Noise-induced hearing loss - An examination of the methods of assessment in a cross-sectional study of 87 industrial workers.

OBJECTIVES: The surveillance of noise-induced hearing loss (NIHL) according to the Health and Safety Executive (HSE) differs from the medico-legal criteria used to assess NIHL. Our study compares the two systems and proposes a novel method of simplifying the medico-legal criteria and applying it to ascertain noise-induced hearing loss. DESIGN: The anonymised audiograms of a group of 87 industrial workers from a single site were analysed with both methods. RESULTS: The comparison showed approximately one-third of the workers assessed in this study had their noise-induced hearing loss underestimated by the HSE criteria. The majority of these individuals were over 40 years of age. CONCLUSIONS: The HSE criteria for noise-induced hearing loss need review and re-alignment with the medico-legal criteria to address the discrepancy between the two systems.

A survey on IVIVC/IVIVR development in the pharmaceutical industry - Past experience and current perspectives.

The present work aimed to describe the current status of IVIVC/IVIVR development in the pharmaceutical industry, focusing on the use and perception of specific approaches as well as successful and failed case studies. Two questionnaires have been distributed to 13 EFPIA partners of the Oral Biopharmaceutics Tools Initiative and to the Pharmacokinetics Working Party of the European Medicines Agency in order to capture the perspectives and experiences of industry scientists and agency members, respectively. Responses from ten companies and three European Agencies were received between May 21st 2014 and January 19th 2016. The majority of the companies acknowledged the importance of IVIVC/IVIVR throughout the drug development stages and a well-balanced rate of return on investment. However, the IVIVC/IVIVR approach seemed to be underutilized in regulatory submissions. Four of the ten companies stated to have an internal guidance related to IVIVC/IVIVR modelling, whereas three felt that an overall strategy is not necessary. Successful models mainly served to support formulation development and to provide a better mechanistic understanding. There was not yet much experience with safe-space IVIVRs as well as the use of physiologically based modelling in the field of IVIVC. At the same time, the responses from both industry and agencies indicated that there might be a need for a regulatory framework to guide the application of these novel approaches. The relevance of IVIVC/IVIVR for oral IR drug products was recognized by most of the companies. For IR formulations, relationships other than Level A correlation were more common outcomes among the provided case studies, such as multiple Level C correlation or safe-space IVIVR, which could be successfully used for requesting regulatory flexibility. Compared to the responses from industry scientists, there was a trend towards a higher appreciation of the BCS among the regulators, but a less positive attitude towards the utility of non-compendial dissolution methods for establishing a successful IVIVC/IVIVR. The lack of appropriate in vivo data and regulatory uncertainty were considered the major difficulties in IVIVC/IVIVR development. The results of this survey provide unique insights into current IVIVC/IVIVR practices in the pharmaceutical industry. Pursuing an IVIVC/IVIVR should be generally encouraged, considering its high value from both industry and regulators' perspective.

Comparison of distortion product otoacoustic emissions and pure tone audiometry in occupational screening for auditory deficit due to noise exposure.

OBJECTIVE: To examine whether distortion product otoacoustic emissions can serve as a replacement for pure tone audiometry in longitudinal screening for occupational noise exposure related auditory deficit. METHODS: A retrospective review was conducted of pure tone audiometry and distortion product otoacoustic emission data obtained sequentially during mandatory screening of brickyard workers (n = 16). Individual pure tone audiometry thresholds were compared with distortion product otoacoustic emission amplitudes, and a correlation of these measurements was conducted. RESULTS: Pure tone audiometry threshold elevation was identified in 13 out of 16 workers. When distortion product otoacoustic emission amplitudes were compared with pure tone audiometry thresholds at matched frequencies, no evidence of a robust relationship was apparent. Seven out of 16 workers had substantial distortion product otoacoustic emissions with elevated pure tone audiometry thresholds. CONCLUSION: No clinically relevant predictive relationship between distortion product otoacoustic emission amplitude and pure tone audiometry threshold was apparent. These results do not support the replacement of pure tone audiometry with distortion product otoacoustic emissions in screening. Distortion product otoacoustic emissions at frequencies associated with elevated pure tone audiometry thresholds are evidence of intact outer hair cell function, suggesting that sites distinct from these contribute to auditory deficit following ototrauma.

Downstream processing of polymer-based amorphous solid dispersions to generate tablet formulations.

