Harnessing Resilience in the Healthy Ageing Discourse: Insights from Attappadi Indigenous Older Adults, Kerala, India.

In this "Decade of Healthy Ageing," the integration of resilience into the healthy aging discourse becomes paramount, particularly in the context of indigenous communities grappling with the enduring effects of historical oppression, persistent poverty, and health disparities in their aging journey. Employing a phenomenological lens, this study seeks to derive the resilient characteristics exhibited by the Attappadi indigenous older adults of Kerala, aiming to explore the role of resilience in their pursuit of healthy aging. In-depth phenomenological interviews (n = 34), observation, and document analysis have revealed four key themes: A life course marked by adversities, Embracing the unyielding strength within, Personal resilience catalysts, and Extrinsic resilience catalysts. The participants exhibited a reasonably well-functioning collective, given their persistent adversities in their life course. Narratives illuminated a notable connection between the presence of resilience characteristics and the overall functioning of older adults. From a social work standpoint on resilience, this article underscores the vital interplay between individual agency and environmental factors in addressing adversity. The article advocates culturally sensitive, asset-based strategies to strengthen indigenous older adults' intrinsic and extrinsic resilience to ensure that they are not left behind in the global pursuit of healthy aging.

Derailed protein turnover in the aging mammalian brain.

Efficient protein turnover is essential for cellular homeostasis and organ function. Loss of proteostasis is a hallmark of aging culminating in severe dysfunction of protein turnover. To investigate protein turnover dynamics as a function of age, we performed continuous in vivo metabolic stable isotope labeling in mice along the aging continuum. First, we discovered that the brain proteome uniquely undergoes dynamic turnover fluctuations during aging compared to heart and liver tissue. Second, trends in protein turnover in the brain proteome during aging showed sex-specific differences that were tightly tied to cellular compartments. Next, parallel analyses of the insoluble proteome revealed that several cellular compartments experience hampered turnover, in part due to misfolding. Finally, we found that age-associated fluctuations in proteasome activity were associated with the turnover of core proteolytic subunits, which was recapitulated by pharmacological suppression of proteasome activity. Taken together, our study provides a proteome-wide atlas of protein turnover across the aging continuum and reveals a link between the turnover of individual proteasome subunits and the age-associated decline in proteasome activity.

Amyloid fibril proteomics of AD brains reveals modifiers of aggregation and toxicity.

BACKGROUND: The accumulation of amyloid beta (Aß) peptides in fibrils is prerequisite for Alzheimer's disease (AD). Our understanding of the proteins that promote Aß fibril formation and mediate neurotoxicity has been limited due to technical challenges in isolating pure amyloid fibrils from brain extracts. METHODS: To investigate how amyloid fibrils form and cause neurotoxicity in AD brain, we developed a robust biochemical strategy. We benchmarked the success of our purifications using electron microscopy, amyloid dyes, and a large panel of Aß immunoassays. Tandem mass-spectrometry based proteomic analysis workflows provided quantitative measures of the amyloid fibril proteome. These methods allowed us to compare amyloid fibril composition from human AD brains, three amyloid mouse models, transgenic Aß42 flies, and Aß42 seeded cultured neurons. RESULTS: Amyloid fibrils are primarily composed by Aß42 and unexpectedly harbor Aß38 but generally lack Aß40 peptides. Multidimensional quantitative proteomics allowed us to redefine the fibril proteome by identifying 20 new amyloid-associated proteins. Notably, we confirmed 57 previously reported plaque-associated proteins. We validated a panel of these proteins as bona fide amyloid-interacting proteins using antibodies and orthogonal proteomic analysis. One metal-binding chaperone metallothionein-3 is tightly associated with amyloid fibrils and modulates fibril formation in vitro. Lastly, we used a transgenic Aß42 fly model to test if knock down or over-expression of fibril-interacting gene homologues modifies neurotoxicity. Here, we could functionally validate 20 genes as modifiers of Aß42 toxicity in vivo. CONCLUSIONS: These discoveries and subsequent confirmation indicate that fibril-associated proteins play a key role in amyloid formation and AD pathology.

A case report: Female primary urethral carcinoma presenting as vulval mass.

