Evaluation of a tiered in vitro testing strategy for assessing the ocular and dermal irritation/corrosion potential of pharmaceutical compounds for worker safety

Introduction: Irritation reactions are a frequently reported occupational illness. The potential adverse effects of pharmaceutical compounds (PCs) on eye and skin can now be assessed using validated in vitro methods.

Objectives: Our overall aim is to reduce animal testing by replacing the historically utilized in vivo test methods with validated in vitro test methods which accurately determine the ocular and dermal irritation/corrosion potential of PCs to inform worker safety within the pharmaceutical space. Bristol–Myers Squibb (BMS) and the Institute for In Vitro Sciences (IIVS) have therefore conceptualized and internally qualified a tiered in vitro testing strategy to inform occupational hazards regarding eye and skin irritation and corrosivity of PCs. For the small scale pre-qualification phase, we paired historical in vivo and newly generated in vitro data for 15 PCs to determine the predictive capacity of in vitro assays already validated for the eye and skin irritation/corrosion endpoints and accepted for certain regulatory submissions. During the post-qualification phase, a group of 24 PCs were subjected exclusively to the developed tiered testing strategy, which is based on three Organisation for Economic Co-operation and Development (OECD) in vitro methods.

Materials and methods: The qualified in vitro testing strategy utilizes the Corrositex^® assay for the corrosivity (OECD TG 435), the Bovine Corneal Opacity and Permeability (BCOP) assay for ocular irritation (OECD TG 437), and the EpiDerm? tissue model-based Skin Irritation Test (SIT) for dermal irritation (OECD TG 439). In the first step, the pH of each PC was determined. For compounds with pH extremes ≥11 or ≤2, the Corrositex^® assay was generally conducted first. For compound(s) that were incompatible with or were negative in the Corrositex^® assay or had pH values between 2 and 11, the BCOP assay and SIT were performed first.

Results: The results of the tiered testing strategy’s qualification phase demonstrated that the BCOP assay is sensitive enough to identify a wide range of eye irritation/corrosion potentials and its over-prediction rate was considered acceptable to inform occupational hazards and ensure the proper handling practices of PCs. The SIT correctly predicted the skin irritation potential of 14 out of the 15 PCs included in the qualification phase, only over-predicting one PC. In the post-qualification phase, four PCs out of four tested were predicted corrosive by the Corrositex^® assay and thus no further testing was needed or conducted. The rest of the PCs were evaluated in the BCOP assay (both neat and as a 20% dilution), with the higher response being used for hazard classification. Four PCs were determined to be severe eye irritants, 1 a moderate irritant, 8 were mild irritants, and 8 were non-irritants. The same set of PCs was evaluated using the SIT and were classified as non-irritants to skin. These results are consistent with the BMS historical in vivo results showing a very low number of PCs as skin irritants.

Conclusions: This tiered in vitro testing strategy, which replaces the use of animal studies, was found to be reasonably accurate in its predictive capacity when compared to historical in vivo results and represents a conservative and reliable platform that can be utilized for the prediction of ocular and dermal irritation/corrosion potential of PCs and for subsequent GHS classification and worker safety hazard communications.     

Getting the most out of your IP--patent management along its life cycle

Effectively managing and optimizing the value of the patent portfolio is a major challenge for many firms, especially those in knowledge intensive industries, such as the pharmaceutical, biotechnological and chemical industry. However, insights on effective patent portfolio strategies are rare. Therefore, in this article we investigate in detail how firms successfully manage and optimize their patent portfolios to increase their overall competitiveness. We discover that successful patent portfolio management is rooted in managing the patents along their life cycles. Based on the findings of ten case studies, we develop a holistic patent life cycle management model reflecting five distinctive phases of patent management: explore, generate, protect, optimize and decline. We conclude with how our findings can be used in practice.     

Childhood sequelae of infant lung disease: exercise and pulmonary function abnormalities after bronchopulmonary dysplasia

To determine the long-term pulmonary sequelae and effect on exercise tolerance of bronchopulmonary dysplasia (BPD), we studied 10 children at a mean age of 10.4 years, who had been born prematurely, survived respiratory distress syndrome, and subsequently developed BPD, and compared them with eight age-matched normal children born at term. Pulmonary function tests and graded exercise stress tests were performed. Residual volume, the ratio between residual volume and total lung capacity, vital capacity, forced expiratory volume in 1 second, forced expiratory flow between 25% and 75% of vital capacity, and maximal expiratory flows at 80%, 70%, and 60% of total lung capacity were all abnormal (P less than 0.02) in the children with BPD, compared with control values. Pre-exercise transcutaneous CO2 tension was higher (P less than 0.05) in the BPD group than in the control group. At maximal workload, tcPCO2 remained high in patients with BPD compared with control values (P less than 0.05). Arterial oxygen saturation at maximal workload fell below pre-exercise levels in the BPD group (P less than 0.05) but not in control children. There were no differences in maximal oxygen consumption between the BPD group and control children. Exercise-induced bronchospasm occurred in 50% of the BPD group, but not in the control group. We conclude that long-term survivors of BPD have evidence of airway obstruction, hyperinflation, and airway hyperreactivity, compared with a control group. Aerobic fitness was not significantly different in the BPD and control groups, but was achieved in the BPD group at the expense of a fall in SaO2 and a rise in tcPCO2.     

