16 research outputs found
Kinetic analysis of the role of plasma protein binding on brain drug uptake: effect of site specific binding and flow
No full textDrug delivery to brain is complicated by multiple factors including low blood-brain barrier (BBB) passive permeability, active BBB efflux transport, and plasma protein binding. The mechanism and quantitative contribution of plasma protein binding to brain drug uptake have been debated for >25 years. In most studies, measured brain drug uptake has exceeded that predicted by the in vitro serum free fraction (fu), leading to the hypothesis that an alteration occurs in the plasma protein as it passes through the capillary circulation producing enhanced disassociation and a marked increased in fu. Drugs bind to specific sites on plasma proteins with the primary contributors being Sudlow site I and II of albumin and the central binding site of á1-acid glycoprotein (AAG). We tested the enhanced dissociation hypothesis using drugs that bind selectively to albumin Sudlow I, albumin Sudlow II, AAG and drugs that bind to more than one site. Brain uptake (Kin) was measured in the absence and presence of plasma protein using the in situ rat brain perfusion technique. Drug fu in the arterial perfusate was measured by ultrafiltration and/or equilibrium dialysis. From the measured brain uptake, a BBB permeability-surface area (PSu) was calculated. Brain uptake Kin for each tested drug agreed with that predicted using the Kety-Crone-Renkin equation [Kin = F(1-e-fu x PSu/F)] from separate measurements of BBB PSu, fu and brain perfusion fluid flow (F). No statistically significant evidence was found for enhanced dissociation. In some experiments, drug uptake Kin was determined in the presence and absence of plasma protein at different F. For drugs with a BBB PSu/F 1.0, plasma protein binding was nonrestrictive on brain uptake so that the single-pass brain extraction exceeded fu. By decreasing F, a compound could be transitioned from restrictive to nonrestrictive. In summary, the results emphasize the importance of plasma protein binding in brain drug uptake and suggest that accurate predictions can be obtained using the modified Kety-Crone Renkin equation
Authors, authorship order, the moving finger writes
No full textThere has been a phenomenal increase in the number of research papers with multiple authors. Increasing academic pressures and halo around individuals with prolific publications have made many aspirants to claim authorship. Increasing number of authors has brought its own issues of author credits, disputes, rivalry, and a degree of unwelcome scramble for credit sharing. Many unresolved issues about authorship and various guidelines and admonitions are more often infringed than adhered to. The position of the first and last author seem to be well recognized in medical and dental journals, but the fate of middle authors is left to guessing and often of inconsequential importance. Most of these issues, as well as fraud, misconduct in medical research publications, have been discussed amply but too of no avail. It is comforting to know that except for small shouts and whispers, dental research has been relatively free from scams and frauds. The complacency, however, needs to be tempered with constant vigil against fraud, falsification and fabrication of research reports. Honest authorship, vigilant editors, robust peer review, and a discerning readership are the sine qua non for a good research paper. Academic institutions and selection committees should be concentrating on the quality of research papers and not enamored of their number
Female Leaders and Pandemic Response: Analysis of Gender Stereotypes in Media
No full textMedia coverage of female politicians can affect how the public perceives them as leaders. The language used by the media to portray female leaders is crucial in constructing their image as politicians. This study explored how female national leaders were represented by the global media during the pandemic and how it resulted in enhancing their stereotypical image. Social constructionism was used as the theoretical framework as the study focused on the gender representations of leaders and the language used by the media, both of which are social constructs.
News articles from the top 25 English-language news websites in the years 2020 and 2021 were selected to collect the data for the research. A combination of quantitative and qualitative assessment was done as part of the content analysis. 78 news articles were analyzed in total on the basis of nine attributes mentioned in the articles: age, professional background, family background, dressing style, characteristics associated with femininity, characteristics associated with masculinity, gender, details on personal lives, and sentiments expressed by the leaders. These attributes were formulated by the author on the basis of knowledge gathered from previous academic research. The results from the quantitative analysis were further evaluated in reference to the findings of previous research to gain a comprehensive understanding of the topic.
