Comparative physicochemical and pharmacokinetic profiles of inhaled beclomethasone dipropionate and budesonide

AbstractThe physicochemical and pharmacokinetic characteristics of BDP and budesonide are somewhat different, but the overall result is that both are well suited for use as inhaled corticosteroids. Both BDP and budesonide are metabolized primarily by the liver, with one of the metabolites of BDP, 17-BMP, having greater receptor affinity than either the parent compound or budesonide, which has no active metabolites. BDP has a lower water solubility than either 17-BMP or budesonide, which have similar water solubilities. Budesonide has lower oral bioavailability than BDP; however, it is generally reported to have a longer plasma half-life than either BDP or 17-BMP. The physicochemical and pharmacokinetic profiles of inhaled BDP and budesonide provide both compounds with a favourable ratio of topical to systemic effects and support their well-established role in the treatment of asthma. The device used to deliver an inhaled corticosteroid influences the lung deposition of the drug and selection of the device should be made with an understanding of the particular advantages and disadvantages of the device for each individual patient

Catecholamines and Hepatic Drug Metabolism

The thesis embodies work designed to investigate the acute effects of catecholamines on the hepatic metabolism of foreign compounds. Most of the studies were performed on the isolated perfused liver of the rat. The historical development of the techniques used in the perfusion of the liver is reviewed. The literature concerning the properties of the hepatic mixed function system responsible for the metabolism of foreign compounds has been reviewed. Previous work on the effects of catecholamines on drug metabolism is also discussed. The operative procedure and the technique for the perfusion of the liver were developed to enable rapid transfer of the liver to the perfusion chamber without a period of anoxia, which has characterised many previous attempts at perfusion of the liver. The liver was perfused with a semisynthetic medium. The viability of the liver was assessed by a variety of tests of biochemical and physiological function and by histological examination. The technique developed allowed the liver to be successfully perfused for periods of up to 6 h, whilst maintaining a functional integrity. The metabolism of the type I and the type II substrates, hexobarbitone and aniline respectively, were investigated. Hexobarbitone is removed by a first order reaction at a rate comparable to that previously reported for the liver in vivo. Aniline metabolism, which has not previously been investigated in the perfused liver, was studied in some detail. Aniline is removed biphasically from the perfusion medium. Half of the aniline removed is converted to an acid-labile conjugate, possibly aniline-N-glucuronide, and a further 25% is converted to p-aminophenol and its conjugates. 3H-aniline added to the perfused liver could be quantitatively accounted for after 3 h perfusion. In agreement with previous findings, it was found that p-aminophenol reacts with haemoglobin, thus making it impossible to detect free p-aminophenol in the perfusion medium. The differences between the pattern of aniline metabolism by the perfused liver and by the whole animal, where aniline is excreted mainly as p-aminophenol and its conjugates, are discussed. The kinetics of aniline removal have been analysed by curve stripping and model fitting. The mathematics of these procedures are described separately in Appendix II. In the perfused liver aniline is distributed throughout a two-compartment system. The first compartment probably represents the total aqueous phase and aniline is removed from this compartment only. The identity of the second compartment is less certain. Several possibilities are discussed and in view of evidence obtained with SKF 525-A, an inhibitor of drug metabolism, it is suggested that the second compartment may represent the binding of aniline to a non-metabolic site of cytochrome P-450. Both adrenaline and noradrenaline inhibit the metabolism of hexobarbitone by the perfused liver but neither catecholamine has any effect on the metabolism of aniline. Catecholamines do not inhibit the metabolism of either aniline or hexobarbitone by the microsomal fraction or by liver slices. It was thus concluded that catecholamines are not inhibiting hexobarbitone removal directly. The possibility that their effect is mediated by cyclic AMP, a compound reported to inhibit hexobarbitone metabolism by the perfused liver, was investigated. Papaverine, an inhibitor Of phosphodiesterase, does not potentiate the inhibitory effects of catecholamines on hexobarbitone metabolism, nor does it cause them to have any inhibitory effect on the metabolism of aniline. Cyclic AMP was shown to inhibit drug metabolism by liver slices, whereas catecholamines are without effect. The probability that cyclic AMP is not important in mediating the effects of catecholamines on drug metabolism is discussed in some detail. Both catecholamines increase the portal pressure in the -perfused liver by over 100%. When Ca2+ is omitted from the perfusion medium it was found that this pressor effect is almost totally inhibited. Catecholamines also no longer in- hibit the metabolism of hexobarbitone. The omission of Ca2+ leaves the metabolic effects of catecholamines relatively unaffected. It was thus suggested that catecholamines might be inhibiting hexobarbitone metabolism through an effect on the hepatic vasculature. In a constant flow system, as used in this study, one way in which such an effect of catecholamines might manifest itself is as a redistribution of perfusate through the liver. It was found that considerable controversy exists as to whether or not catecholamines can cause a redistribution of blood flow within the liver. The available evidence is assessed separately in Appendix II. The effects of adrenaline on the intrahepatic distribution of perfusate have been investigated by X-radiography, and by perfusing the liver with Indian ink followed by histology. It was concluded from these studies that catecholamines can cause a redistribution of blood flow within the liver, away from the periphery of the lobes towards more central regions. (Abstract shortened by ProQuest.)