Application of amorphous solid dispersions (ASDs) is considered one of the most promising approaches to increase the dissolution rate and extent of bioavailability of poorly water soluble drugs. Such intervention is often required for new drug candidates in that enablement, bioavailability is not sufficient to generate a useful product. Importantly, tableting of ASDs is often complicated by a number of pharmaceutical and technological challenges including poor flowability and compressibility of the powders, compression-induced phase changes or phase separation and slow disintegration due to the formation of a gelling polymer network (GPN). The design principles of an ASD-based system include its ability to generate supersaturated systems of the drug of interest during dissolution. These metastable solutions can be prone to precipitation and crystallization reducing the biopharmaceutical performance of the dosage form. The main aim of the research in this area is to maintain the supersaturated state and optimally enhance bioavailability, meaning that crystallization should be delayed or inhibited during dissolution, as well as in solid phase (e.g., during manufacturing and storage). Based on the expanding use of ASD technology as well as their downstream processing, there is an acute need to summarize the results achieved to this point to better understand progress and future risks. The aim of this review is to focus on the conversion of ASDs into tablets highlighting results from various viewpoints.

Use of a population pharmacokinetic approach for the clinical development of a fixed-dose subcutaneous formulation of trastuzumab.

A new subcutaneous (s.c.) trastuzumab formulation provides savings in terms of time and is preferred by patients and health care professionals relative to standard intravenous (i.v.) administration due to simpler and more rapid administration (2-5 minutes). Selection of the s.c. dose was based on a pharmacokinetic bridging approach that aimed to achieve noninferior trastuzumab serum trough concentrations (Ctrough) vs. reference i.v. administration. Using population modeling and simulation, we showed that a fixed 600-mg trastuzumab s.c. dose, administered thrice-weekly (Q3W) without a loading dose, would provide Ctrough (predose Cycle 8) and area under the time-concentration curve (AUC0-21 days, Cycle 7) at least as high as Q3W i.v. administration. The model was retrospectively validated using observed pharmacokinetic data from an independent phase III study of (neo)adjuvant trastuzumab (HannaH). These results provide a strong pharmacokinetic rationale for the trastuzumab s.c. 600-mg fixed dose, supported by the noninferior efficacy of this regimen vs. reference i.v. administration.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e87; doi:10.1038/psp.2013.63; advance online publication 2 January 2014.

Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.

Outcomes of silastic trapezium replacements.

Trapezio-metacarpal joint arthritis is common, affecting 7% of men and 15% of women. Numerous surgical techniques are described for this condition but it is not clear which is best. Eighty-six silicone trapezium replacements were assessed at an average of 46 months (six to 156 months) postoperatively for patient satisfaction, pain, key and power grip strength, range of motion, complications and disability with DASH score. Patient satisfaction was 92%. There was excellent pain reduction from 4.2 to 0.6 on a scale of 0 to 5. Strength was 72% and 84% of age-sex-matched normal data for key and power grips, respectively. The complication rate was low, with two cases of persistent pain. One resolved spontaneously, the other resolved following revision of the silicone implant. The average DASH score was 30. Silicone trapezium replacement is an effective operation that offers the patient good pain relief, strength and good function with few complications.

Dorsally displaced fractures of the distal radius - a study of preferred treatment options among UK trauma and orthopaedic surgeons.

Distal radius fractures are common, and surgeons have in their armament a variety of ways of treating them. In this study, 50 orthopaedic surgeons in the UK were shown five clinical scenarios and radiographs from patients with various fracture patterns of the distal radius, and were asked for their preferred management. There was a wide variation in the preferred treatment for each scenario presented. Across all of the cases, 52% of surgeons preferred to use a volar locking-plate compared with 21% who chose fixation with Kirschner wires. There was very little consensus among surgeons with regard to the optimal method of fixation for patients sustaining dorsally displaced fractures of the distal radius. This disagreement is not surprising as there is currently no high level evidence to guide surgeons as to the best management option for this common and potentially debilitating injury.

Monoglyceride-based self-assembling copolymers as carriers for poorly water-soluble drugs.

To develop self-assembling polymers forming polymeric micelles and increasing the solubility of poorly soluble drugs, amphiphilic polymers containing a hydrophilic PEG moiety and a hydrophobic moiety derived from monoglycerides and polyethers were designed. The biodegradable copolymers were obtained via a polycondensation reaction of polyethylene glycol (PEG), monooleylglyceride (MOG) and succinic anhydride (SA). Polymers with molecular weight below 10,000 g/mol containing a minimum of 40 mol% PEG and a maximum of 10 mol% MOG self-assembled spontaneously in aqueous media upon gentle mixing. They formed particles with a diameter of 10 nm although some aggregation was evident. The critical micellar concentration varied between 3x10(-4) and 4x10(-3) g/ml, depending on the polymer. The cloud point (> or = 66 degrees C) and flocculation point (> or = 0.89 M) increased with the PEG chain length. At a 1% concentration, the polymers increased the solubility of poorly water-soluble drug candidates up to 500-fold. Drug solubility increased as a function of the polymer concentration. HPMC capsules filled with these polymers disintegrated and released model drugs rapidly. Polymer with long PEG chains had a lower cytotoxicity (MTT test) on Caco-2 cells. All of these data suggest that the object polymers, in particular PEG1000/MOG/SA (45/5/50) might be potential candidates for improving the oral biopharmaceutical performance of poorly soluble drugs.