The results of the study suggest that the gender of the leader plays a crucial role in their media portrayal. Feminine traits are often associated with female leaders rather than their competency as leaders. Moreover, irrelevant aspects such as personal details, family, and professional background are given importance while covering news related to female leaders. While, initially, the thesis was also interested to explore whether the stereotypes were challenged, the findings of this study confirms that the language used by the media to represent female national leaders during the pandemic reiterated their stereotypical image as politicians. The results also cite the importance of media representations of female leaders and how present concept of leadership needs to improvise
Reimagining Spiritual Horizons: Critical Reflections on Reinventing Sanatana Dharma
No full textThis commentary critically examines Mukundan P.R\u27s significant work Reinventing Sanatana Dharma: The Spiritual Movement of Navajyoti Sree Karunakara Guru for a New India and a New World Order, New Delhi, India, Authors Press, 2024, Pages: 212, Rs. 500, Paperback, ISBN: 97-93-5529-976-5. The book critically reinterprets the Indian philosophical concept of Sanatana Dharma through the teachings of Navajyoti Sree Karunakara Guru, a spiritual visionary born in Kerala, India. The book challenges the traditional perceptions of Hindu philosophy, presenting Sanatana Dharma as a universal, non-discriminatory spiritual science. It explores key distinctions between Sanatana Dharma and mainstream Hinduism, addressing themes such as the spiritual evolution of consciousness, the significance of a true guru, and the reinterpretation of certain key Upanishadic concepts. While the book’s non-linear structure challenges narrative flow, its interdisciplinary approach—bridging Indian scriptures and contemporary scientific insights—offers a fresh perspective on spirituality. This review, therefore, highlights the book’s contribution to spiritual discourse and its potential to inspire a re-examination of Indian philosophy. In addition, the commentary also hints at what the author names a ‘syncretic monotheism’, which integrates the most profound principles of various religions into the overarching framework of Sanatana Dharma, contributing to sustainable development, making it an engaging resource for scholars, seekers, and readers interested in the intersection of religion and spirituality
Role of site-specific binding to plasma albumin in drug availability to
No full textABSTRACT Many studies have reported greater drug uptake into brain than that predicted based upon existing models using the free fraction (f u ) of drug in arterial serum. To explain this difference, circulating plasma proteins have been suggested to interact with capillary membrane in vivo to produce a conformational change that favors net drug dissociation and elevation of f u . Albumin, the principal binding protein in plasma, has two main drug binding sites, Sudlow I and II. We tested this hypothesis using drugs that bind selectively to either site I (warfarin) or site II (ibuprofen), as well as mixed ligands that have affinity for both sites (tolbutamide and valproate). Brain uptake was determined in the presence and absence of albumin using the in situ rat brain perfusion technique. Unidirectional brain uptake transfer constants (K in ) were measured and compared with those predicted using the modified Kety-Crone-Renkin model: Ϫfu ϫ PSu/F ), where F is perfusion flow and PS u is the permeability-surface area product to free drug of brain capillaries. The results demonstrated good agreement between measured and predicted K in over a 100-fold range in perfusion fluid albumin concentration using albumin from three different species (i.e., human, bovine, and rat), as well as whole-rat serum. K in decreased in the presence of albumin in direct proportion to perfusion fluid f u with constant PS u . The results show that brain uptake of selected Sudlow site I and II ligands matches that predicted by the modified Kety-Crone-Renkin model with no evidence for enhanced dissociation
Time-dependent Mechanical Properties and Structural Behaviour of Graphene Nanoplatelet-reinforced Concrete