INTRODUCTION: Primary urethral carcinoma is a rare disease with overall poorer outcomes in the past. It is relatively more uncommon in female sex. CLINICAL PRESENTATION: We present a case of a female with primary urethral carcinoma that presented atypically as a vulval mass without any features of storage, voiding lower urinary tract symptoms, or gross haematuria. DISCUSSION: As primary urethral carcinoma is rare in occurrence, prospective studies are limited so as the recommendations to guide treatment options. Treatment recommendations are still on development from different small-scale studies as well as from data in higher volume centers. Management options depends on location, extent, histology of the lesion as well as on sex of the patient and fitness of the patient. CONCLUSION: Early diagnosis and treatment with multidisciplinary consult and multimodality will improve the overall survival rate and quality of life of the patients.

Cocrystals by Design: A Rational Coformer Selection Approach for Tackling the API Problems.

Active pharmaceutical ingredients (API) with unfavorable physicochemical properties and stability present a significant challenge during their processing into final dosage forms. Cocrystallization of such APIs with suitable coformers is an efficient approach to mitigate the solubility and stability concerns. A considerable number of cocrystal-based products are currently being marketed and show an upward trend. However, to improve the API properties by cocrystallization, coformer selection plays a paramount role. Selection of suitable coformers not only improves the drug's physicochemical properties but also improves the therapeutic effectiveness and reduces side effects. Numerous coformers have been used till date to prepare pharmaceutically acceptable cocrystals. The carboxylic acid-based coformers, such as fumaric acid, oxalic acid, succinic acid, and citric acid, are the most commonly used coformers in the currently marketed cocrystal-based products. Carboxylic acid-based coformers are capable of forming the hydrogen bond and contain smaller carbon chain with the APIs. This review summarizes the role of coformers in improving the physicochemical and pharmaceutical properties of APIs, and deeply explains the utility of afore-mentioned coformers in API cocrystal formation. The review concludes with a brief discussion on the patentability and regulatory issues related to pharmaceutical cocrystals.

Current Trends in API Co-Processing: Spherical Crystallization and Co-Precipitation Techniques.

Active Pharmaceutical Ingredients (APIs) do not always exhibit processable physical properties, which makes their processing in an industrial setup very demanding. These issues often lead to poor robustness and higher cost of the drug product. The issue can be mitigated by co-processing the APIs using suitable solvent media-based techniques to streamline pharmaceutical manufacturing operations. Some of the co-processing methods are the amalgamation of API purification and granulation steps. These techniques also exhibit adequate robustness for successful adoption by the pharmaceutical industry to manufacture high quality drug products. Spherical crystallization and co-precipitation are solvent media-based co-processing approaches that enhances the micromeritic and dissolution characteristics of problematic APIs. These methods not only improve API characteristics but also enable direct compression into tablets. These methods are economical and time-saving as they have the potential for effectively circumventing the granulation step, which can be a major source of variability in the product. This review highlights the recent advancements pertaining to these techniques to aid researchers in adopting the right co-processing method. Similarly, the possibility of scaling up the production of co-processed APIs by these techniques is discussed. The continuous manufacturability by co-processing is outlined with a short note on Process Analytical Technology (PAT) applicability in monitoring and improving the process.

Co-Crystallization Approach to Enhance the Stability of Moisture-Sensitive Drugs.

Stability is an essential quality attribute of any pharmaceutical formulation. Poor stability can change the color and physical appearance of a drug, directly impacting the patient's perception. Unstable drug products may also face loss of active pharmaceutical ingredients (APIs) and degradation, making the medicine ineffective and toxic. Moisture content is known to be the leading cause of the degradation of nearly 50% of medicinal products, leading to impurities in solid dose formulations. The polarity of the atoms in an API and the surface chemistry of API particles majorly influence the affinity towards water molecules. Moisture induces chemical reactions, including free water that has also been identified as an important factor in determining drug product stability. Among the various approaches, crystal engineering and specifically co-crystals, have a proven ability to increase the stability of moisture-sensitive APIs. Other approaches, such as changing the salt form, can lead to solubility issues, thus making the co-crystal approach more suited to enhancing hygroscopic stability. There are many reported studies where co-crystals have exhibited reduced hygroscopicity compared to pure API, thereby improving the product's stability. In this review, the authors focus on recent updates and trends in these studies related to improving the hygroscopic stability of compounds, discuss the reasons behind the enhanced stability, and briefly discuss the screening of co-formers for moisture-sensitive drugs.

