Pharmaceutical Research Research Articles

ORAL DISINTEGRANTING TABLETS: AN OVERVIEW

Especially for patients who have dysphagia or difficulty swallowing, oral disintegrating tablets (ODTs) have developed as a novel dosage form to address a number of issues related to traditional solid dosage forms. An overview of the formulation techniques, assessment criteria, and uses of ODTs in pharmaceutical research are given in this study. In order to accomplish quick disintegration and dissolution of the tablet matrix upon contact with saliva, formulation processes such as sublimation, lyophilization, and direct compression have been thoroughly investigated. When evaluating the quality qualities of ODTs, evaluation metrics such as drug content homogeneity, hardness, friability, and disintegration time are essential. To improve patient acceptance and palatability, superdisintegrants and a variety of taste-masking techniques have been used. Furthermore, ODTs adaptability goes beyond traditional oral administration they may be used for emergency and travel medicine, as well as in paediatric and geriatric populations. All things considered, ODTs present a viable platform for enhancing patient convenience and compliance, which maximises therapeutic results. ODTs provide a number of benefits, such as improved patient compliance, simplicity of administration, and greater bioavailability because of their quick dissolving and larger surface area. To sum up, oral disintegrating tablets offer a potentially effective option for individuals who need readily administrable and comfortable dose forms. ODTs will be further optimised by ongoing research and development into manufacturing and formulation processes, increasing their applicability to a wider range of patient demographics and therapeutic areas.

Immunomodulatory, Antioxidant, and Potential Anticancer Activity of the Polysaccharides of the Fungus Fomitiporia chilensis.

Fomitiporia species have aroused the interest of numerous investigations that reveal their biological activity and medicinal potential. The present investigation shows the antioxidant, anticancer, and immunomodulatory activity of acidic polysaccharides obtained from the fungus Fomitiporia chilensis. The acidic polysaccharides were obtained for acidic precipitation with 2% O-N-cetylpyridinium bromide. Chemical analysis was performed using FT-IR and GC-MS methods. The antioxidant capacity of acidic polysaccharides from F. chilensis was evaluated by scavenging free radicals with an ABTS assay. Macrophage proliferation and cytokine production assays were used to determine the immunomodulatory capacity of the polysaccharides. Anti-tumor and cytotoxicity activity was evaluated with an MTT assay in the U-937, HTC-116, and HGF-1 cell lines. The effect of polysaccharides on the cell cycle of the HCT-116 cell line was determined for flow cytometry. Fourier Transform-infrared characterization revealed characteristic absorption peaks for polysaccharides, whereas the GC-MS analysis detected three peaks corresponding to D-galactose, galacturonic acid, and D-glucose. The secreted TNF-α concentration was increased when the cell was treated with 2 mg mL-1 polysaccharides, whereas the IL-6 concentration was increased with all of the evaluated polysaccharide concentrations. A cell cycle analysis of HTC-116 treated with polysaccharides evidenced that the acidic polysaccharides from F. chilensis induce an increase in the G0/G1 cell cycle phase, increasing the apoptotic cell percentage. Results from a proteomic analysis suggest that some of the molecular mechanisms involved in their antioxidant and cellular detoxifying effects and justify their traditional use in heart diseases. Proteomic data are available through ProteomeXchange under identifier PXD048361. The study on acidic polysaccharides from F. chilensis has unveiled their diverse biological activities, including antioxidant, anticancer, and immunomodulatory effects. These findings underscore the promising therapeutic applications of acidic polysaccharides from F. chilensis, warranting further pharmaceutical and medicinal research exploration.

Revolutionizing Drug Discovery: A Comprehensive Review of Computer-Aided Drug Design Approaches

Abstract: Computer-Aided Drug Design (CADD) has significantly advanced the drug discovery process, offering tools to enhance efficiency and reduce costs. This review explores essential CADD methodologies, including molecular docking, virtual screening, ADMET profiling, homology modeling, and Quantitative Structure-Activity Relationship (QSAR) models. Molecular docking predicts interactions between drugs and targets, while virtual screening evaluates large compound libraries to identify promising candidates. ADMET profiling assesses pharmacokinetic and toxicological properties early in development. Homology modeling constructs three-dimensional protein models to aid target identification, and QSAR models predict biological activities based on chemical structures. These integrated approaches streamline drug development, providing a robust framework for modern pharmaceutical research.

A Trapping-Micro-LC-FAIMS/dCV-MS Strategy for Ultrasensitive and Robust Targeted Quantification of Protein Drugs and Biomarkers.

