Bioequivalence evaluation of new microparticulate capsule and marketed tablet dosage forms of lornoxicam in healthy volunteers

Purpose: To compare oral bioavailability and pharmacokinetic parameters of different lornoxicam formulations and to assess similarity in plasma level profiles by statistical techniques. Methods: An open-label, two-period crossover trial was followed in 24 healthy Pakistani volunteers (22 males, 2 females). Each participant received a single dose of lornoxicam controlled release (CR) microparticles and two doses (morning and evening) of conventional lornoxicam immediate release (IR) tablet formulation. The microparticles were prepared by spray drying method. The formulations were administered again in an alternate manner after a washout period of one week. Pharmacokinetic parameters were determined by Kinetica 4.0 software using plasma concentration-time data. Moreover, data were statistically analyzed at 90 % confidence interval (CI) and Schuirmann’s two one-sided t-test procedure. Results: Peak plasma concentration (Cmax) was 20.2 % lower for CR formulation compared to IR formulation (270.90 ng/ml vs 339.44 ng/ml, respectively) while time taken to attain Cmax (tmax) was 5.25 and 2.08 h, respectively. Area under the plasma drug level versus time (AUC) curve was comparable for both CR and IR formulations. The 90 % confidence interval (CI) values computed for Cmax, AUC0-24, and AUC0-∞ , after log transformation, were 87.21, 108.51 and 102.74 %, respectively, and were within predefined bioequivalence range (80 - 125 %). Conclusion: The findings suggest that CR formulation of lornoxicam did not change the overall pharmacokinetic properties of lornoxicam in terms of extent and rate of lornoxicam absorption.

Development of two charge transfer complex spectrophotometric methods for determination of tofisopam in tablet dosage form

Purpose: To develop a simple, fast and sensitive spectrophotometric method for the determination of tofisopam in tablet dosage form. Methods: Tofisopam as n-electron donor was reacted with two π-acceptors, namely, chloranilic acid (ChA), and 7,7,8,8 tetracyanoquinodimethane (TCNQ) to form charge transfer complexes. The complexes were evaluated spectrophotometrically at 520 and 824 nm for ChA and TCNQ, respectively. The optimum conditions for the reaction were determined and optimized. The developed method was compared with Japanese Pharmacopeia method. Results: The calibration curve was linear in the ranges 25 – 125 and 30 – 150 μg/mL for ChA and TCNQ, respectively. The lower limit of detection was 8.0 and 10.0 μg/mL for ChA and TCNQ, respectively while the slope and intercept of the calibration curves were 0.0025 and 0.011 and 0.0115 and -0.237, for ChA and TCNQ, respectively. Conclusion: The developed methods for tofisopam have good accuracy and precision, and comparable to a standard pharmacopeial method. The methods can be applied for routine analysis and in quality control.

Liquid chromatographic-mass spectrometric method for determination of drug content uniformity of two commonly used dermatology medications in a split-tablet dosage form

Purpose: To develop and validate a simple, efficient and reliable Liquid chromatographic-mass spectrometric (LC-MS/MS) method for the quantitative determination of two dermatological drugs, Lamisil® (terbinafine) and Proscar® (finasteride), in split tablet dosage form. Methods: Thirty tablets each of the 2 studied medications were randomly selected. Tablets were weighed and divided into 3 groups. Ten tablets of each drug were kept intact, another group of 10 tablets were manually split into halves using a tablet cutter and weighed with an analytical balance; a third group were split into quarters and weighed. All intact and split tablets were individually dissolved in a water: methanol mixture (4:1), sonicated, filtered and further diluted with mobile phase. Optimal chromatographic separation and mass spectrometric detection were achieved using an Agilent 1200 HPLC system coupled with an Agilent 6410 triple quadrupole mass spectrometer. Analytes were eluted through an Agilent eclipse plus C8 analytical column (150 mm × 4.6 mm, 5 μm) with a mobile phase composed of solvent A (water) containing 0.1% formic acid and 5mM ammonium formate pH 7.5, and solvent B (acetonitrile mixed with water in a ratio A:B 55:45) at a flow rate of 0.8 mL min-1 with a total run time of 12 min. Mass spectrometric detection was carried out using positive ionization mode with analyte quantitation monitored by multiple reaction monitoring (MRM) mode. Results: The proposed analytical method proved to be specific, robust and adequately sensitive. The results showed a good linear fit over the concentration range of 20 - 100 ng mL-1 for both analytes, with a correlation coefficient (r2) ≥ 0.999 and 0.998 for finasteride and terbinafine, respectively. Following tablet splitting, the drug content of the split tablets fell outside of the proxy USP specification for at least 14 halves (70 %) and 34 quarters (85 %) of FIN, as well as 16 halves (80 %) and 37 quarters (92.5 %) of TBN. Mean weight loss, after splitting, was 0.58 and 2.22 % for FIN half- and quarter tablets, respectively, and 3.96 and 4.09 % for TBN half- and quarter tablets,respectively. Conclusion: The proposed LC-MS/MS method has successfully been used to provide precise drug content uniformity of split tablets of FIN and TBN. Unequal distribution of the drug on the split tablets is indicated by the high standard deviation beyond the accepted value. Hence, it is recommended not to split non-scored tablets especially, for those medications with significant toxicity