Unraveling the Link: A Comprehensive Literature Review of Type 2 Diabetes and Menopause Onset.

Women with diabetes mellitus (DM), a metabolic endocrine illness, may experience a variety of reproductive problems. The age at menopause onset has been extensively studied as a major predictor of women's health in the future; however, its relationship to diabetes in Indian women has received less attention. This literature review looked at the consequences of diabetes in women as well as the association between diabetes and the age at which menopause begins. The average age at menopause onset among women with type 2 diabetes mellitus (T2DM) has decreased globally. According to one Indian study, the average menopause age dropped to 45 years for 26% of women with T2DM. In the current review, 10 studies indicated that women with T2DM displayed an imbalanced hormonal profile resulting in an extended anovulatory period. Two investigations highlighted the significance of altered body composition of women with T2DM, thereby suggesting obesity as the primary risk factor of ovarian aging and early climacteric symptoms. T2DM may lower the average age at menopause onset; however, further research on Indian women is necessary. There is a need of studies on T2DM in premenopausal women are needed to demonstrate how the changes in body composition impact the age at which menopause begins. Delaying the onset of menopause in women with T2DM necessitates diet and lifestyle interventions to minimize ovarian aging and hormonal imbalance.

Evaluation of glycemic status among hypercholesterolemic patients on atorvastatin in a tertiary care hospital - A retrospective study.

INTRODUCTION: Statins are effective in reducing low-density lipoprotein cholesterol and are favorable in primary and secondary prevention of cardiovascular disease. Recent large trials have linked the use of statins and increased incidence of new-onset diabetes mellitus, the possibility of worsening of glucose level in individuals with diabetes following statin therapy, and this possibility is increased with the use of atorvastatin. This study was undertaken to analyze the possibility of the diabetogenic potential of atorvastatin among hypercholesterolemic patients. MATERIALS AND METHODS: This retrospective cohort study was conducted in the cardiology department from July 2019 to December 2019. Patients on atorvastatin for more than 6 months with normoglycemia on commencement of therapy were included. The occurrence of prediabetes or new-onset diabetes mellitus after atorvastatin therapy is the outcome of the study. Adverse drug effects to atorvastatin were also recorded and WHO-UMC causality assessment was performed. Descriptive statistics were performed for baseline and demographic characteristics. RESULTS: Sixty study participants were included in the study. Eighteen (30%) study participants developed prediabetes with an HbA1c value of 5.97 ± 0.22 and 17 (28%) of participants developed new-onset diabetes mellitus with an HbA1c value of 7.24 ± 0.50. Atorvastatin at dose of 40 mg was found to be the most frequently prescribed dose. CONCLUSION: Atorvastatin has a dose-dependent risk of developing new-onset diabetes mellitus. Hence, the following statin therapy glycemic status should be periodically monitored especially in patients with a large dose of atorvastatin and also in patients with higher risk factors for diabetes.

Electron Tomographic Methods for Studying Organelles of the Murine Chemical Synapse.

Electron tomography of the chemical synapse provides important architectural information regarding the organization of synaptic organelles including synaptic vesicles, Nissl bodies, and early endosomes. Here, we describe methods for the preparation of select murine brain regions for high-pressure freezing, freeze substitution, and EM tomographic analysis of synaptic structures. The method uses fresh brain slices prepared using a vibratome and biopsy punches to collect specific brain regions of interest suitable for subsequent preservation and EM tomographic imaging.

Levetiracetam Treatment Normalizes Levels of Presynaptic Endocytosis Machinery and Restores Nonamyloidogenic APP Processing in App Knock-in Mice.

