at the time, the standard medical practice was to offer the mother varicellazoster immunoglobulin (VZIG) to boost her defence to the virus. The appellant’s mother however was not offered this treatment and contracted chickenpox resulting the appellant’s condition...

Phenytoin metabolism by human cytochrome P450 : involvement of P450 3A and 2C forms in secondary metabolism and drug-protein adduct formation

The anticonvulsant phenytoin (5,5-diphenylhydantoin) provokes a skin rash in 5 to 10% of patients, which heralds the start of an idiosyncratic reaction that may result from covalent modification of normal self proteins by reactive drug metabolites. Phenytoin is metabolized by cytochrome P450 (P450) enzymes primarily to 5-(p-hydroxyphenyl-),5-phenylhydantoin (HPPH), which may be further metabolized to a catechol that spontaneously oxidizes to semiquinone and quinone species that covalently modify proteins. The aim of this study was to determine which P450s catalyze HPPH metabolism to the catechol, proposed to be the final enzymatic step in phenytoin bioactivation. Recombinant human P450s were coexpressed with NADPH-cytochrome P450 reductase in Escherichia coli. Novel bicistronic expression vectors were constructed for P450 2C19 and the three major variants of P450 2C9, i.e., 2C9*1, 2C9*2, and 2C9*3. HPPH metabolism and covalent adduct formation were assessed in parallel. P450 2C19 was the most effective catalyst of HPPH oxidation to the catechol metabolite and was also associated with the highest levels of covalent adduct formation. P450 3A4, 3A5, 3A7, 2C9*1, and 2C9*2 also catalyzed bioactivation of HPPH, but to a lesser extent. Fluorographic analysis showed that the major targets of adduct formation in bacterial membranes were the catalytic P450 forms, as suggested from experiments with human liver microsomes. These results suggest that P450 2C19 and other forms from the 2C and 3A subfamilies may be targets as well as catalysts of drug-protein adduct formation from phenytoin.

Establishing a framework for transforming student engagement, success and retention in higher education institutions [Final Report]

The perennial issues of student engagement, success and retention (SESR) in higher education continue to attract attention as key indicators of learning and teaching quality. This project aimed to establish and provide a holistic framework that would allow higher education institutions (HEIs) manage and improve their student engagement and retention strategies and programs. The framework and main project deliverable is a Maturity Model (MM) for Student Engagement, Success and Retention (SESR-MM). The project involved three Australian universities with experience and reputations in SESR activities: Queensland University of Technology (lead institution), the University of Queensland and Griffith University, working cooperatively to develop and trial the project deliverables. Project findings suggest that the SESR-MM has the potential to positively transform the holistic—academic, social and personal—engagement experiences of students in Australian universities, and that the SESR-MM is a useful mechanism for sharing good practice and improving programs designed to enhance the student experience.

Proton-transfer and non-transfer compounds of the multi-purpose drug dapsone [4-(4-Aminophenylsulfonyl)aniline] with 3,5-dinitrosalicylic acid and 5-nitroisophthalic acid

The structures of the compounds from the reaction of the drug dapsone [4-(4-aminophenylsulfonyl)aniline] with 3,5-dinitrosalicylic acid, the salt hydrate [4-(4-aminohenylsulfonyl)anilinium 2-carboxy-4,6-dinitrophenolate monohydrate] (1) and the 1:1 adduct with 5-nitroisophthalic acid [4-(4-aminophenylsulfonyl)aniline 5-nitrobenzene-1,3-dicarboxylic acid] (2) have been determined. Crystals of 1 are triclinic, space group P-1, with unit cell dimensions a = 8.2043(3), b = 11.4000(6), c = 11.8261(6)Å, α = 110.891(5), β = 91.927(3), γ = 98.590(4)deg. and Z = 4. Compound 2 is orthorhombic, space group Pbcn, with unit cell dimensions a = 20.2662(6), b = 12.7161(4), c = 15.9423(5)Å and Z = 8. In 1, intermolecular analinium N-H…O and water O-H…O and O-H…N hydrogen-bonding interactions with sulfone, carboxyl, phenolate and nitro O-atom and aniline N-atom acceptors give a two-dimensional layered structure. With 2, the intermolecular interactions involve both aniline N-H…O and carboxylic acid O-H…O and O-H…N hydrogen bonds to sulfone, carboxyl, nitro and aniline acceptors, giving a three-dimensional network structure. In both structures π--π aromatic ring associations are present.