Evaluation of SV40-transformed synovial fibroblasts in the study of rheumatoid arthritis pathogenesis

The SV40 T antigen has been used to generate immortalized cells from rheumatoid arthritis (RA) synovial fibroblasts (RASFs) that are commonly used in lieu of primary RASFs. In the current study, we investigated the effect of stimulation by tissue necrosis factor alpha (TNF-α) and interleukin 17 (IL-17) on primary and immortalized RASFs in order to gauge the appropriateness of the use of immortalized RASFs, the MH7A cell line, in the study of RA pathogenesis. Changes in the levels of secretion and expression of 8 proteins associated with RA upon stimulation were assessed by multiplex immunoassay. IL-17 stimulation had a minimal impact on protein secretion and expression for primary and immortalized cells. Basic fibroblast growth factor (FGF-2) was not detectable for the primary cells but was detectable for the immortalized cells. In contrast, monocyte chemoattractant protein 1 (MCP-1) was detectable for primary cells but was undetectable for immortalized cells. In general, protein expression and secretion by cells stimulated with TNF-α were significantly increased. For primary cells, several proteins were below the limit of detection for unstimulated cells and cells stimulated with IL-17, while levels for TNF-α-stimulated cells were within the detectable range. For the same proteins, expression was observed for immortalized cells, regardless of stimulation, suggestive of constitutive activation of the NF-κB signaling pathway. The current study therefore provides strong evidence that immortalized and primary RASFs differ in regard to protein expression and secretion and therefore may not be appropriate for use in the study of RA pathogenesis.     

Future ophthalmology practice pattern: A survey of Saudi Board of Ophthalmology residents

Purpose

The main purpose of the study was to examine and identify factors that influence the future practice pattern of Saudi Board of Ophthalmology residents as well as their academic goals. This study also aimed to compare the plans and career goals of the current Saudi ophthalmology residents with a former cohort of Saudi ophthalmology residents.

Complications in paediatric liver transplant from Kuwait when transplanted abroad

Background and study aimsSince the introduction of liver transplantation (LTx) in children suffering from liver failure in 1963, many centres around the world have offered this service to children that have no other alternative. The aim of this retrospective study is to analyse the results of paediatric liver transplant in Kuwait over the last decade.Patients and methodsA retrospective chart review was done involving paediatric patients during the time period of 1995–2004. The information collected included patient demographics, indications for liver transplantation, survival of both patient and allograft, and complications.ResultsA total of 16 cases were found and analysed. The mean age was 3.6 years (ranged 5 months–17 years). There were nine boys and seven girls. The most common indications for LTx were biliary atresia and metabolic liver disease. All the liver transplants were done abroad. There were totally nine deceased donor and seven living related cases. The complications were acute cellular rejection in five, hypertension in two, biliary complications in four, cytomegalovirus (CMV) infection in three and post lymphoproliferative disease in two cases. All but one patient are presently alive.ConclusionThe above information demonstrates that LTx in Kuwati children is safe and improves the quality of life for those that would otherwise have no other alternative.     

Perineal approach to vascular anatomy during transobturator cystocele repair

Objective  To evaluate the risk of vascular injury during transobturator approach of cystocele repair.
Design  Dissection of the obturator area by perineal approach was performed after placement of mesh needles used for cystocele mesh repair.
Setting  Surgery school of Paris.
Population or sample  Twenty obturator regions in ten fresh female cadavers.
Methods  Transperineal dissection of the obturator area was conducted in ten fresh female anatomic subjects after inserting anterior Prolift^® needles.
Main outcome measures  The vascular anatomy of the obturator region was mapped. Distances between needles and vascular structures of the obturator area were measured three times and averaged for each side.
Results  The anterior cannula-equipped needle perforated the gracilis and the adductor brevis muscles. The mean (SD) distance to the anterior obturator vessels was 21.2 (1.6) mm on the right side and 20.4 (1.5) mm on the left. The posterior needle perforated the adductor magnus. Its distance to the posterior division of the obturator vessels was 1.8 (1.0) mm on the right side and 1.1 (0.9) mm on the left.
Conclusions  During mesh cystocele repair by transobturator approach, the posterior obturator vessels division seems at risk of injury during the posterior needle insertion.