No full textConcrete with high volumes of supplementary cementitious materials often have lower early age compressive strength and slower strength gain with time. It has been reported that the addition of graphene nanoplatelets (GNPs) enhances concrete compressive strength. However, the ability of GNPs to increase the early age concrete compressive strength has not been investigated, and there has been limited testing of structural elements of GNP-containing concrete. This study examines the mechanical properties of low cement concrete between 1- and 28-days of curing with varying GNP concentrations. Furthermore, reinforced concrete beams with GNPs were tested at 3 and 28 days to investigate their structural behaviour. The results show compressive strength increases of up to 31% at early ages for a GNP concentration of 0.15 wt% of cement, but no overall changes in the structural behaviour.The presentation of the authors' names and (or) special characters in the title of the pdf file of the accepted manuscript may differ slightly from what is displayed on the item page. The information in the pdf file of the accepted manuscript reflects the original submission by the author
Applications of Clinically Relevant Dissolution Testing : Workshop Summary Report
No full textThis publication summarizes the proceedings of day 3 of a 3-day workshop on "Dissolution and Translational Modeling Strategies Enabling Patient-Centric Product Development." Specifically, this publication discusses the current approaches in building clinical relevance into drug product development for solid oral dosage forms, along with challenges that both industry and regulatory agencies are facing in setting clinically relevant drug product specifications (CRDPS) as presented at the workshop. The concept of clinical relevance is a multidisciplinary effort which implies an understanding of the relationship between the critical quality attributes (CQAs) and their impact on predetermined clinical outcomes. Developing this level of understanding, in many cases, requires introducing deliberate but meaningful variations into the critical material attributes (CMAs) and critical process parameters (CPPs) to establish a relationship between the resulting in vitro dissolution/release profiles and in vivo PK performance, a surrogate for clinical outcomes. Alternatively, with the intention of improving the efficiency of the drug product development process by limiting the burden of conducting in vivo studies, this understanding can be either built, or at least enhanced, through in silico efforts, such as IVIVC and physiologically based pharmacokinetic (PBPK) absorption modeling and simulation (M&S). These approaches enable dissolution testing to establish safe boundaries and reject drug product batches falling outside of the established safe range (e.g., due to inadequate in vivo performance) enabling the method to become clinically relevant. Ultimately, these efforts contribute towards patient-centric drug product development and allow regulatory flexibility throughout the lifecycle of the drug product.</p
Brain endothelial permeability, transport, and flow assessed over 10 orders of magnitude using the in situ brain perfusion technique
No full textBackground Cerebral blood flow normally places a limit on the magnitude of brain vascular permeability (P) that can be measured in vivo. At normal cerebral blood flow, this limit falls at the lower end of lipophilicity for most FDAapproved CNS drugs. In this study, we report on two methods that can be used to overcome this limitation and measure brain vascular permeability values that are up to ~1000 times higher using the in situ brain perfusion technique.
Methods Rat brain was perfused with physiological saline at increased flow rate and in the presence of various concentrations of plasma protein, serum albumin or alpha-acid glycoprotein. Plasma protein was added to the saline perfusion fluid to lower extraction into the measurable range using the Crone Renkin “diffusion-flow” equation to calculate brain PoS.
Results Cerebrovascular Po was determined for 125 solutes, of which 78 showed little or no evidence of active efflux transport. Fifty of the solutes were in the lipophilicity zone (Log Poct 1–5) of most FDA-approved CNS drugs. Care was taken to ensure the integrity of the brain vasculature during perfusion and to measure flow accurately using markers that had been verified for the flow rates. The results showed a linear relationship between Log Po and Log Poct over ~10 orders of magnitude with values for diazepam, estradiol, testosterone, and other agents that exceed prior published values by fivefold to 200-fold.
Conclusions The results show that brain vascular permeability can be measured directly in vivo for highly lipophilic solutes and the PS values obtained match reasonably with that predicted by the Crone-Renkin flow diffusion equation with care taken to validate the accuracy for the component measurements and with no need to invoke “enhanced” or “induced” dissociation
Impact of the US FDA “Biopharmaceutics Classification System” (BCS) Guidance on Global Drug Development
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