Learning and development opportunities as a tool for the retention of volunteers : a motivation perspective

The growing reliance on volunteers in Australia has heightened the need for non-profit organisations to retain these valuable resources. However, the current literature on volunteer retention is limited. One potential way volunteers can be retained is by providing learning and development opportunities (LDOs). This study investigates the relationship between volunteer perceptions of LDOs, their motivations for volunteering, and retention. Analyses revealed significant main effects for LDOs and volunteer motivations on retention and several interactive effects demonstrating that LDOs can have differential effects on retention depending on the reasons for volunteering.

Polysubstance use in cannabis users referred for treatment: drug use profiles, psychiatric comorbidity and cannabis-related beliefs

Background: Population-based surveys demonstrate cannabis users are more likely to use both illicit and licit substances, compared with non-cannabis users. Few studies have examined the substance use profiles of cannabis users referred for treatment. Co-existing mental health symptoms and underlying cannabis-related beliefs associated with these profiles remains unexplored. Methods: Comprehensive drug use and dependence severity (Severity of Dependence Scale-Cannabis) data were collected on a sample of 826 cannabis users referred for treatment. Patients completed the General Health Questionnaire, Cannabis Expectancy Questionnaire, Cannabis Refusal Self-Efficacy Questionnaire, and Positive Symptoms and Manic-Excitement subscales of the Brief Psychiatric Rating Scale. Latent class analysis was performed on last month use of drugs to identify patterns of multiple drug use. Mental health comorbidity and cannabis beliefs were examined by identified drug use pattern. Results: A three-class solution provided the best fit to the data: (1) cannabis and tobacco users (n = 176), (2) cannabis, tobacco, and alcohol users (n = 498), and (3) wide-ranging sub- stance users (n = 132). Wide-ranging substance users (3) reported higher levels of cannabis dependence severity, negative cannabis expectancies, lower opportunistic, and emotional relief self-efficacy, higher levels of depression and anxiety and higher manic-excitement and positive psychotic symptoms. Conclusion: In a sample of cannabis users referred for treatment, wide-ranging substance use was associated with elevated risk on measures of cannabis dependence, co-morbid psychopathology, and dysfunctional cannabis cognitions. These findings have implications for cognitive-behavioral assessment and treatment.

Crushed tablets : does the administration of food vehicles and thickened fluids to aid medication swallowing alter drug release?

Purpose. To evaluate the influence of co-administered vehicles on in vitro dissolution in simulated gastric fluid of crushed immediate release tablets as an indicator for potential drug bioavailability compromise. Methods. Release and dissolution of crushed amlodipine, atenolol, carbamazepine and warfarin tablets were tested with six foods and drinks that are frequently used in the clinical setting as mixers for crushed medications (water, orange juice, honey, yoghurt, strawberry jam and water thickened with Easythick powder) in comparison to whole tablets. Five commercial thickening agents (Easythick Advanced, Janbak F, Karicare, Nutilis, Viscaid) at three thickness levels were tested for their effect on the dissolution of crushed atenolol tablets. Results. Atenolol dissolution was unaffected by mixing crushed tablets with thin fluids or food mixers in comparison to whole tablets or crushed tablets in water, but amlodipine was delayed by mixing with jam. Mixing crushed warfarin and carbamazepine tablets with honey, jam or yoghurt caused them to resemble the slow dissolution of whole tablets rather than the faster dissolution of crushed tablets in water or orange juice. Crushing and mixing any of the four medications with thickened water caused a significant delay in dissolution. When tested with atenolol, all types of thickening agents at the greatest thickness significantly restricted dissolution, and products that are primarily based on xanthan gum also delayed dissolution at the intermediate thickness level. Conclusions. Dissolution testing, while simplistic, is a widely used and accepted method for comparing drug release from different formulations as an indicator for in vivo bioavailability. Thickened fluids have the potential to retard drug dissolution when used at the thickest levels. These findings highlight potential clinical implications of the addition of these agents to medications for the purpose of dose delivery and indicate that further investigation of thickened fluids and their potential to influence therapeutic outcomes is warranted.

Preclinical drug development must consider the impact on metastasis

Recently, two landmark reports on antiangiogenic therapy were published: Paez-Ribes and colleagues and Ebos and colleagues . The Board of the Metastasis Research Society (MRS) congratulates the authors for their informative articles that help to explain the puzzle of why antiangiogenic agents have had a relatively minor or no significant impact on patient survival. Using four model systems and several different strategies, these researchers showed that inhibition of angiogenesis reduced primary tumor growth and microvessel density in keeping with many earlier reports, but strikingly, accelerated invasion and metastasis.