Usefulness of a novel Caco-2 cell perfusion system II. Characterization of monolayer properties and peptidase activity.

In this study, the enzymatic activity and the influence of support filters and extracellular matrix proteins on the differentiation of Caco-2 cells grown in a perfusion system (Minucells and MinutissueTM) were examined and compared to traditional culturing approaches. Differences were observed regarding the differentiation of Caco-2 cells using the traditional approach and perfusion system such that the cell monolayers grown in a perfusion system showed a significant increase in dipeptidase activities (18.20 +/- 0.43nmol x min(-1) x cm(-2)) compared to the cells cultivated using the 21-day protocol (9.45 +/- 0.50 nmol x min(-1) x cm(-2)). The peptidase activity of Caco-2 cells was strikingly inhibited when Matrigel extracellular protein was used for coating polycarbonate support filters. While the enzymatic activities of the cell monolayers differentiated in the perfusion system were up-regulated, the transepithelial electrical resistance values of the cell monolayers (171 +/- 52 and 251 +/- 62 omega x cm2 for polycarbonate and polyester, respectively) decreased compared to the traditional Snapwell inserts (644 +/- 119 omega x cm2). The results suggested that the perfusion systems were useful permeability models which reduce workload, resources and manpower needed to obtain useful Caco-2 monolayers. In addition, the approach offers an efficient tool for long-term culturing of highly differentiated Caco-2 cell monolayers.

Ponseti casting: a new soft option.

We have modified the Ponseti casting technique by using a below-knee Softcast instead of an above-knee plaster of Paris cast. Treatment was initiated as soon as possible after birth and the Pirani score was recorded at each visit. Following the manipulation techniques of Ponseti, a below-knee Softcast was applied directly over a stockinette for a snug fit and particular attention was paid to creating a deep groove above the heel to prevent slippage. If necessary, a percutaneous Achilles tenotomy was performed and casting continued until the child was fitted with Denis Browne abduction boots. Between April 2003 and May 2007 we treated 51 consecutive babies with 80 idiopathic club feet with a mean age at presentation of 4.5 weeks (4 days to 62 weeks). The initial mean Pirani score was 5.5 (3 to 6). It took a mean of 8.5 weeks (4 to 53) of weekly manipulation and casting to reach the stage of percutaneous Achilles tenotomy. A total of 20 feet (25%) did not require a tenotomy and for the 60 that did, the mean Pirani score at time of operation was 2.5 (0.5 to 3). Denis Browne boots were applied at a mean of 10 weeks (4 to 56) after presentation. The mean time from tenotomy to boots was 3.3 weeks (2 to 10). We experienced one case of cast-slippage during a period of non-attendance, which prolonged the casting process. One case of prolonged casting required repeated tenotomy, and three feet required repeated tenotomy and casting after relapsing while in Denis Browne boots. We believe the use of a below-knee Softcast in conjunction with Ponseti manipulation techniques shows promising initial results which are comparable to those using above-knee plaster of Paris casts.

Cauda equina syndrome: an anatomically driven review.

Cauda equina syndrome results from an injury to the lumbosacral nerve roots below the tip of the conus medullaris, occuring in between 2 and 6% of all laminectomies performed for lumbar disc herniation. This article relates the anatomy of the nervous system of the bladder, rectum, anus and sexual organs to the signs and symptoms of cauda equina syndrome, and reviews the literature for the acute management of these patients.

A review of 1241 trauma cases: a study of efficiency in trauma theatres.