The administration of exogenous prostaglandin may improve ovulation in pacu (Piaractus mesopotamicus)

Based on the reports of unsuccessful ovulation in pacu (Piaractus mesopotamicus) by fish farmers and researchers undertaking artificial reproduction programs, we evaluated the use of prostaglandin F (PGF) to improve pacu ovulation. This study was conducted during two spawning seasons (2009/2010 and 2010/2011) with two samplings in the first season and one sampling in the second season. A total of 45 females was sampled in this study. The control group was injected with carp pituitary extract (crude extract, 6 mg/kg), and the treatment group received PGF (2 mL per fish in the 2009/2010 season and 5 mL per fish in the 2010/2011 season) in addition to the crude extract. In both seasons, 100% (N = 4, 2009/2010 first sampling; N = 5, 2009/2010 second sampling; and N = 3, 2010/2011) of the PGF-treated fish spawned. In contrast, 53.0% (N = 9) and 83.3% (N = 10) of the control fish spawned in the first and second samplings of the 2009/2010 season, respectively, and only 25.0% (N = 1) spawned in the 2010/2011 season. Fecundity, fertility, and hatching rates did not differ (P > 0.05) between the treated and control fish. Based on oocyte volume frequency analysis, ovaries of the control fish had more (P < 0.05) vitellogenic oocytes with germinal vesicle breakdown that remained unovulated after spawning, whereas more (P < 0.05) of previtellogenic oocytes were present in the ovaries of the PGF-treated fish. In conclusion, administration of exogenous prostaglandin may improve the outcome of hormonally induced spawning in tropical migratory fish. (C) 2012 Elsevier B.V. All rights reserved.

Exogenous paraoxonase-1 during oocyte maturation improves bovine embryo development in vitro.

The aims of this study were (i) to measure the direct effects of exogenous human recombinant PON1 (rPON1) on bovine oocyte maturation at the molecular level (gene expression) and (ii) to measure the carry-over effects of PON1 on pre-implantation embryo development in vitro.

Effect of Combination between CaCl2 Dosage and Electric Stimulation Period on Meat Quality Duck Adult

Research entitled “The effect of combination between CaCl2 dosage and length of electric stimulation on adult meat quality duck quality”. The aim was to know the effect of combination between CaCl2 and length of electric stimulation on quality. It was conducted at Technology of Animal Production Laboratory in Animal Science Faculty, Jenderal Soedirman University on June 2nd up to August 30rd 2002. Materials used in this research were 27 Tegal duck adult. Experimental design with Completely Randomized Design (CRD) with factorial 3 x 3 was performed in this research. The first factor was CaCl2 was dosage (a1=50cc; a2=100cc; and a3=150cc) and the second factor was length of electric stimulation period (b1=10 sec; b2=20 sec; and b3=30 sec). Each experiment was repeated three times, and variable of this research were pH, tenderness, WHC and CL. The result of research shows that CaCl2 dosage (50, 100, and 150 cc); length of electric stimulation and their interaction were gave no significant effect (P>0,05) on pH, tenderness, WHC and CL in adult duck meat. Conclusion of this research was CaCl2 dosage, electric stimulation period and their interaction gave the same effect on pH, tenderness, WHC and CL adult duck meat. (Animal Production 5(1): 25-34 (2003) Key word: Tenderness, WHC and CL, Duck, Meat, Electrical, Calsium Chlorida

Predicting driver's hypovigilance on monotonous roads: literature review.

