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...

A needle in a haystack : the use of routinely collected emergency department injury surveillance data to help identify physical child abuse

A retrospective, descriptive analysis of a sample of children under 18 years presenting to a hospital emergency department (ED) for treatment of an injury was conducted. The aim was to explore characteristics and identify differences between children assigned abuse codes and children assigned unintentional injury codes using an injury surveillance database. Only 0.1% of children had been assigned the abuse code and 3.9% a code indicating possible abuse. Children between 2-5 years formed the largest proportion of those coded to abuse. Superficial injury and bruising were the most common types of injury seen in children in the abuse group and the possible abuse group (26.9% and 18.8% respectively), whereas those with unintentional injury were most likely to present with open wounds (18.4%). This study demonstrates that routinely collected injury surveillance data can be a useful source of information for describing injury characteristics in children assigned abuse codes compared to those assigned no abuse codes.

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.

Comprehensive Addictive Behaviors and Disorders, Volume 1 : Principles of Addiction

"Principles of Addiction provides a solid understanding of the definitional and diagnostic differences between use, abuse, and disorder. It describes in great detail the characteristics of these syndromes and various etiological models. The book's three main sections examine the nature of addiction, including epidemiology, symptoms, and course; alcohol and drug use among adolescents and college students; and detailed descriptions of a wide variety of addictive behaviors and disorders, encompassing not only drugs and alcohol, but caffeine, food, gambling, exercise, sex, work, social networking, and many other areas. This volume is especially important in providing a basic introduction to the field as well as an in-depth review of our current understanding of the nature and process of addictive behaviors. Principles of Addiction is one of three volumes comprising the 2,500-page series, Comprehensive Addictive Behaviors and Disorders. This series provides the most complete collection of current knowledge on addictive behaviors and disorders to date. In short, it is the definitive reference work on addictions."--publisher website

Comprehensive Addictive Behaviors and Disorders, Volume 2 : Biological Research on Addiction

"Biological Research on Addiction examines the neurobiological mechanisms of drug use and drug addiction, describing how the brain responds to addictive substances as well as how it is affected by drugs of abuse. The book's four main sections examine behavioral and molecular biology; neuroscience; genetics; and neuroimaging and neuropharmacology as they relate to the addictive process. This volume is especially effective in presenting current knowledge on the key neurobiological and genetic elements in an individual's susceptibility to drug dependence, as well as the processes by which some individuals proceed from casual drug use to drug dependence. Biological Research on Addiction is one of three volumes comprising the 2,500-page series, Comprehensive Addictive Behaviors and Disorders. This series provides the most complete collection of current knowledge on addictive behaviors and disorders to date. In short, it is the definitive reference work on addictions."--publisher website

Church's wall of silence on sexual abuse

A SINGLE document was all it took to illuminate a dark secret in the Church of England. The two-page child protection report, unearthed by police in the archives of the diocese of Manchester, was proof, at last, that a former cathedral choirboy -- alleging years of sexual abuse by one of Britain's most senior clergyman -- was not alone. There was another boy. Also a solo soprano, on the other side of the world, who was singing from the same hymn sheet about The Very Reverend Robert Waddington. "There had been a previous referral about sexual impropriety some time ago from Australia, where RW had been the headmaster at a school. An ex-pupil had made a complaint to the Bishop of (north) Queensland who had relayed it to the Archbishop (of York)," the 2003 report says. Eli Ward's family had prompted the secret report when they told church officials, without Ward's knowledge, of the alleged abuse he suffered in the mid-1980s.

Former Archbishop of York ‘covered up’ sex abuse scandal

The former Archbishop of York stood accused last night of covering up allegations that a senior Church of England clergyman had abused choirboys and school pupils. Lord Hope of Thornes was made aware of the accusations against the Very Rev Robert Waddington, a former Dean of Manchester Cathedral and once the cleric in overall charge of Church schools, in 1999 and again in 2003. Waddington was stripped of his right to conduct church services but the archbishop did not report concerns about alleged past abuse or a potential continuing threat to children to police or child protection agencies. The extent of Waddington’s alleged history of abuse and the Church’s inaction has been revealed through a joint investigation by The Times and The Australian newspaper in Sydney.

UK church orders abuse inquiry

THE Church of England has ordered a formal independent investigation into the handling of child-sex allegations against a senior clergyman in Australia and Britain. Archbishop of York John Sentamu at the weekend commissioned the high-level inquiry into the alleged child sex abuse in the 1960s and 80s by the late Reverend Robert Waddington, and the church's response to complaints over the past 15 years. It comes as the head of Australia's Anglican Church, Archbishop Phillip Aspinall, flew to north Queensland to meet the region's bishop over the revelations, which centre on Waddington's stint as principal of St Barnabas boarding school at Ravenshoe, west of Cairns, and later as dean of Manchester.

