Drug Research Articles

7886 Impact of Withania somnifera (Ashwagandha) Supplement on Androgen Signalling Pathways

Abstract Disclosure: I.S. Barata: None. J. Yakubu: None. T. Du Toit: None. A.V. Pandey: None. Supplements derived from plant extracts are often used as alternatives to pharmaceutical drugs. These products are often perceived as safe despite the absence of scientific evidence regarding their efficacy and safety and are less strictly regulated than pharmaceutical products. Winter cherry (Withania somnifera, commonly known as ashwagandha) is used as a testosterone booster supplement in multiple countries. Withania somnifera extract was found to increase testosterone and androgen precursors in a small clinical study. However, there is a lack of data regarding effects of Withania somnifera on the steroidogenic pathways. Steroidogenesis impacts not only sexual differentiation, reproduction, and fertility but also other physiological processes, including hypertension and obesity. Moreover, the modulation of hormone signaling is an important target in hormone-responsive pathogenesis, and overproduction of androgens has been implicated in the pathogenesis of prostate cancer (PCa) and polycystic ovarian syndrome (PCOS). In humans, testosterone is mainly produced in the testes after conversion of pregnenolone to 17-hydroxypregnenolone (17-OHPreg) and dehydroepiandrosterone (DHEA, the precursor of androgens) by adrenal CYP17A1, which catalyzes both the 17-hydroxylation of steroids for cortisol production and the breakage of 17,20 bonds (17,20 lyase) in 17-OHPreg to produce DHEA. The intake of substances that may increase androgen levels by people with PCa or PCOS or with predisposition to these conditions may trigger pathogenesis or worsen prognosis by accelerating disease progression. We investigated the effects of Withania somnifera in modulating the adrenal steroidogenic pathway and the possible consequences on the pathogenesis of androgen-responsive conditions, specifically PCa. Adrenal cells were treated with the extract of Withania somnifera to characterize its effect on adrenal steroid profile and CYP17A1 hydroxylase and lyase activities. Prostate cancer proliferation was assessed by direct incubation of prostate cancer cells with extracts as well as with conditioned media from adrenal cells treated for 48h, to simulate natural steroidogenesis. The results suggest that adrenal steroid hormone biosynthesis can be altered by the intake of Withania somnifera extract and that this supplement may affect proliferation of PCa cells. Moreover, the reported testosterone booster effect of Withania somnifera supplementation does not appear to be through increased adrenal androgen production. Presentation: 6/1/2024

Green Synthesis of Electroactive Magnesium Ferrite Nanoparticles for the Selective Determination of Mefenamic Acid in Blood, Pharmaceutical Products, and Wastewater

Mefenamic acid (MNA) treats sports injuries, rheumatoid arthritis, and osteoarthritis. However, improper use/disposal of MNA results in the accumulation of toxic metabolites that may serious disease. The purpose of this study is to fabricate a nano ferrite-based electrochemical sensor for robust, and sensitive determination of MNA. Magnesium ferrite nanoparticles (MgFe4O7-NPs) were synthesized using a green approach using a Mentha leaf extract. The analytical characterization of MgFe4O7-NPs displayed a hexagonal structure and a particle size of less than 21 nm with rough and porous morphology. The synthesized MgFe4O7-NPs were used to fabricate an electrochemical sensor by modifying a glassy carbon electrode (MgFe4O7-NPs/GCE). The cyclic voltammetry (CV) characterization of the electrode confirms excellent redox and diffusion control for electroactive species. Thus, the MgFe4O7-NPs/GCE was used to determine MNA by differential pulse voltammetry (DPV). The results showed a linear relationship between oxidation peak current and concentration of MNA from 10 × 10−9 to 2.30 × 10−4 M (R 2 = 0.9918) with a detection limit of 1.12 × 10−9 M. The analytical performance of the fabricated sensor has been evaluated for MNA in blood samples, pharmaceutical tablets, and water samples with satisfactory results.