Drivers' ability to react to unpredictable events deteriorates when exposed to highly predictable and uneventful driving tasks. Particularly, highway design reduces the driving task mainly to a lane-keeping one. It contributes to hypovigilance and road crashes as drivers are often not aware that their driving behaviour is impaired. Monotony increases fatigue, however, the fatigue community has mainly focused on endogenous factors leading to fatigue such as sleep deprivation. This paper focuses on the exogenous factor monotony which contributes to hypovigilance. Objective measurements of the effects of monotonous driving conditions on the driver and the vehicle's dynamics is systematically reviewed with the aim of justifying the relevance of the need for a mathematical framework that could predict hypovigilance in real-time. Although electroencephalography (EEG) is one of the most reliable measures of vigilance, it is obtrusive. This suggests to predict from observable variables the time when the driver is hypovigilant. Outlined is a vision for future research in the modelling of driver vigilance decrement due to monotonous driving conditions. A mathematical model for predicting drivers’ hypovigilance using information like lane positioning, steering wheel movements and eye blinks is provided. Such a modelling of driver vigilance should enable the future development of an in-vehicle device that detects driver hypovigilance in advance, thus offering the potential to enhance road safety and prevent road crashes.

Business model construction : the importance of regime of appropriability strategies

To date, most theories of business models have theorized value capture assuming that appropriability regimes were exogenous and that the firm would face a unique, ideal-typical appropriability regime. This has led theory contributions to focus on governance structures to minimize transaction costs, to downplay the interdepencies between value capture and value creation, and to ignore revenue generation strategies. We propose a reconceptualization of business models value capture mechanisms that rely on assumptions of endogeneity and multiplicity of appropriability regimes. This new approach to business model construction highlights the interdependencies and trade-offs between value creation and value capture offered by different types and combinations of appropriability regimes. The theory is illustrated by the analysis of three cases of open source software business models

Coating of biomaterial scaffolds with the collagen-mimetic peptide GFOGER for bone defect repair

Healing large bone defects and non-unions remains a significant clinical problem. Current treatments, consisting of auto and allografts, are limited by donor supply and morbidity, insufficient bioactivity and risk of infection. Biotherapeutics, including cells, genes and proteins, represent promising alternative therapies, but these strategies are limited by technical roadblocks to biotherapeutic delivery, cell sourcing, high cost, and regulatory hurdles. In the present study, the collagen-mimetic peptide, GFOGER, was used to coat synthetic PCL scaffolds to promote bone formation in critically-sized segmental defects in rats. GFOGER is a synthetic triple helical peptide that binds to the [alpha]2[beta]1 integrin receptor involved in osteogenesis. GFOGER coatings passively adsorbed onto polymeric scaffolds, in the absence of exogenous cells or growth factors, significantly accelerated and increased bone formation in non-healing femoral defects compared to uncoated scaffolds and empty defects. Despite differences in bone volume, no differences in torsional strength were detected after 12 weeks, indicating that bone mass but not bone quality was improved in this model. This work demonstrates a simple, cell/growth factor-free strategy to promote bone formation in challenging, non-healing bone defects. This biomaterial coating strategy represents a cost-effective and facile approach, translatable into a robust clinical therapy for musculoskeletal applications.