Treatment and removal strategies for estrogens from wastewater

Natural and synthetic steroidal estrogens (estrone, 17β-estradiol and 17α-ethinylestradiol) are endocrine disrupters, that are discharged consistently from the sewage treatment works into surface waters, thereby causing endocrine disrupting effects to aquatic organisms at trace concentrations (nanogram per litre). Several years of research have been focused on their fate, behaviour and removal in the environment but primarily in the sewage treatment works which acts as a sink for these compounds. This review attempts to summarize the factors involved in the removal of these chemicals from the sewage treatment works. Biological processes, and to a limited extent physio-chemical properties, play a vital role in the endocrinal deactivation of which these compounds. The efficiency of these processes is highly dependent on operating parameters (such as sludge retention time, redox potential, etc) that govern the secondary treatment process of a functional sewage treatment works. Although advanced treatment technologies are available, cost and operational considerations do not make them a sustainable solution

Towards a formative assessment of classroom competencies (FACCs) for postgraduate medical trainees

Background An assumption of clinical competency is no longer acceptable or feasible in routine clinical practice. We sought to determine the feasibility, practicability and efficacy of undertaking a formal assessment of clinical competency for all postgraduate medical trainees in a large NHS foundation trust. Methods FY1 doctors were asked to complete a questionnaire to determine prior experience and self reported confidence in performing the GMC core competencies. From this a consensus panel of key partners considered and developed an 8 station Objective Structured Clinical Examination (OSCE) circuit to assess clinical competencies in all training grade medical staff... The OSCE was then administered to all training grade doctors as part of their NHS trust induction process. Results 106 (87.6% of all trainees) participated in the assessment during the first 14 days of appointment. Candidates achieved high median raw percentage scores for the majority of stations however analysis of pre defined critical errors and omissions identified important areas for concern. Performance of newly qualified FY1 doctor was significantly better than other grades for the arterial blood gas estimation and nasogastric tube insertion stations. Discussion Delivering a formal classroom assessment of clinical competencies to all trainees as part of the induction process was both feasible and useful. The assessment identified areas of concern for future training and also served to reassure as to the proficiency of trainees in undertaking the majority of core competencies

Defective spermatogenesis: Martin et al. respond

This is an Open Access article - Copyright @ National Institute of Environmental Health Science.BACKGROUND: Male reproductive tract abnormalities such as hypospadias and cryptorchidism, and testicular cancer have been proposed to comprise a common syndrome together with impaired spermatogenesis with a common etiology resulting from the disruption of gonadal development during fetal life, the testicular dysgenesis syndrome (TDS). The hypothesis that in utero exposure to estrogenic agents could induce these disorders was first proposed in 1993. The only quantitative summary estimate of the association between prenatal exposure to estrogenic agents and testicular cancer was published over 10 years ago, and other systematic reviews of the association between estrogenic compounds, other than the potent pharmaceutical estrogen diethylstilbestrol (DES), and TDS end points have remained inconclusive. OBJECTIVES: We conducted a quantitative meta-analysis of the association between the end points related to TDS and prenatal exposure to estrogenic agents. Inclusion in this analysis was based on mechanistic criteria, and the plausibility of an estrogen receptor (ER)-α–mediated mode of action was specifically explored. RESULTS: We included in this meta-analysis eight studies investigating the etiology of hypospadias and/or cryptorchidism that had not been identified in previous systematic reviews. Four additional studies of pharmaceutical estrogens yielded a statistically significant updated summary estimate for testicular cancer. CONCLUSIONS: The doubling of the risk ratios for all three end points investigated after DES exposure is consistent with a shared etiology and the TDS hypothesis but does not constitute evidence of an estrogenic mode of action. Results of the subset analyses point to the existence of unidentified sources of heterogeneity between studies or within the study population

Increased Expression of Histone Proteins during Estrogen-Mediated Cell Proliferation

There is concern about the potential risk posed by compounds with estrogen-like activity present in the environment. As previous studies have shown that combined exposure to such compounds results in dose additivity, it should be possible to assess estrogen exposure with suitable biomarkers of effect

