26 research outputs found
Clinical Relevance of Dissolution Testing in Quality by Design
Quality by design (QbD) has recently been introduced in pharmaceutical product development in a regulatory context and the process of implementing such concepts in the drug approval process is presently on-going. This has the potential to allow for a more flexible regulatory approach based on understanding and optimisation of how design of a product and its manufacturing process may affect product quality. Thus, adding restrictions to manufacturing beyond what can be motivated by clinical quality brings no benefits but only additional costs. This leads to a challenge for biopharmaceutical scientists to link clinical product performance to critical manufacturing attributes. In vitro dissolution testing is clearly a key tool for this purpose and the present bioequivalence guidelines and biopharmaceutical classification system (BCS) provides a platform for regulatory applications of in vitro dissolution as a marker for consistency in clinical outcomes. However, the application of these concepts might need to be further developed in the context of QbD to take advantage of the higher level of understanding that is implied and displayed in regulatory documentation utilising QbD concepts. Aspects that should be considered include identification of rate limiting steps in the absorption process that can be linked to pharmacokinetic variables and used for prediction of bioavailability variables, in vivo relevance of in vitro dissolution test conditions and performance/interpretation of specific bioavailability studies on critical formulation/process variables. This article will give some examples and suggestions how clinical relevance of dissolution testing can be achieved in the context of QbD derived from a specific case study for a BCS II compound
The reference frame for encoding and retention of motion depends on stimulus set size
YesThe goal of this study was to investigate the reference
frames used in perceptual encoding and storage of visual
motion information. In our experiments, observers viewed
multiple moving objects and reported the direction of motion
of a randomly selected item. Using a vector-decomposition
technique, we computed performance during smooth pursuit
with respect to a spatiotopic (nonretinotopic) and to a
retinotopic component and compared them with performance
during fixation, which served as the baseline. For the stimulus
encoding stage, which precedes memory, we found that the
reference frame depends on the stimulus set size. For a single
moving target, the spatiotopic reference frame had the most
significant contribution with some additional contribution
from the retinotopic reference frame. When the number of
items increased (Set Sizes 3 to 7), the spatiotopic reference
frame was able to account for the performance. Finally, when
the number of items became larger than 7, the distinction
between reference frames vanished. We interpret this finding
as a switch to a more abstract nonmetric encoding of motion
direction. We found that the retinotopic reference frame was
not used in memory. Taken together with other studies, our
results suggest that, whereas a retinotopic reference frame
may be employed for controlling eye movements, perception
and memory use primarily nonretinotopic reference frames.
Furthermore, the use of nonretinotopic reference frames appears
to be capacity limited. In the case of complex stimuli, the
visual system may use perceptual grouping in order to simplify
the complexity of stimuli or resort to a nonmetric abstract
coding of motion information
Association of respiratory symptoms and lung function with occupation in the multinational Burden of Obstructive Lung Disease (BOLD) study
Background
Chronic obstructive pulmonary disease has been associated with exposures in the workplace. We aimed to assess the association of respiratory symptoms and lung function with occupation in the Burden of Obstructive Lung Disease study.
Methods
We analysed cross-sectional data from 28 823 adults (≥40 years) in 34 countries. We considered 11 occupations and grouped them by likelihood of exposure to organic dusts, inorganic dusts and fumes. The association of chronic cough, chronic phlegm, wheeze, dyspnoea, forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1)/FVC with occupation was assessed, per study site, using multivariable regression. These estimates were then meta-analysed. Sensitivity analyses explored differences between sexes and gross national income.
Results
Overall, working in settings with potentially high exposure to dusts or fumes was associated with respiratory symptoms but not lung function differences. The most common occupation was farming. Compared to people not working in any of the 11 considered occupations, those who were farmers for ≥20 years were more likely to have chronic cough (OR 1.52, 95% CI 1.19–1.94), wheeze (OR 1.37, 95% CI 1.16–1.63) and dyspnoea (OR 1.83, 95% CI 1.53–2.20), but not lower FVC (β=0.02 L, 95% CI −0.02–0.06 L) or lower FEV1/FVC (β=0.04%, 95% CI −0.49–0.58%). Some findings differed by sex and gross national income.
Conclusion
At a population level, the occupational exposures considered in this study do not appear to be major determinants of differences in lung function, although they are associated with more respiratory symptoms. Because not all work settings were included in this study, respiratory surveillance should still be encouraged among high-risk dusty and fume job workers, especially in low- and middle-income countries.publishedVersio
Effect of renal denervation on blood pressure in the presence of antihypertensive drugs: 6-month efficacy and safety results from the SPYRAL HTN-ON MED proof-of-concept randomised trial.