Heparan sulfate mediates the proliferation and differentiation of rat mesenchymal stem cells

The growth and differentiation of mesenchymal stem cells is controlled by various growth factors, the activities of which can be modulated by heparan sulfates. We have previously underscored the necessity of sulfated glycosaminoglycans for the FGF-2-stimulated differentiation of osteoprogenitor cells. Here we show that exogenous application of heparan sulfate to cultures of primary rat MSCs stimulates their proliferation leading to increased expression of osteogenic markers and enhanced bone nodule formation. FGF-2 can also increase the proliferation and osteogenic differentiation of rMSCs when applied exogenously during their linear growth. However, as opposed to exogenous HS, the continuous use of FGF-2 during in vitro differentiation completely blocked rMSC mineralization. Furthermore, we show that the effects of both FGF-2 and HS are mediated through FGF receptor 1 (FGFR1) and that inhibition of signaling through this receptor arrests cell growth resulting in the cells being unable to reach the critical density necessary to induce differentiation. Interestingly, blocking FGFR1 signaling in post-confluent osteogenic cultures significantly increased calcium deposition. Taken together our data clearly suggests that FGFR1 signaling plays an important role during osteogenic differentiation, firstly by stimulating cell growth that is closely followed by an inhibitory affect once the cells have reached confluence. It also underlines the importance of HS as a co-receptor for the signaling of endogenous FGF-2 and suggests that purified glycosaminoglycans may be attractive alternatives to growth factors for improved ex vivo growth and differentiation of MSCs.

To work or not to work? Child development and maternal labor supply

We estimate the effect of early child development on maternal labor force participation. Mothers of poorly developing children may remain at home to care for their children. Alternatively, mothers may enter the labor force to pay for additional educational and health resources. Which action dominates is the empirical question we answer in this paper. We control for the potential endogeneity of child development by using an instrumental variables approach, uniquely exploiting exogenous variation in child development associated with child handedness. We find that a one unit increase in poor child development decreases maternal labor force participation by approximately 10 percentage points.

Performance pressure an empirical analysis using world and Euro cups data

There is a notable shortage of empirical research directed at measuring the magnitude and direction of stress effects on performance in a controlled environment. One reason for this is the inherent difficulties in identifying and isolating direct performance measures for individuals. Additionally most traditional work environments contain a multitude of exogenous factors impacting individual performance, but controlling for all such factors is generally unfeasible (omitted variable bias). Moreover, instead of asking individuals about their self-reported stress levels we observe workers' behavior in situations that can be classified as stressful. For this reason we have stepped outside the traditional workplace in an attempt to gain greater controllability of these factors using the sports environment as our experimental space. We empirically investigate the relationship between stress and performance, in an extreme pressure situation (football penalty kicks) in a winner take all sporting environment (FIFA World Cup and UEFA European Cup competitions). Specifically, we examine all the penalty shootouts between 1976 and 2008 covering in total 16 events. The results indicate that extreme stressors can have a positive or negative impact on Individuals' performance. On the other hand, more commonly experienced stressors do not affect professionals' performances.

Social Participation of Community Dwelling Stroke Survivors [Published Abstract: From the Quality of Care and Outcomes Research in Cardiovascular Disease and Stroke Conference 2009]

Disability following a stroke can impose various restrictions on patients’ attempts at participating in life roles. The measurement of social participation, for instance, is important in estimating recovery and assessing quality of care at the community level. Thus, the identification of factors influencing social participation is essential in developing effective measures for promoting the reintegration of stroke survivors into the community. Data were collected from 188 stroke survivors (mean age 71.7 years) 12 months after discharge from a stroke rehabilitation hospital. Of these survivors, 128 (61 %) had suffered a first ever stroke, and 81 (43 %) had a right hemisphere lesion. Most (n = 156, 83 %) were living in their own home, though 32 (17 %) were living in residential care facilities. Path analysis was used to test a hypothesized model of participation restriction which included the direct and indirect effects between social, psychological and physical outcomes and demographic variables. Participation restriction was the dependent variable. Exogenous independent variables were age, functional ability, living arrangement and gender. Endogenous independent variables were depressive symptoms, state self-esteem and social support satisfaction. The path coefficients showed functional ability having the largest direct effect on participation restriction. The results also showed that more depressive symptoms, low state self-esteem, female gender, older age and living in a residential care facility had a direct effect on participation restriction. The explanatory variables accounted for 71% of the variance in explaining participation restriction. Prediction models have empirical and practical applications such as suggesting important factors to be considered in promoting stroke recovery. The findings suggest that interventions offered over the course of rehabilitation should be aimed at improving functional ability and promoting psychological aspects of recovery. These are likely to enhance stroke survivors resume or maximize their social participation so that they may fulfill productive and positive life roles.

