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.

Loss reduction experiences in electric power distribution companies of Iran

The experiences of the loss reduction projects in electric power distribution companies (EPDCs) of Iran are presented. The loss reduction methods, which are proposed individually by 14 EPDCs, corresponding energy saving (ES), Investment costs (IC), and loss rate reductions are provided. In order to illustrate the effectiveness and performance of the loss reduction methods, three parameters are proposed as energy saving per investment costs (ESIC), energy saving per quantity (ESPQ), and investment costs per quantity (ICPQ). The overall ESIC of 14 EPDC as well as individual average and standard deviation of the EISC for each method is presented and compared. In addition, the average and standard deviation of the ESPQs and ICPQs for the loss reduction methods, individually, are provided and investigated. These parameters are useful for EPDCs that intend to reduce the electric losses in distribution networks as a benchmark and as a background in the planning purposes.

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.

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.

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

Examining corporate governance disclosures of listed companies in Fiji

In 2009, the Capital Markets Development Authority (CMDA) - Fiji’s capital market regulator - introduced the Code of Corporate Governance (the Code). The Code is ‘principle-based’ and requires companies listed on the South Pacific Stock Exchange (SPSE) and the financial intermediaries to disclose their compliance with the Code’s principles. While compliance with the Code is mandatory, the nature and extent of disclosure is at the discretion of the complying entities. Agency theory and signalling theory suggest that firms with higher expected levels of agency costs will provide greater levels of voluntary disclosures as signals of strong corporate governance. Thus, the study seeks to test these theories by examining the heterogeneity of corporate governance disclosures by firms listed on SPSE, and determining the characteristics of firms that provide similar levels of disclosures. We conducted a content analysis of corporate governance disclosures on the annual reports of firms from 2008-2012. The study finds that large, non-family owned firms with high levels of shareholder dispersion provide greater quantity and higher quality corporate governance disclosures. For firms that are relatively smaller, family owned and have low levels of shareholder dispersion, the quantity and quality of corporate governance disclosures are much lower. Some of these firms provide boilerplate disclosures with minimal changes in the following years. These findings support the propositions of agency and signalling theory, which suggest that firms with higher separation between agents and principals will provide more voluntary disclosures to reduce expected agency costs transfers. Semi-structured interviews conducted with key stakeholders further reinforce the findings. The interviews also reveal that complying entities positively perceive the introduction of the Code. Furthermore, while compliance with Code brought about additional costs, they believed that most of these costs were minimal and one-off, and the benefits of greater corporate disclosure to improve user decision making outweighed the costs. The study contributes to the literature as it provides insight into the experience of a small capital market with introducing a ‘principle-based’ Code that attempts to encourage corporate governance practices through enhanced disclosure. The study also assists policy makers better understand complying entities’ motivations for compliance and the extent of compliance.

Proteins, drug targets and the mechanisms they control : the simple truth about complex networks

Realizing the promise of molecularly targeted inhibitors for cancer therapy will require a new level of knowledge about how a drug target is wired into the control circuitry of a complex cellular network. Here we review general homeostatic principles of cellular networks that enable the cell to be resilient in the face of molecular perturbations, while at the same time being sensitive to subtle input signals. Insights into such mechanisms may facilitate the development of combination therapies that take advantage of the cellular control circuitry, with the aim of achieving higher efficacy at a lower drug dosage and with a reduced probability of drug-resistance development.

The True Cost of Greenhouse Gas Emissions: Analysis of 1,000 Global Companies

This study elucidated the shadow price of greenhouse gas (GHG) emissions for 1,024 international companies worldwide that were surveyed from 15 industries in 37 major countries. Our results indicate that the shadow price of GHG at the firm level is much higher than indicated in previous studies. The higher shadow price was found in this study as a result of the use of Scope 3 GHG emissions data. The results of this research indicate that a firm would carry a high cost of GHG emissions if Scope 3 GHG emissions were the focus of the discussion of corporate social responsibility. In addition, such shadow prices were determined to differ substantially among countries, among sectors, and within sectors. Although a number of studies have calculated the shadow price of GHG emissions, these studies have employed country-level or industry-level data or a small sample of firm-level data in one country. This new data from a worldwide firm analysis of the shadow price of GHG emissions can play an important role in developing climate policy and promoting sustainable development.

Examining the cost efficiency of Chinese hydroelectric companies using a finite mixture model

This paper evaluates the operational activities of Chinese hydroelectric power companies over the period 2000-2010 using a finite mixture model that controls for unobserved heterogeneity. In so doing, a stochastic frontier latent class model, which allows for the existence of different technologies, is adopted to estimate cost frontiers. This procedure not only enables us to identify different groups among the hydro-power companies analysed, but also permits the analysis of their cost efficiency. The main result is that three groups are identified in the sample, each equipped with different technologies, suggesting that distinct business strategies need to be adapted to the characteristics of China's hydro-power companies. Some managerial implications are developed. © 2012 Elsevier B.V.

Contributions of the private sector to global biodiversity protection: case study of the Fortune 500 companies

Since the inception of the UN Convention on Biological Diversity (CBD) in 1992, little progress has been achieved in terms of involving the business community in protecting biological diversity worldwide. This article assesses the current activities of US Fortune 500 companies with respect to global biodiversity protection and the goals of the CBD. Data and information collected from 500 companies within eight major industrial sectors were further categorized at the company level to assess each company's involvement in global biodiversity protection. Our findings show that although companies' business profiles highly influence their decision-making process regarding the adoption of biodiversity protection policies and measures, their revenue profiles are less influential. We show that despite generating low revenues, companies in the utility sector are more active in the adoption of biodiversity protection policy than those in the financial sector, which generate high revenues. This study also demonstrates that companies must be convinced of the major effects of biodiversity loss on their bottom lines to be motivated to protect biological diversity. Companies' business and business-related risk profiles can also influence the adoption of biodiversity protection policies within the company. The study further demonstrates that a measurable biodiversity impact indicator is necessary for the companies to get seriously involved in the mitigation action. Finally, this study proposes a three-step biodiversity loss mitigation action framework that is drawn upon the assessment of the 500 companies that can contribute to develop an elaborative framework of business sector-specific mitigation plan. © 2013 Copyright Taylor and Francis Group, LLC.