Toxic amyloid-beta (Aß) peptides, produced by sequential proteolytic cleavage of the amyloid precursor protein (APP), play a key role in the initial stage of Alzheimer's disease (AD). Increasing evidence indicates that Aß42 induces neuronal circuit hyperexcitability in the early stages of AD pathology. As a result, researchers have investigated treatments that modulate the excitatory/inhibitory imbalance as potential AD therapies. For example, levetiracetam, an atypical antiepileptic drug used to quell hyperexcitability, has garnered recent interest in the AD field, even though its exact mechanism(s) of action remains elusive. Here, we show that in APP knock-in mouse models of amyloid pathology, chronic levetiracetam administration decreases cortical Aß42 levels and lowers the amyloid plaque burden. In addition, using multiplexed tandem mass tag-quantitative mass spectrometry-based proteomic analysis, we determined that chronic levetiracetam administration selectively normalizes levels of presynaptic endocytic proteins. Finally, we found that levetiracetam treatment selectively lowers beta carboxyl-terminal fragment levels, while the abundance of full-length APP remains unchanged. In summary, this work reports that chronic treatment with levetiracetam serves as a useful therapeutic in AD by normalizing levels of presynaptic endocytic proteins and altering APP cleavage preference, leading to a decrease in both Aß42 levels and the amyloid plaque burden. These novel findings provide novel evidence for the previously documented therapeutic value of levetiracetam to mitigate AD pathology.

Pulse-Chase Proteomics of the App Knockin Mouse Models of Alzheimer's Disease Reveals that Synaptic Dysfunction Originates in Presynaptic Terminals.

Compromised protein homeostasis underlies accumulation of plaques and tangles in Alzheimer's disease (AD). To observe protein turnover at early stages of amyloid beta (Aß) proteotoxicity, we performed pulse-chase proteomics on mouse brains in three genetic models of AD that knock in alleles of amyloid precursor protein (APP) prior to the accumulation of plaques and during disease progression. At initial stages of Aß accumulation, the turnover of proteins associated with presynaptic terminals is selectively impaired. Presynaptic proteins with impaired turnover, particularly synaptic vesicle (SV)-associated proteins, have elevated levels, misfold in both a plaque-dependent and -independent manner, and interact with APP and Aß. Concurrent with elevated levels of SV-associated proteins, we found an enlargement of the SV pool as well as enhancement of presynaptic potentiation. Together, our findings reveal that the presynaptic terminal is particularly vulnerable and represents a critical site for manifestation of initial AD etiology. A record of this paper's transparent peer review process is included in the Supplemental Information.

Amorphous solid dispersion of nisoldipine by solvent evaporation technique: preparation, characterization, in vitro, in vivo evaluation, and scale up feasibility study.

The present study was designed to determine the applicability of a newly derived dimensionless number precipitation parameter, "supersaturation holding capacity (SHC)" in development of amorphous solid dispersion (ASD) of a rapidly crystallizing drug, nisoldipine. Also, ASD preparation from lab scale formulation technique to scalable spray drying technique followed by oral bioavailability study was demonstrated. Solution state screening of polymers was performed by determining nucleation induction time (tin) and SHC. With screened polymers, lab scale ASDs of nisoldipine were prepared using rotary evaporation (solvent evaporation) method, and the optimized stable ASDs were scaled up by spray drying. The ASDs were characterized by DSC, PXRD, and FTIR for amorphous nature and evaluated for apparent solubility, dissolution, and solid-state stability improvement. The spray dried ASDs were additionally evaluated for micrometric properties and oral bioavailability study.PVP grades demonstrated superior crystal growth inhibition properties (with 2-4-fold enhancements in SHC). ASDs prepared by both lab scale and scale-up technique using PVP stabilized the amorphous nisoldipine via antiplasticization effect that maintained the stability under accelerated stability conditions (40 °C/75% RH) for 6 months. Additionally, FTIR study confirmed the role of intermolecular interactions in amorphous state stabilization of PVP-based solid dispersions. PVP-based spray dried ASDs improved the apparent solubility 4-fold for PVP K17 and more than 3-fold for remaining spray dried ASDs. The enhanced solubility was translated to improved dissolution of the drug when compared with crystalline and amorphous form complementing the outcome of the solution state study. The spray dried ASD showed 2.3 and > 3-fold the improvement in Cmax and AUC (0-24 h) respectively when compared with crystalline nisoldipine during oral bioavailability study which highlights the significance of SHC parameter of polymers. The spray dried ASD has shown improved micromeritics properties then crystalline nisoldipine in terms of flow behavior.This unique study provides a rational strategy for selection of appropriate polymer in development of ASDs that can tackle both precipitation during dissolution and amorphous state stabilization in solid state and also considers the SHC in scale-up study. Graphical abstract.