Predicting effects of monotony on driver’s vigilance

Monotony has been identified as a contributing factor to road crashes. Drivers’ ability to react to unpredictable events deteriorates when exposed to highly predictable and uneventful driving tasks, such as driving on Australian rural roads, many of which are monotonous by nature. Highway design in particular attempts to reduce the driver’s task to a merely lane-keeping one. Such a task provides little stimulation and is monotonous, thus affecting the driver’s attention which is no longer directed towards the road. Inattention contributes to crashes, especially for professional drivers. Monotony has been studied mainly from the endogenous perspective (for instance through sleep deprivation) without taking into account the influence of the task itself (repetitiveness) or the surrounding environment. The aim and novelty of this thesis is to develop a methodology (mathematical framework) able to predict driver lapses of vigilance under monotonous environments in real time, using endogenous and exogenous data collected from the driver, the vehicle and the environment. Existing approaches have tended to neglect the specificity of task monotony, leaving the question of the existence of a “monotonous state” unanswered. Furthermore the issue of detecting vigilance decrement before it occurs (predictions) has not been investigated in the literature, let alone in real time. A multidisciplinary approach is necessary to explain how vigilance evolves in monotonous conditions. Such an approach needs to draw on psychology, physiology, road safety, computer science and mathematics. The systemic approach proposed in this study is unique with its predictive dimension and allows us to define, in real time, the impacts of monotony on the driver’s ability to drive. Such methodology is based on mathematical models integrating data available in vehicles to the vigilance state of the driver during a monotonous driving task in various environments. The model integrates different data measuring driver’s endogenous and exogenous factors (related to the driver, the vehicle and the surrounding environment). Electroencephalography (EEG) is used to measure driver vigilance since it has been shown to be the most reliable and real time methodology to assess vigilance level. There are a variety of mathematical models suitable to provide a framework for predictions however, to find the most accurate model, a collection of mathematical models were trained in this thesis and the most reliable was found. The methodology developed in this research is first applied to a theoretically sound measure of sustained attention called Sustained Attention Response to Task (SART) as adapted by Michael (2010), Michael and Meuter (2006, 2007). This experiment induced impairments due to monotony during a vigilance task. Analyses performed in this thesis confirm and extend findings from Michael (2010) that monotony leads to an important vigilance impairment independent of fatigue. This thesis is also the first to show that monotony changes the dynamics of vigilance evolution and tends to create a “monotonous state” characterised by reduced vigilance. Personality traits such as being a low sensation seeker can mitigate this vigilance decrement. It is also evident that lapses in vigilance can be predicted accurately with Bayesian modelling and Neural Networks. This framework was then applied to the driving task by designing a simulated monotonous driving task. The design of such task requires multidisciplinary knowledge and involved psychologist Rebecca Michael. Monotony was varied through both the road design and the road environment variables. This experiment demonstrated that road monotony can lead to driving impairment. Particularly monotonous road scenery was shown to have the most impact compared to monotonous road design. Next, this study identified a variety of surrogate measures that are correlated with vigilance levels obtained from the EEG. Such vigilance states can be predicted with these surrogate measures. This means that vigilance decrement can be detected in a car without the use of an EEG device. Amongst the different mathematical models tested in this thesis, only Neural Networks predicted the vigilance levels accurately. The results of both these experiments provide valuable information about the methodology to predict vigilance decrement. Such an issue is quite complex and requires modelling that can adapt to highly inter-individual differences. Only Neural Networks proved accurate in both studies, suggesting that these models are the most likely to be accurate when used on real roads or for further research on vigilance modelling. This research provides a better understanding of the driving task under monotonous conditions. Results demonstrate that mathematical modelling can be used to determine the driver’s vigilance state when driving using surrogate measures identified during this study. This research has opened up avenues for future research and could result in the development of an in-vehicle device predicting driver vigilance decrement. Such a device could contribute to a reduction in crashes and therefore improve road safety.