The method of capillary electrophoresis for quantitative determination of hydrophobized hyaluronic acid in its micellar forms

Micelles based on hydrophobized hyaluronic acid (HA) are frequently used in targeted drug delivery systems. Capillary zone electrophoresis (CZE) was utilized for the quantitative determination of hydrophobized and native HA. A universal methodology was developed, suitable for the quantitative analysis of amphiphilic derivatives of hyaluronan (oleyl hyaluronan and hyaluronan conjugate with naphthalimide fluorophore) and native HA with varying molecular weights (15, 150, and 800 kDa). Furthermore, methodologies were proposed for the simultaneous quantification of a drug substance and oleyl hyaluronan in micellar forms based on the latter. The CE technique was applied for analyzing oleyl-hyaluronan-based micellar forms of two poorly soluble drug substances with oppositely charged ionic forms (loperamide and rifabutin). The examples contained in the study demonstrate a range of analytical sensitivity (LOD) for hyaluronan from 11 to 40 μg/mL and for the drug substance from 0.4 to 0.6 μg/mL. The study also showcases the accurate quantitative determination of rifabutin and loperamide in oleyl-hyaluronan-based micellar forms without the need for sample preparation. Thus, the proposed methodologies can be used to quantify native HA or its amphiphilic derivatives and simultaneously determine drug substances of various nature.

Development of a high-fidelity digital twin using the discrete element method for a continuous direct compression process. Part 2. Validation of calibration workflow

This paper is the second in a series of two that describes the application of discrete element method (DEM) and reduced order modeling to predict the effect of disturbances in the concentration of drug substance at the inlet of a continuous powder mixer on the concentration of the drug substance at the outlet of the mixer. In the companion publication, small-scale material characterization tests, a careful DEM parameter calibration and DEM simulations of the manufacturing process were used to develop a reliable RTD models. In the current work, the same calibration workflow was employed to evaluate the predictive ability of the resulting reduced-order model for an extended design space. DEM simulations were extrapolated using a relay race method and the cumulative RTD was accurately parameterized using the n-CSTR model. By performing experiments and simulations, a calibrated DEM model predicted the response of a continuous powder mixer to step changes in the inlet concentration of an API. Thus, carefully calibrated DEM models was used to guide and reduce experimental work and to establish an adequate control strategy. In addition, a further reduction in the computational effort was obtained by using the relay race method to extrapolate results. The predicted RTD curves were then parameterized to develop reduced order models and used to simulate the process in a matter of seconds. Overall, a control strategy evaluation tool based on high-fidelity DEM simulations was developed using material-sparing small-scale characterization tests.

Mass balance analysis for therapeutic peptides: Case studies, applications, and perspectives

The concept of mass balance is discussed as it pertains to the pharmaceutical development of therapeutic peptides. Case studies are presented demonstrating how to perform a mass balance assessment on solid drug substance and solution drug product, and the role of mass balance in the context of the overall product control strategy is discussed. Utilizing mass balance as a specification test where the result is calculated from other critical quality attribute tests, each with their own specification, offers little value as a formalized quality acceptance criterion and may create more deviations, non-value added investigations, and potential batch failures. While useful in characterizing the performance of analytical methods and as part of a rigorous understanding of the manufacturing process and control strategy development, mass balance should not be required as a specification control and should instead be demonstrated during method development and through well-designed forced degradation experiments. Analytical method variability is discussed in relation to the analytical target profile, and the overall impact of sources of variability on the mass balance calculation is described in support of this position.

Synthesis, Photocatalytic and Bio Activity of ZnO-TiO2 Nanocomposites: A Review Study

Zinc oxide and titanium dioxide are materials with strong photocatalytic and antimicrobial activity. This activity is greater when the material is in nanocrystalline form. It has been seen that these properties are also present in the ZnO-TiO2 nanocomposite material, and the extent depends on multiple factors, such as crystallinity, structural composition, crystallite size, and morphology. These structural properties can be varied by acting on the synthesis of the material, obtaining a wide variety of composites: random nanoparticles, nanorods, nanowires, nanotubes, nanofibers, tetrapods, core–shell, hollow spheres, inverse opal structures (IOSs), hierarchical structures, and films. When an interface between nanocrystallites of the two oxides is created, the composite system manages to have photocatalytic activity greater than that of the two separate oxides, and in certain circumstances, even greater than P25. The antimicrobial activity results also improved for the composite system compared to the two separate oxides. These two aspects make these materials interesting in various fields, such as wastewater and air treatment, energy devices, solar filters, and pharmaceutical products and in the context of the restoration of monumental cultural assets, in which their use has a preventive purpose in the formation of biofilms. In this review we analyse the synthesis techniques of ZnO-TiO2 nanocomposites, correlating them to the shape obtained, as well as the photocatalytic and antimicrobial activity. It is also illustrated how ZnO-TiO2 nanocomposites can have a less negative impact on toxicity for humans and the environment compared to the more toxic ZnO nanoparticles or ZnO.