Acute appendicitis presenting as small bowel obstruction: two case reports

Acute appendicitis is a common surgical problem however the diagnosis is often overlooked when it presents as a small bowel obstruction. In this report we present two cases of elderly patients who presented with small bowel obstruction and raised inflammatory markers. Both patients were successfully treated with a laparotomy, adhesiolysis and appendicectomy and went on to make a good recovery

Fate and occurrence of alkylphenolic compounds in sewage sludges determined by liquid chromatography tandem mass spectrometry

This is the author's accepted manuscript. The final published article is available from the link below. Copyright @ 2009 Taylor & Francis.An analytical method has been developed and applied to determine the concentrations of the nonionic alkylphenol polyethoxylate surfactants and their metabolites, alkylphenoxy carboxylates and alkyphenols, in sewage sludges. The compounds were extracted with methanol/acetone (1:1 v/v) from sludge, and concentrated extracts were cleaned by silica solid‐phase extraction prior to determination by liquid chromatography tandem mass spectrometry. The recoveries, determined by spiking sewage sludge at two concentrations, ranged from 51% to 89% with method detection limits from 6 µg kg−1 to 60 µg kg−1. The methodology was subsequently applied to sludge samples obtained from a carbonaceous activated sludge plant, a nitrifying/denitrifying activated sludge plant and a nitrifying/denitrifying activated sludge plant with phosphorus removal. Concentrations of nonylphenolic compounds were two to three times higher than their octyl analogues. Long‐chain nonylphenol polyethoxylates (NP3–12EO) ranged from 16 µg kg−1 to 11754 µg kg−1. The estrogenic metabolite nonylphenol was present at concentrations ranging from 33 µg kg−1 to 6696 µg kg−1.Public Utilities Board of Singapore, Thames Water and Yorkshire Water

A framework for cumulative risk assessment in the 21st century

The ILSI Health and Environmental Sciences Institute (HESI) has developed a framework to support a transition in the way in which information for chemical risk assessment is obtained and used (RISK21). The approach is based on detailed problem formulation, where exposure drives the data acquisition process in order to enable informed decision-making on human health safety as soon as sufficient evidence is available. Information is evaluated in a transparent and consistent way with the aim of optimizing available resources. In the context of risk assessment, cumulative risk assessment (CRA) poses additional problems and questions that can be addressed using the RISK21 approach. The focus in CRA to date has generally been on chemicals that have common mechanisms of action. Recently, concern has also been expressed about chemicals acting on multiple pathways that lead to a common health outcome, and non-chemical other conditions (non-chemical stressors) that can lead to or modify a common outcome. Acknowledging that CRAs, as described above, are more conceptually, methodologically and computationally complex than traditional single-stressor risk assessments, RISK21 further developed the framework for implementation of workable processes and procedures for conducting assessments of combined effects from exposure to multiple chemicals and non-chemical stressors. As part of the problem formulation process, this evidence-based framework allows the identification of the circumstances in which it is appropriate to conduct a CRA for a group of compounds. A tiered approach is then proposed, where additional chemical stressors and/or non-chemical modulating factors (ModFs) are considered sequentially. Criteria are provided to facilitate the decision on whether or not to include ModFs in the formal quantitative assessment, with the intention to help focus the use of available resources to have the greatest potential to protect public health

PGC-1α controls mitochondrial biogenesis and dynamics in lead-induced neurotoxicity

Due to its role in regulation of mitochondrial function, PGC1α is emerging as an important player in ageing and neurodegenerative disorders. PGC1α exerts its neuroprotective effects by promoting mitochondrial biogenesis (MB) and functioning. However, the precise regulatory role of PGC1α in the control of mitochondrial dynamics (MD) and neurotoxicity is still unknown. Here we elucidate the role of PGC1α in vitro and in vivo in the regulatory context of MB and MD in response to lead (II) acetate as a relevant model of neurotoxicity. We show that there is an adaptive response (AR) to lead, orchestrated by the BAP31-calcium signalling system operating between the ER and mitochondria. We find that this hormetic response is controlled by a cell-tolerated increase of PGC1α expression, which in turn induces a balanced expression of fusion/fission genes by binding to their promoters and implying its direct role in regulation of MD. However, dysregulation of PGC1α expression through either stable downregulation or overexpression, renders cells more susceptible to lead insult leading to mitochondrial fragmentation and cell death. Our data provide novel evidence that PGC1α expression is a key regulator of MD and the maintenance of tolerated PGC1α expression may offer a promising strategy for neuroprotective therapies.España Ministerio de Economía y Competitividad SAF2012-3902