St Barnabas abuse allegations build up

MORE victims have made child-sex allegations against senior Anglican clergymen at a shut-down north Queensland boarding school, as church officials confirmed they had sat on a 2004 report about complaints from Britain into one of the suspected serial abusers. Former students Mark McClintock and Greg Shaw have this week come forward with allegations against Robert Waddington, headmaster at St Barnabas boarding school, in Ravenshoe southwest of Cairns, in the 1960s. Waddington later returned to Britain and rose to become head of education for the Church of England and Dean of Manchester. Another former student at St Barnabas, who does not want to be named, also contacted The Weekend Australian with allegations of abuse in the 60s by former Anglican brother Peter Gilbert, who was hired by Waddington and jailed in 2006 for child-sex offences in South Australia.

Robert Waddington's cycle of abuse stretches beyond 50 years

THE Church of England banished serial pedophile priest Robert Waddington to Australia, where he abused children across a decade, after suspicions were raised about him molesting choirboys in his London parish. In an alleged church cover-up spanning almost 60 years, Waddington was suddenly and unexpectedly sent to a small school in regional Queensland in 1956 amid claims he was molesting the son of an English politician. Last month the Church of England ordered an independent inquiry into the handling of allegations against Waddington, after a joint investigation by The Australian and The Times of London. But it can now be revealed that Waddington - who died in 2007, facing allegations he abused students in Australia in the 1960s and English choirboys in the 80s and 90s - was molesting children as soon as he joined the church in 1953. The latest allegations have been made by Ray Munn, 70, who was recruited by Waddington, then a curate at St John's church in Bethnal Green, East London, to sing in the choir in 1953. He was almost immediately groomed by the Cambridge University-educated clergyman, who took him on holidays in the English countryside, before he began molesting the then 11-year-old.

Anglican Church fails to report abuse

Evidence has emerged that the Anglican Church in Britain failed to alert police about a senior member of the clergy who's alleged to have abused children in both the Britain and Australia. Anglican Priest Reverend Robert Waddington was principal of a school in North Queensland in 1960s. He went on to become the Dean of Manchester, but he died five years ago. Allegations of abuse reached the Anglican Church in England in the late 1990s - but no action was taken. The diocese of North Queensland has begun its own investigation but it seems crucial documents may have been lost.

Woman abuse in Canada : sociological reflections on the past, suggestions for the future

Woman abuse in Canada started receiving much sociological attention in the mid-1980s. This article describes past scholarly achievements, assesses current contributions, and suggests progressive ways of responding to future challenges. Special attention is given to how broader political economic forces help shape and constrain research on a variety of highly injurious male-to-female assaults that occur in private settings.

Bayesian imputation of non-chosen attribute values in revealed preference surveys

Obtaining attribute values of non-chosen alternatives in a revealed preference context is challenging because non-chosen alternative attributes are unobserved by choosers, chooser perceptions of attribute values may not reflect reality, existing methods for imputing these values suffer from shortcomings, and obtaining non-chosen attribute values is resource intensive. This paper presents a unique Bayesian (multiple) Imputation Multinomial Logit model that imputes unobserved travel times and distances of non-chosen travel modes based on random draws from the conditional posterior distribution of missing values. The calibrated Bayesian (multiple) Imputation Multinomial Logit model imputes non-chosen time and distance values that convincingly replicate observed choice behavior. Although network skims were used for calibration, more realistic data such as supplemental geographically referenced surveys or stated preference data may be preferred. The model is ideally suited for imputing variation in intrazonal non-chosen mode attributes and for assessing the marginal impacts of travel policies, programs, or prices within traffic analysis zones.

Bad apples, bad barrel: Exploring institutional responses to child sexual abuse by Catholic clergy in Australia

This paper considers constructions of institutional culture and power in the cover-up of child sexual abuse (CSA) by clergy in the Roman Catholic Church of Australia. The issue of cover-up has previously been considered in international inquiries as an institutional failing that has caused significant harm to victims of CSA by Catholic Clergy. Evidence given by select representatives of the Catholic Church in two government inquiries into institutional abuse carried out in Australia is considered here. This evidence suggests that, where cover-up has occurred, it has been reliant on the abuse of institutional power and resulted in direct emotional, psychological and spiritual harm to victims of abuse. Despite international recognition of cover-up as institutional abuse, evidence presented by Roman Catholic Representatives to the Victorian Inquiry denied there was an institutionalised cover-up. Responding to this evidence, this paper queries whether the primary foundation of cover-up conforms to the ‘bad apple theory’ in that it relates only to a few individuals, or the ‘bad barrel theory’ of institutional structure and culture.