Determination of seven synthetic colourants in pharmaceutics, foods, and beverages by a validated HPLC-PDA method: A risk assessment study

A simple, rapid, sensitive and reliable high-performance liquid chromatography method based-on ultraviolet determination was developed and validated for the simultaneous determination of the tartrazine-TR, sunset yellow-SY, ponceau-4R P4R, allura red-AR, patent blue-PBV, brilliant blue-BB, erythrosine B-EB. The limit of detections were found as ≤0.083 µg/mL, determination coefficiencies were found as ≥0.999 in the range of 0.5 – 20 µg/mL for all colourants. Precision was ≤6.75 (RSD) and accuracy was between (-6.52) and 6.80 (RE%). This developed analytical method was successfully used to quantitatively detect the presence of these synthetic colourants in confectionery (n = 13), beverages (n = 12) and pharmaceutical products (n = 13) and a risk assessment was made based on the lowest exposure scenario. The risk index values determined in confectionery range between 0.10 and 5.78 (1.46 ± 1.52, mean ± SD), in beverages range between 0.001 and 2.79 (0.034 ± 0.082The risk index of five of the monitored confectionery samples (38.50 %) was determined to be above one in terms of the relevant food dyes.

Prevalence and Determinants of Self-Medication Among Pregnant Women at an Antenatal Clinic at Soba Teaching Hospital, Sudan: A Cross-Sectional Analysis.

BACKGROUND Rates of self-medication among pregnant women are high, due to the promotion of herbal and dietary supplements and lack of awareness of possible adverse effects. This study evaluated self-medication in pregnant women attending an antenatal clinic at Soba Teaching Hospital, Sudan. MATERIAL AND METHODS A quantitative study was conducted using a pre-tested semi-structured interviewer-administered questionnaire, which consisted of 25 questions divided into 4 sections: demographic and obstetric; self-medication source, recommendations, and conditions; most commonly used medications and herbal medicine; reasons for self-medications. A total of 230 pregnant women were included in the study. The chi-square test was used to test associations between variables and the binary logistic regression model was used to evaluate the relationship between self-medication practice and explanatory variables. A P value of <0.05 was deemed significant in the final model. RESULTS Of the 230 pregnant women interviewed, 67% were multigravida, 184 (80%) practiced self-medication, 45.6% used pharmaceutical products, commonly analgesics (32.5%), and 21.9% used herbal remedies, including peppermint (19.4%) and citrus fruits (17.5%). Self-medication was used for nausea (49.5%) and heartburn (46.2%). Reasons for self-medication included belief in safety (40%) and the expense of physician fees (28.1%). Socio-demographic characteristics and the prevalence of self-medication in pregnant women showed no significant associations. CONCLUSIONS The findings from this study showed that the prevalence of self-medication reported by pregnant women attending antenatal clinics in Sudan was high and included approved drugs and herbal medicines, mainly from pharmacies, and was driven by the perception that all medications supplied by pharmacies were safe.

Impact of a short-term pharmacy study abroad Program: student outcomes and program evaluation

ObjectiveThis study examined the impact of a short-term study abroad program, focusing on program evaluation, attendee satisfaction, and acquired knowledge and skills. A questionnaire survey was conducted covering various aspects including demographics, program evaluation, and feedback.ResultsResults indicated higher female participation due to gender imbalances in pharmacy students in Egypt, with senior students recognizing the value of international experience. Attendee satisfaction was high, with positive feedback on accommodation, tours, and workshop materials. Field visits and workshops provided valuable experiential learning, with attendees suggesting extending the program’s duration. The program equipped attendees with knowledge and skills relevant to pharmaceutical products and services, leading to improved competences and perceptions. The study concludes that such study abroad experiences profoundly impact personal growth and recommends integrating them into educational curricula for valuable experiences.