Role of intratumoural heterogeneity in cancer drug resistance : molecular and clinical perspectives

Drug resistance continues to be a major barrier to the delivery of curative therapies in cancer. Historically, drug resistance has been associated with over-expression of drug transporters, changes in drug kinetics or amplification of drug targets. However, the emergence of resistance in patients treated with new-targeted therapies has provided new insight into the complexities underlying cancer drug resistance. Recent data now implicate intratumoural heterogeneity as a major driver of drug resistance. Single cell sequencing studies that identified multiple genetically distinct variants within human tumours clearly demonstrate the heterogeneous nature of human tumours. The major contributors to intratumoural heterogeneity are (i) genetic variation, (ii) stochastic processes, (iii) the microenvironment and (iv) cell and tissue plasticity. Each of these factors impacts on drug sensitivity. To deliver curative therapies to patients, modification of current therapeutic strategies to include methods that estimate intratumoural heterogeneity and plasticity will be essential.

Investigating online recognition for blood donor retention : an experiential donor value approach

Recognising that charitable behaviour can be motivated by public recognition and emotional satisfaction, not-for-profit organisations have developed strategies that leverage self-interest over altruism by facilitating individuals to donate conspicuously. Initially developed as novel marketing programs to increase donation income, such conspicuous tokens of recognition are being recognised as important value propositions to nurture donor relationships. Despite this, there is little empirical evidence that identifies when donations can be increased through conspicuous recognition. Furthermore, social media’s growing popularity for self-expression, as well as the increasing use of technology in donor relationship management strategies, makes an examination of virtual conspicuous tokens of recognition in relation to what value donors seek particularly insightful. Therefore, this research examined the impact of experiential donor value and virtual conspicuous tokens of recognition on blood donor intentions. Using online survey data from 186 Australian blood donors, results show that in fact emotional value is a stronger predictor of intentions to donate blood than altruistic value, while social value is the strongest predictor of intentions if provided with recognition. Clear linkages between dimensions of donor value (altruistic, emotional and social) and conspicuous donation behaviour (CDB) were identified. The findings provide valuable insights into the use of conspicuous donation tokens of recognition on social media, and contribute to our understanding into the under-researched areas of donor value and CDB.

Salaries, recruitment, and retention for CRNA faculty - Part 1

The nature of differences in salaries between academic faculty and Certified Registered Nurse Anesthetists (CRNAs) working in clinical positions using recently collected data are explored. The differences in median salaries among program directors, assistant program directors, academic faculty, and clinical faculty are large. Furthermore, survey results imply that the most important barrier to recruiting teaching faculty is salary differentials. Part 1 of this 2-part column discusses salaries, recruitment, and retention of CRNA faculty; Part 2, to be published in the June 2008 issue, will focus on clinical faculty contributions to the education of CRNAs.

Relationship between expectation management and client retention in online Cognitive Behavioural Therapy

Background Engaging clients from the outset of psychotherapy is important for therapeutic success. However, there is little research evaluating therapists’ initial attempts to engage clients. This article reports retrospective analysis of data from a trial of online Cognitive Behavioural Therapy (CBT) for depression. Qualitative and quantitative methods were used to evaluate how therapists manage clients’ expectations at the outset of therapy and its relationship with client retention in the therapeutic intervention. Aims To develop a system to codify expectation management in initial sessions of online CBT and evaluate its relationship with retention. Method Initial qualitative research using conversation analysis identified three different communication practices used by therapists at the start of first sessions: no expectation management, some expectation management, and comprehensive expectation management. These findings were developed into a coding scheme that enabled substantial inter-rater agreement (weighted Kappa = 0.78; 95% CI: 0.52 to 0.94) and was applied to all trial data. Results Adjusting for a range of client variables, primary analysis of data from 147 clients found comprehensive expectation management was associated with clients remaining in therapy for 1.4 sessions longer than those who received no expectation management (95% CI: -0.2 to 3.0). This finding was supported by a sensitivity analysis including an additional 21 clients (1.6 sessions, 95% CI: 0.2 to 3.1). Conclusions Using a combination of qualitative and quantitative methods, this study suggests a relationship between expectation management and client retention in online CBT for depression, which has implications for professional practice. A larger prospective study would enable a more precise estimate of retention.

The -Omics in drug development

New advancement in genomics, proteomics, and metabonomics created significant excitement about the use of these relatively new technologies in drug design, discovery, development, and molecular-targeted therapeutics by identifying new drug targets and better tools for safety and efficacy studies in preclinical and clinical stages of drug development as well as diagnostics. In this chapter, we will briefly discuss the application of genomics, proteomics, and metabonomics in drug discovery and development