: Previous catheter-based renal denervation studies have reported variable efficacy results. We aimed to evaluate safety and blood pressure response after renal denervation or sham control in patients with uncontrolled hypertension on antihypertensive medications with drug adherence testing. : In this international, randomised, single-blind, sham-control, proof-of-concept trial, patients with uncontrolled hypertension (aged 20-80 years) were enrolled at 25 centres in the USA, Germany, Japan, UK, Australia, Austria, and Greece. Eligible patients had an office systolic blood pressure of between 150 mm Hg and 180 mm Hg and a diastolic blood pressure of 90 mm Hg or higher; a 24 h ambulatory systolic blood pressure of between 140 mm Hg and 170 mm Hg at second screening; and were on one to three antihypertensive drugs with stable doses for at least 6 weeks. Patients underwent renal angiography and were randomly assigned to undergo renal denervation or sham control. Patients, caregivers, and those assessing blood pressure were masked to randomisation assignments. The primary efficacy endpoint was blood pressure change from baseline (measured at screening visit two), based on ambulatory blood pressure measurements assessed at 6 months, as compared between treatment groups. Drug surveillance was used to assess medication adherence. The primary analysis was done in the intention-to-treat population. Safety events were assessed through 6 months as per major adverse events. This trial is registered with ClinicalTrials.gov, number NCT02439775, and follow-up is ongoing. : Between July 22, 2015, and June 14, 2017, 467 patients were screened and enrolled. This analysis presents results for the first 80 patients randomly assigned to renal denervation (n=38) and sham control (n=42). Office and 24 h ambulatory blood pressure decreased significantly from baseline to 6 months in the renal denervation group (mean baseline-adjusted treatment differences in 24 h systolic blood pressure -7·0 mm Hg, 95% CI -12·0 to -2·1; p=0·0059, 24 h diastolic blood pressure -4·3 mm Hg, -7·8 to -0·8; p=0.0174, office systolic blood pressure -6·6 mm Hg, -12·4 to -0·9; p=0·0250, and office diastolic blood pressure -4·2 mm Hg, -7·7 to -0·7; p=0·0190). The change in blood pressure was significantly greater at 6 months in the renal denervation group than the sham-control group for office systolic blood pressure (difference -6·8 mm Hg, 95% CI -12·5 to -1·1; p=0·0205), 24 h systolic blood pressure (difference -7·4 mm Hg, -12·5 to -2·3; p=0·0051), office diastolic blood pressure (difference -3·5 mm Hg, -7·0 to -0·0; p=0·0478), and 24 h diastolic blood pressure (difference -4·1 mm Hg, -7·8 to -0·4; p=0·0292). Evaluation of hourly changes in 24 h systolic blood pressure and diastolic blood pressure showed blood pressure reduction throughout 24 h for the renal denervation group. 3 month blood pressure reductions were not significantly different between groups. Medication adherence was about 60% and varied for individual patients throughout the study. No major adverse events were recorded in either group. : Renal denervation in the main renal arteries and branches significantly reduced blood pressure compared with sham control with no major safety events. Incomplete medication adherence was common. : Medtronic.<br/
Cohort Profile: Burden of Obstructive Lung Disease (BOLD) study
The Burden of Obstructive Lung Disease (BOLD) study was established to assess the prevalence of chronic airflow obstruction, a key characteristic of chronic obstructive pulmonary disease, and its risk factors in adults (≥40 years) from general populations across the world.
The baseline study was conducted between 2003 and 2016, in 41 sites across Africa, Asia, Europe, North America, the Caribbean and Oceania, and collected high-quality pre- and post-bronchodilator spirometry from 28 828 participants.
The follow-up study was conducted between 2019 and 2021, in 18 sites across Africa, Asia, Europe and the Caribbean. At baseline, there were in these sites 12 502 participants with high-quality spirometry. A total of 6452 were followed up, with 5936 completing the study core questionnaire. Of these, 4044 also provided high-quality pre- and post-bronchodilator spirometry.
On both occasions, the core questionnaire covered information on respiratory symptoms, doctor diagnoses, health care use, medication use and ealth status, as well as potential risk factors. Information on occupation, environmental exposures and diet was also collected
Prevalence and determinants of chronic respiratory diseases in adults in Sudan
BACKGROUND:
Chronic respiratory diseases (CRDs) are considered a significant cause of morbidity and mortality worldwide, although data from Africa are limited. This study aimed to determine the prevalence and determinants of CRDs in Khartoum, Sudan.
METHODS:
Data were collected from 516 participants aged ≥40 years, who had completed a questionnaire and undertook pre- and post-bronchodilator spirometry testing. Trained field workers administered the questionnaires and conducted spirometry. Survey-weighted prevalence of respiratory symptoms and spirometric abnormalities were estimated. Regression analysis models were used to identify risk factors for chronic lung diseases.
RESULTS:
Using the Third National Health and Nutrition Examination Survey, 1988–1994 (NHANES III) reference equations, the prevalence of chronic airflow obstruction (CAO) was 10%. The main risk factor was older age, 60–69 years (OR 3.16, 95% CI 1.20–8.31). Lower education, high body mass index and a history of TB were also identified as significant risk factors. The prevalence of a low forced vital capacity (FVC) using NHANES III was 62.7% (SE 2.2) and 11.3% (SE 1.4) using locally derived values.
CONCLUSION:
The prevalence of spirometric abnormality, mainly low FVC, was high, suggesting that CRD is of substantial public health importance in urban Sudan. Strategies for the prevention and control of these problems are needed
Prevalence and determinants of chronic respiratory diseases in adults in Khartoum State, Sudan
Background: Chronic respiratory diseases are considered a significant cause of morbidity and mortality worldwide, although data from Africa are limited. This study aimed to determine the prevalence and determinants of chronic respiratory diseases in Khartoum, Sudan. Methods: Data was collected from 516 participants, aged ≥ 40, who had completed a questionnaire and undertook pre- and post-bronchodilator spirometry testing. Trained field workers conducted questionnaires and spirometry. Survey-weighted prevalence of respiratory symptoms and spirometric abnormalities were estimated. Regression analysis models were used to identify risk factors for chronic lung diseases. Results: Using the NHANESIII reference equations, the prevalence of Chronic Airflow Obstruction (CAO) was 10%. The main risk factor was older age 60-69 years (Odds ratio 3.16, 95% Confidence Interval 1.20 – 8.31). Lower education, high body mass index and a history of tuberculosis were also identified as significant risk factors. The prevalence of a low forced vital capacity (FVC) using NHANES III was 62.7% [SE 2.2] and 11.3% [SE 1.4] using locally derived values. Conclusion: The prevalence of spirometric abnormality mainly (low FVC); was high suggesting that chronic respiratory disease is of substantial public health importance in urban Sudan. Strategies for the prevention and control of these problems are needed