Development and application of a physiologically-based pharmacokinetic model for ractopamine in goats.

Physiologically Based Pharmacokinetic (PBPK) models can provide forecasts of the drug residues within the organism. Ractopamine (RAC) is a typical β-agonist. In this study, we developed a PBPK model for RAC in goats. The goal was to predict the distribution of the drug after multiple oral administrations. The preliminary PBPK model for RAC in goats performed well in predicting the drug's distribution in most tissues. In our sensitivity analysis, we found that the parameter of Qclu (Blood Flow Volume through Lungs) had the greatest impact on the RAC concentrations in plasma, liver, and kidney and was the most sensitive parameter. Furthermore, our study aimed to assess the withdrawal time (WT) of RAC in different tissues after RAC long-term exposure in goats. We found that the WT of RAC in the kidney was the longest, lasting for 13 days. Overall, the insights gained from this study have important implications for optimizing drug administration in goats and ensuring appropriate withdrawal times to prevent any potential risks.

Pharmaceuticals and personal care products contamination in the rivers of Chennai city during the COVID-19 pandemic.

Pharmaceuticals and personal care products (PPCPs) monitoring in surface water is crucial to address the escalating threat of antimicrobial resistance and safeguard public health. This study aimed to investigate the occurrence of 21 different PPCPs, including wastewater chemical markers, antibiotics, and parabens in the surface water of Chennai city using Ultra Performance Liquid Chromatography-Triple Quadrupole Mass Spectrometry (UPLC-MS/MS) analysis. It is noteworthy that chemical markers viz., carbamazepine (CBZ) and caffeine (CAF) were detected in all the sites and contributed to more than 95% of the total PPCPs load indicating a significant intrusion of wastewater. Among the antibiotics, fluoroquinolones were dominant in this study. Interestingly, a significant and strong correlation was seen between fluoroquinolones, CBZ and CAF (R2 = 0.880-0.928, p < 0.05), suggesting similarities in their sources. More than 50% of the sites exhibited a risk for antimicrobial resistance (RQAMR) withRQAMR > 1 for ciprofloxacin, indicating a significantpublic health concern. The ecotoxicological risk assessment of PPCPs showed no risk to any organisms, except for triclosan, which posed a risk to fish and daphnids at one sitenear an open drain in Buckingham canal.

Edible oil-based switchable-hydrophilicity solvent liquid-liquid microextraction coupled with HPLC-DAD for determination of parabens in food and pharmaceutical products

Edible oil-based switchable-hydrophilicity solvent liquid-liquid microextraction coupled with HPLC-DAD for determination of parabens in food and pharmaceutical products

3D soft material printer as a mesoscale additive biomanufacturing platform for in-space manufacturing

With the burgeoning in-space manufacturing (ISM) industry, developing an on-demand additive manufacturing (AM) platform will be crucial for long-term space habitation. However, acute space boundary conditions, such as limited physical space, microgravity, vacuum, and others pose unique challenges for designing the printing process, the platform’s structure, and the materials’ printability. An AM platform operable in a space environment would enable production at the point of need (PoN), for example, on-demand food, nutrition, and pharmaceutical products. This research is focused on the design, fabrication, and testing of a 3D printer confined within CubeSat boundaries to study the feasibility of soft material printing aimed toward potential ISM applications. The printer unit was built using components off the shelf (COTS) while adhering to the severe spatial boundary conditions posed by the CubeSat dimensions and was tested using an edible material ink to demonstrate multi-layer prints of soft materials. Printing in ambient Earth conditions as well as under vacuum displayed consistent layer cohesion and comparison to 3D model data although vacuum prints showed visibly dehydrated prints owing to outgassing of air bubbles. The printer equipment’s structural integrity was validated under simulated launch and operation conditions using a vibration testing setup according to the NASA-recommended microsatellites standards. The results indicated that the printer assembly maintained its structural and operational integrity during and after testing. Using soft materials as the basis of testing allows scalability when expanding to more complex and structural materials to produce spare parts using a frugally engineered modular manufacturing platform.