BACKGROUND: Our trauma department has recently moved to a newly built University hospital. Its geographic situation and the fact that all surgical sub-specialties are represented make it a very busy level 1 trauma centre. Our aim was to assess our activity and efficiency in trauma looking at 1241 consecutive trauma operations over a period of 6 months. Furthermore we evaluate the impact of the move to the new hospital on our activity. METHOD: A total of 1241 consecutive trauma operations were reviewed, looking at transit times of patients to theatre, the duration of induction of anaesthesia, time to prepare and drape the patients and duration of surgery. Daily starting and finishing times were also analysed. We looked at operations done from April 2006 to July 2006 in our old site and compared the timings to the first 2 months in the new University hospital. In addition, we looked at the most recent 2 months in our new hospital. RESULTS: The mean number of cases done daily and the distribution of time in trauma theatre were not significantly different in the 2 hospitals. A mean of 4.9 trauma operations are done per day with a mean of 18.6% of trauma lists starting on time. Furthermore, only around 55% of total theatre time is spent operating. The efficiency of trauma theatre utilisation is far from optimal but seems to correspond with the findings in the general literature. CONCLUSION: Activity and theatre utilisation in trauma should be monitored regularly in order to assess the time distribution of surgical cases. This monitoring enables the department to highlight causes of inefficiencies and has been shown to improve the activity in trauma theatres.

Parallel artificial membrane permeability assay (PAMPA) combined with a 10-day multiscreen Caco-2 cell culture as a tool for assessing new drug candidates.

The parallel artificial membrane permeability assay (PAMPA) is extensively used for the evaluation of early drug candidates. It is high throughput, low cost and is amenable to automation. This method has been shown useful in assessing transmembrane, non-energy dependent, diffusion of drugs such that reasonable predictability with in vivo (passive) absorption is possible. Cell cultures mimicking the gastrointestinal tract such as the CACO-2 cultures have the advantage of taking into account other transport mechanism including paracellular and carrier-mediated uptake but are lower throughput and labor-intensive. In this study, the applicability of two high throughput permeability assays namely PAMPA (PSR4p, pION Inc.) and 96-well Caco-2 cell assay (MultiScreen, Millipore) were used to rank drug permeability as well as to predict passive and active drug absorption/secretion for a series of marketed drugs as well as a collection of structurally diverse drug candidates. CACO-2 cells were cultured using MultiScreen hardware over a period of 10 days with the integrity of the cells assessed using transepithelial electrical resistance (TEER) and by the ability of the monolayer to the transport a paracellular marker, sodium fluorescence. Effective permeability (Peff) data were calculated using spectrophotometric data and were binned based on a pre-defined cut-off values as either highly and poorly permeable. A comparison of a well characterized drug training set indicate at least 85% concordance between the data generated from PAMPA and Caco-2 MultiScreen. The values obtained using the MultiScreen approach were also similar to data obtained from the literature using the conventional 21-day Caco-2 cell assay. Differences between PAMPA and CACO-2 ranking were useful indicators of either drug efflux (PAMPA (Peff) > CACO-2 (Peff)) or absorptive transport (CACO-2 (Peff) > PAMPA (Peff)). These results indicate that PAMPA combined with the MultiScreen Caco-2 cell culture may be a useful high throughput screening for predicting passive diffusion and active transport of new drugs.

Supersaturating drug delivery systems: effect of hydrophilic cyclodextrins and other excipients on the formation and stabilization of supersaturated drug solutions.

Supersaturating drug delivery systems (SDDS) utilize two important design elements in their preparation including converting the drug of interest into a high energy state or other rapidly dissolving form to facilitate the formation of supersaturated drug solutions and providing a means for stabilizing the formed supersaturated solution such that significant drug absorption is possible from the gastrointestinal tract. This has been referred to as a "spring" and "parachute" approach. The current effort is designed to assess materials which may affect properties in SDDS. To this end, a series of excipients was tested in a co-solvent/solvent quench method to assess their ability to attain and maintain supersaturation for a group of 14 drug development candidates. The approach focussed on hydrophilic cyclodextrins including hydroxypropyl-beta-cyclodextrin (HPbetaCD) and sulfobutyl-beta-cyclodextrin (SBEbetaCD). Various rheological polymers and surfactants were also included in the study. Consistent with previous investigations, the pharmaceutical polymers, as a class, had minimal effects on the extent of supersaturation but tended to be good stabilizers while the surfactants tended to provide for the greatest degree of supersaturation but the formed systems were poorly stable. This study found that hydrophilic cyclodextrins, especially SBEbetaCD, gave superior results in terms of attaining and maintaining supersaturation. A knowledge of the behavior and performance of excipients in this context can be useful in designing solid oral dosage forms for difficult-to-formulate drugs and drug candidates.

Delivery of a DNAzyme targeting c-myc to HT29 colon carcinoma cells using a gold nanoparticulate approach.