Classification of the crystallization tendency of active pharmaceutical ingredients (APIs) and nutraceuticals based on their nucleation and crystal growth behaviour in solution state.

Supersaturated drug delivery systems are commonly used to address the problems of poor aqueous solubility posed by most of the active pharmaceutical ingredients (APIs). However, the supersaturated systems are highly unstable due to their high free energy levels and demonstrate a tendency to precipitate. Understanding the crystallization tendency based on the mechanisms of crystallization, that is nucleation and crystal growth, is imperative to design formulation strategies and select appropriate precipitation inhibitors. This study aims to provide a classification system, based on both the nucleation and crystal growth tendency in the solution state of 60 APIs and nutraceuticals (in absence of polymer) from their desupersaturation profiles monitored by UV-Visible spectroscopy. The APIs and nutraceuticals are divided into four classes based on their induction time (tind) and crystal growth rate as fast nucleators-fast crystal growth (class I), fast nucleators-slow crystal growth (class II), slow nucleators-fast crystal growth (class III) and slow nucleators-slow crystal growth (class IV). Most of the molecules fall in the class I and class IV. An easy-to-use protocol for nucleation and crystal growth studies has been optimized. This protocol will find application to assess the crystallization tendency of the molecules in the preliminary screening stages, enabling appropriate formulation strategies to inhibit crystallization.

Co amorphous valsartan nifedipine system: Preparation, characterization, in vitro and in vivo evaluation.

Co amorphous systems are supersaturated drug delivery systems which offer a basic platform for delivery of multicomponent adducts (combination of more than one active pharmaceutical ingredient (API)) and/or as a fixed dose combination therapy, in addition to their potential to improve the apparent solubility, dissolution rate and ultimately bioavailability of poorly water soluble APIs. In the present work, a new drug-drug co amorphous system namely valsartan-nifedipine was prepared by quench cooling technique. Prepared co amorphous system was characterized for its solid state behavior with the help of Fourier Transform Infrared spectroscopy (FTIR), Differential Scanning Calorimetry (DSC) and Powder X Ray Diffractometry (PXRD). The optimized co amorphous system was stable for 1 month when exposed to accelerated stability condition (40 ±â€¯2 °C and 75 ±â€¯5% RH). The improved stability of amorphous nifedipine in co amorphous system was attributed to improved miscibility and intra and intermolecular non-covalent interactions mainly due to presence of hydrogen bonding between valsartan and nifedipine which was studied by FTIR analysis. Co amorphous systems were evaluated by mainly in vitro dissolution and in vivo benefit. In vitro dissolution study showed nearly 5.66 folds and 1.61 folds improvement which was translated to 3.63 and 2.19 times enhancement in vivo Cmax for nifedipine and valsartan respectively.

Quantification of niclosamide polymorphic forms - A comparative study by Raman, NIR and MIR using chemometric techniques.

Niclosamide, an anthelmintic drug recently repurposed for its activity against cancer, crystallizes into three solvated forms, two monohydrates (NHa, NHb) and one anhydrous (NAn) form. NAn is sensitive to pseudopolymorphic transformations that affect its dissolution and consequently, its bioavailability. NAn exhibits a polymorphic conversion to metastable monohydrate (NHa) form during high-energy milling in presence of poorly soluble solvents like water. It is hence very important to quantify polymorphic conversion from NAn to NHa, as water is a commonly used solvent during various processing like ball milling and wet granulation. This main objective of the study was to examine the feasibility of Raman, NIR and MIR spectroscopic techniques for identification and quantification of polymorphic forms of niclosamide in binary mixtures and multicomponent mixtures. Calibration models were developed and validated by vibrational spectroscopic techniques in binary mixtures of NAn and NHa and in multicomponent mixtures by chemometric techniques. These techniques were further used to identify and quantify NHa during ball milling, granulation and in presence of other polymorphic forms of niclosamide. Identification and quantification of pseudopolymorphs in binary and multicomponent mixtures with an acceptable recovery of 100.13-102.99% for Raman and 100.07-101.28% for NIR with low % RSD of 2.38-3.12 for both techniques were obtained. The % NHa determined during ball milling and granulation was similar by NIR and Raman. Raman spectroscopy however showed a greater advantage over other techniques in determining the NHa in presence of NHb due to significant difference in the spectral region of hydrates, when compared to NIR and MIR.