Roller compaction: Measuring ribbon porosity by terahertz spectroscopy and machine learning

Roller compaction is a crucial unit operation in pharmaceutical manufacturing, with its ribbon porosity widely recognised as a critical quality attribute. Terahertz spectroscopy has emerged as a fast and non-destructive technique to measure porosity in pharmaceutical products. From a sensing perspective, the irregular shape and uneven surface of fragmented ribbon pieces can affect the accuracy and precision of the measurements, particularly for techniques that probe only a small sampling volume. It is known that the porosity is not uniform within the ribbon structure, with variations expected across the width of the ribbon and in the microstructure corresponding to its surface texture. However, typical pharmaceutical analysis methods, such as envelope density, only report an average bulk porosity, are slow to operate and limited in accuracy. To address this challenge, we developed and trained convolutional neural network models using THz spectra as input to classify four types of topography typically encountered in ribbons: ridge, valley, flat plane and edge points. The classifiers achieved 91% validation accuracy in both identifying outliers and differentiating between ribbons of smooth and knurled surfaces. For the more challenging task of distinguishing between the ridges and valleys of knurled surfaces, an 81% testing accuracy was achieved. Once each measurement is paired with its topography, resolving the density distribution within the sample is possible. This data can be combined to arrive at an average bulk porosity value compatible with conventional pharmaceutical analysis.

Mechanisms of drug release from a melt-milled, poorly soluble drug substance

Increasing the dissolution kinetics of low aqueous soluble drugs is one of the main priorities in drug formulation. New strategies must be developed, which should consider the two main dissolution mechanisms: surface reaction and diffusion.One promising tool is the so-called solid crystal suspension, a solid dispersion consisting of purely crystalline substances. In this concept, reducing the drug particle size and embedding the particles in a hydrophilic excipient increases the dissolution kinetics. Therefore, a solid crystal suspension containing submicron drug particles was produced via a modified stirred media milling process. A geometrical phase-field approach was used to model the dissolution behavior of the drug particles.A carrier material, xylitol, and the model drug substance, griseofulvin, were ground in a pearl mill. The in-vitro dissolution profile of the product was modeled to gain a deep physical understanding of the dissolution process. The used numerical tool has the potential to be a valuable approach for predicting the dissolution behavior of newly developed formulation strategies.

Exposure to microplastics contaminated with pharmaceuticals and personal care products: Histological effects on Ucides cordatus

Pharmaceuticals and personal care products (PPCPs) are known to interact with microplastics (MPs) in aquatic environments, with substances such as the antimicrobial triclosan (TCS) and the synthetic hormone 17α-ethinylestradiol (EE2) being prevalent. These persistent contaminants are linked to toxic effects in aquatic organisms. This study aimed to investigate histological and morphometric changes in the gills of Ucides cordatus exposed to microplastics alone and microplastics contaminated with PPCPs. The experimental design included four treatment groups: 1) control (C), 2) virgin microplastics (MP), 3) microplastics fortified with triclosan (MPT), and 4) microplastics fortified with 17α-ethinylestradiol (MPE), with exposure durations of 3 or 7 days. Significant differences were observed in the histopathological indices for treatments with PPCP-fortified microplastics at 3 days (MPT and MPE) and 7 days (MPT). Notable pathologies included necrosis, fibrosis, and circulatory disorders. Exposure duration was significantly associated with morphometric changes, including secondary lamellar width in MPT and secondary lamellar length in MPE. These findings indicate that exposure to microplastics contaminated with PPCPs may impair the osmoregulatory and respiratory functions of Ucides cordatus.

Computer-Aided formulation design for pharmaceutical drug product development, part 01: Materials exploration through a visualization tool

An interactive tool has been developed to help design oral solid dosage form formulations. The tool enables quantitative explorations and comparisons of physical, bulk, and mechanical properties, and takes into account functional characteristics as well. In this manner, comparisons and clustering of both excipients and APIs can be carried out. These comparisons enable the generation of alternatives as well as surrogate identification, so as to spare resources and material.Multiple data sources were merged to create a “joint” data table with all relevant properties. Four main workflow activities are supported: Explore Materials, Search Similar APIs, Search Similar Excipients and Search Material Clusters.Multi-dimensional filtering can be superimposed to each functionality. Suggested visualizations are made particularly accessible by providing them as “standard plots”.The underlying philosophy is to empower formulation scientists to explore options, rather than prescribe decisions on exclusively mathematical grounds. The tool described here is the first step towards a holistic optimization incorporating predictions of mixture properties. Methodology of use is illustrated through three material selection application examples.