The objective of the current study was to develop cellular delivery approaches for catalytic DNA enzymes (DNAzymes) which cleave targeted messenger RNA, using vectors based on colloidal gold. The model DNAzyme was a 32mer oligonucleotide designed to specifically interact with and cleave c-myc mRNA. Colloidal gold particles were prepared by reduction of tetrachlororauric [III] acid with sodium citrate. Particles could be produced in the 1-90 nm range. A cationic substrate linked to transferrin was electrostatically/hydrophobically bound to the gold particle. These vectors were then treated with the DNAzyme to yield the condensed DNA-cationic polymer-particulate product. The pH (4-11.5), the quantity of the DNAzymes (0.079-0.567 microg/probe), the cationic polymer (polylysine (PL) or polyethylenimine (PEI)) as well as the surfactant (PVP) concentration (0-0.5%) were varied to give stable constructs which decomplexed under the desired conditions (i.e., in lysosomes and at lower pH values). Cellular uptake of the FITC-labelled c-myc DNAzyme incorporated in this vector was measured using FACS analysis in human HT29 colon carcinoma cells. Data suggested that PEI gave better delivery efficiencies than PL. The use of PVP to stabilize the formed dispersions was detrimental to DNAzyme delivery when PL was used but had little effect in the PEI systems. In the best cases, delivery to 77% of the cells was possible using PEI with the PVP stabilizer and completing the DNA condensation at pH 5.5 with 0.118 microg of DNAzyme/probe. In contrast, the best conditions for PL gave only transfection to 43% of the cells (no PVP, condensed at pH 5.7 and with a loading of 0.079 microg DNAzyme/probe). The PL probe tended to be more toxic than the PEI-based systems (65% cell death in PL transfected cells compared to 22% for PEI). These results suggest that cellular targeting using colloidal gold appears feasible for DNAzyme delivery.

Spontaneously self-assembled micelles from poly(ethylene glycol)-b-poly(epsilon-caprolactone-co-trimethylene carbonate) for drug solubilization.

Di-block copolymers composed of polyethylene glycol (PEG) and a second block of (co)polyesters of epsilon-caprolactone (CL) and/or trimethylene carbonate (TMC) were synthesized and characterized. Tin octoate was used as catalyst and polymerization were completed over a period of 24 h with high conversion (> 95%). Self-assembling properties in water were evaluated. All di-block copolymers behave similarly except when PCL served as the second block. Stable crew-cut micelles of about 20 nm were obtained by direct dissolution of the liquid di-block copolymers in water at room temperature. When PCL was present as the second block, no solubilization occurred. Drug encapsulation of poorly water-soluble drugs belonging to biopharmaceutics classification system (BCS) class II (ketoprofen and furosemide) was evaluated. Experimental solubility for these two drugs shows a significant enhancement such that a maximum value of 23.4 mg/ml was obtained for ketoprofen in a 10% w/v micellar solution as compared to 0.14 mg in water. In the case of furosemide, the solubility increased from 0.04 mg/ml in water to about 3.2 mg/ml in a 10% w/v micellar solution. Enzymatic degradation of diblock copolymers was also studied in the presence of Pseudomonas lipase in a phosphate buffer solution (pH 7.4). Results indicated rapid degradation of copolymers containing relatively higher amounts of CL compared to TMC suggesting the potential in vivo degradation.

Delayed diagnosis of synovial sarcoma of the foot.

Soft tissue sarcomas are relatively rare in the population, rarely encountered by the average orthopedic surgeon, and may only be seen once in a lifetime by a general practitioner. Although rare, it is a serious condition that, if diagnosed early, can result in improved prognosis. This article presents a case of a delayed diagnosis of a soft tissue sarcoma and highlights possible pitfalls and causes for such delays in hope of educating and reducing such incidences in the future.

Transport mechanisms of mmePEG750P(CL-co-TMC) polymeric micelles across the intestinal barrier.

Monomethylether poly(ethyleneglycol)(750)-poly(caprolactone-co-trimethylene carbonate) (mmePEG750)P(CL-co-TMC)) which spontaneously form micelles, can cross lipid bilayers via passive diffusion and demonstrate an oral bioavailability of 40% in rats. The aim of the current work was to study the transport mechanism(s) of drug-loaded mmePEG750P(CL-co-TMC) micelles across the intestinal barrier. The transport of radiolabelled polymer across Caco-2 cell monolayer was investigated by disrupting tight junctions and by inhibiting endocytosis. The polymer and drugs loaded in micelles independently crossed Caco-2 cell monolayers and did not use either the paracellular route or M-cells. The polymer did not affect P-gp pumps. This mechanistic study suggests that whereas drug-loaded micelles were absorbed by fluid-phase endocytosis, polymeric unimers diffused passively across the membrane concomitantly with micellar endocytosis.