Formulation and evaluation of cyclodextrin complexes for improved anticancer activity of repurposed drug: Niclosamide.

Niclosamide, previously used as an anthelmintic drug is currently being repurposed for its anticancer activity. Niclosamide is a brick like biopharmaceutical classification system (BCS) class II drug with poor aqueous solubility and dissolution consequently leading to low bioavailability. By considering the physicochemical properties and geometry of niclosamide, inclusion complex with cyclodextrin was prepared by freeze drying method and characterized using FT-IR, DSC, PXRD, and 1HNMR. In silico molecular modeling study was performed to study the possible interactions between niclosamide and cyclodextrin. The anticancer activity of niclosamide formulation was evaluated through in vitro cell cytotoxicity study using various cancer cell lines. The potential of niclosamide complex for improvement of the bioavailability was evaluated in male BALB/c mice. In vitro cytotoxicity studies indicated significantly higher cytotoxicity at lower concentrations and the pharmacokinetic studies showed significant improvement in Cmax and Tmax of niclosamide from cyclodextrin complex in comparison to pure niclosamide alone.

Cellulose based polymers in development of amorphous solid dispersions.

Cellulose derivatives have gained immense popularity as stabilizers for amorphous solid dispersion owing to their diverse physicochemical properties. More than 20 amorphous solid dispersion-based products that have been approved for marketing consist of cellulose derivatives as stabilizers, thus highlighting their importance in generation of amorphous solid dispersions. These polymers offer numerous advantages like drug solubilization, crystallization inhibition and improvement in release patterns of drugs. Exploring their potential and exploiting their chemistry and pH responsive behaviour have led to the synthesis of new derivatives that has broadened the scope of the use of cellulose derivatives in amorphous formulation development. The present review aims to provide an overview of different mechanisms by which these cellulose derivatives inhibit the crystallization of drugs in the solid state and from supersaturated solution. A summary of different categories of cellulose derivatives along with the newly explored polymers has been provided. A special segment on strengths, weaknesses, opportunities, and threats (SWOT) analysis and critical quality attributes (CQAs) which affect the performance of the cellulose based amorphous solid dispersion will aid the researchers in identifying the major challenges in the development of cellulose based solid dispersion and serve as a guide for further formulation development.

Determination of precipitation inhibitory potential of polymers from amorphous solid dispersions.

Precipitation inhibitory potential of polymers screened from precipitation study may be altered once it is formulated in amorphous solid dispersions (ASDs). OBJECTIVE: Present study was embarked with an objective to determine whether the polymers retain the same inhibitory potential after formulating them into ASDs. METHODS: Screening of polymers was based on a new dimensionless parameter 'Supersaturation Holding Capacity (SHC)' calculated from the precipitation study. Nifedipine ASDs were formulated using HPMC E3 and HPMC E50 (high SHC values), and HPMC K100M, PVP K25, and HPC M (low to moderate SHC values). Generated ASDs were characterized by DSC, FTIR, and PXRD and evaluated for stability under accelerated conditions (40˚C and 75% RH) for 6 months. RESULTS: Thermal analysis of the ASDs and theoretical prediction of the glass transition temperature (Tg) suggested a linear dependency of Tg on the content of HPMC E3 and HPMC E50. Under accelerated stability conditions, all ASDs of nifedipine with HPMC E3 and HPMC E50 (except ASDs with 70% drug load) were stable, which could be attributed to the molecular level dispersion of the drug in these polymers. SHC parameter calculated from the apparent solubility profile gave following rank order HPMC E50 (3.4) > HPMC E3 (3.2) > HPMC K100M (1.29) > PVP K25 (1.09) > HPC M (0.99). SHC calculated from the apparent solubility profile of ASDs demonstrated good agreement between the solution state and solid state screening of the polymers for precipitation inhibition. During dissolution study, nearly four-fold enhancement has been observed with ASDs comprising HPMC E3 and HPMC E50. CONCLUSIONS: The outcome of the study concluded that SHC can be a promising parameter in the screening of polymers for the development of the ASDs.