Geographical and environmental factors in pharmaceuticals and personal care products removal from drinking water plants

Pharmaceuticals and personal care products (PPCPs) are unintentionally released into the environment from treated and untreated wastewater, agricultural runoff, and stormwater, and enter drinking water treatment plants (DWTPs). However, very little is known about the occurrence of PPCPs and their removal effectiveness during the drinking water treatment processes (conventional or advanced treatment) in multiple DWTPs, especially within the same geographical area. To address this important knowledge gap, source and finished drinking water samples were collected monthly from May to September in 2018 and 2019 from four DWTPs in Northern Ohio, USA. The total and individual PPCP concentrations varied among DWTPs and sampling dates in both source and finished water. Despite the site and time differences, caffeine and 17-beta-estradiol were detected at a frequency of 100% in all four DWTPs on all dates, while acetaminophen, estrone and nicotine consistently were not detected. Significant correlations were identified between the source water PPCPs and some environmental variables, such as dissolved organic carbon (DOC), temperature and pH. The PPCP removal efficiency from finished water samples varied depending on DWTP (61.2–84.2%), sampling month (28.3–89.7%), and different PPCP compounds (31.2% and 99.3%). Overall, this study demonstrated that PPCPs were consistently present in low concentrations (ng/L) in the freshwater systems; conventional treatment methods could only partially mitigate PPCP contaminants, while advanced techniques, such as UV-peroxide treatment, provided better removal efficiencies. PPCP removal also depended on the season, with summer demonstrating the highest removal in all four treatment plants.

Chitosan‐Coated Glass Beads as Stabilizer of Insulin; A Novel Strategy for the Storage of Pharmaceutical Proteins

AbstractBesides the pharmaceutical protein production challenge, storing and transporting them between industrial sectors and the administration site have always been problematic. Insulin, an example of the most widely used therapeutic protein, aggregates into unstable larger particles and, in many cases, into amyloid fibrils under environmental stresses. In this study, chitosan was used to decorate the surface of glass beads (to produce Chi@GB) to increase the structural stability of insulin against environmental stresses. FT‐IR spectroscopy characterized the beads, and HPLC determined the chitosan loading. The results showed that the modified beads could inhibit insulin fibrillation. In addition, the beads can be used in biopharmaceutical containers of insulin or other proteins for long‐term storage of their commercial products.

2‐Oxazoline‐Based Polymer for Pharmaceutical Products Adsorption in Aqueous Media

ABSTRACTWe present the synthesis and comprehensive evaluation of a novel 2‐oxazoline‐based polymer (polyPhOx) functionalized with phenyl groups, designed for the efficient adsorption of pharmaceutical contaminants from aqueous solutions. Employing living polymerization techniques (CROP) with two distinct initiators, we optimize reaction parameters including time, temperature, and initiator concentration. The rigorous characterization of the obtained polymer is depicted as well as the demonstration of its significant binding capacity for various pharmaceuticals, exploiting π–π and electrostatic interactions to achieve superior adsorption efficiency. Adsorption experiments are performed using high concentrations of model pharmaceuticals, including aspirin, ibuprofen, metoclopramide, pyramidone, oestradiol, and indomethacin, in hydroalcoholic solutions. Initial investigations confirm polyPhOx's exceptional efficacy, particularly with hydrophobic compounds such as oestradiol, achieving adsorption capacities of up to 56.67 mg g−1. Further validation in real environmental samples highlights the polymer's practical applicability, showing substantial removal rates even under complex matrix conditions and bringing hope for effective water purification solutions. Remarkably, polyPhOx retains high adsorption performance after 10 cycles, underscoring its potential for sustainable and cost‐effective water purification. This study not only introduces a promising material for environmental remediation but also demonstrates its robustness and reusability, paving the way for advanced wastewater treatment solutions targeting persistent pharmaceutical pollutants.