The sensitivity of LC-MS in quantifying target proteins in plasma/tissues is significantly hindered by coeluted matrix interferences. While antibody-based immuno-enrichment effectively reduces interferences, developing and optimizing antibodies are often time-consuming and costly. Here, by leveraging the orthogonal separation capability of Field Asymmetric Ion Mobility Spectrometry (FAIMS), we developed a FAIMS/differential-compensation-voltage (FAIMS/dCV) method for antibody-free, robust, and ultrasensitive quantification of target proteins directly from plasma/tissue digests. By comparing the intensity-CV profiles of the target vs coeluted endogenous interferences, the FAIMS/dCV approach identifies the optimal CV for quantification of each target protein, thus maximizing the signal-to-noise ratio (S/N). Compared to quantification without FAIMS, this technique dramatically reduces endogenous interferences, showing a median improvement of the S/N by 14.8-fold for the quantification of 17 representative protein drugs and biomarkers in plasma or tissues and a 5.2-fold median increase in S/N over conventional FAIMS approach, which uses the peak CV of each target. We also discovered that the established CV parameters remain consistent over months and are matrix-independent, affirming the robustness of the developed FAIMS/dCV method and the transferability of the method across matrices. The developed method was successfully demonstrated in three applications: the quantification of monoclonal antibodies with subng/mL LOQ in plasma, an investigation of the time courses of evolocumab and its target PCSK9 in a preclinical setting, and a clinical investigation of low abundance obesity-related biomarkers. This innovative and easy-to-use method has extensive potential in clinical and pharmaceutical research, particularly where sensitive and high-throughput quantification of protein drugs and biomarkers is required.

Accelerate drug repurposing with in-silico molecular modelling techniques, tools and databases: A comprehensive review

Exploring innovative ways to accelerate drug repurposing through in-silico molecular modeling techniques, tools, and databases is paramount in modern pharmaceutical research. Exploring the vast landscape of drug repurposing presents both a challenge and an opportunity in the realm of pharmaceutical research. With the escalating costs and time-consuming nature of developing new drugs from scratch, the urgency to identify novel therapeutic uses for existing compounds has never been more pressing. Readers can expect a detailed exploration of how computational methods are revolutionizing drug repurposing efforts, offering insights into accelerated drug discovery and development timelines. This comprehensive review dives deep into the opportunities and challenges of leveraging computational approaches to identify new therapeutic uses for existing drugs and this article highlights the potential of in-silico methods to revolutionize drug discovery by repurposing existing compounds efficiently and cost-effectively, ultimately leading to faster development timelines and improved patient outcomes and will be focused for In-silico molecular modeling techniques, tools, and databases as powerful allies in expediting this crucial process.

Fluorescent covalent organic framework as an ultrasensitive fluorescent probe for tyrosinase activity monitoring and inhibitor screening

BackgroundAs a significant biomarker of melanocytic lesions, tyrosinase (TYR) plays an essential role in the clinical diagnosis and treatment of melanin-related diseases. Thus, it is important to develop robust methods for assessing TYR activity. Covalent organic frameworks (COFs) have garnered considerable attention owing to their unique properties, including high chemical stability, good biocompatibility, and large surface area compared with organic dyes, noble metal nanoclusters, and semiconductor quantum dots. However, most COFs are insoluble in water and exhibit weak or no fluorescence emission. Therefore, the development of a water-soluble fluorescent COF for detecting TYR activity in biological samples remains highly desired. ResultsIn this work, a sensitive and facile fluorometric method based on fluorescent COF was constructed for the detection of TYR activity in human serum samples. The water-soluble COF was fabricated through the condensation polymerization of 4′,4‴,4′′′′′,4′′′′′′′-(1,2-ethene-diylidene) tetrakis [1,1′-biphenyl]-4-carboxaldehyde and 2,4,6-tris-(4-aminophenyl)-triazine. The resulting COF displayed yellow-green fluorescence with a maximum emission peak at 560 nm. Tyrosine was catalyzed by TYR to produce melanin-like polymers which formed a coating on the surface of COF and effectively quenched its fluorescence due to fluorescence resonance energy transfer. The proposed approach demonstrated a strong linear correlation in the range of 0.5–80 U/L with a low detection limit of 0.09 U/L. Additionally, the limit of detection for kojic acid, serving as a representative TYR inhibitor, was determined to be 0.0004 μg/mL. SignificanceOur proposed fluorometric sensing platform exhibited exceptional selectivity, sensitivity, and satisfactory recoveries in human serum samples, which is of paramount importance for the clinical diagnostics of melanin-related diseases. Furthermore, the proposed approach was further employed for the screening of TYR inhibitors, suggesting the potential applications in clinical treatment and pharmaceutical research.

Development of tungsten trioxide nano-flakes intercalated on tannic acid-functionalized reduced graphene oxide for flexible acebutolol sensors

Acebutolol (ACE) is commonly used to treat hypertension and high blood pressure. Large doses of ACE can have adverse effects with potentially life-threatening consequences. It is, therefore, essential to develop a simple, low-cost, reliable, and reproducible device for detecting ACE in biofluids. This study explores the potential of unique two-dimensional nano-flakes, such as tungsten trioxide (WO3). Graphene oxide (GO) typically exhibits lower electrical conductivity than pristine graphene due to the presence of oxygen-containing functional groups that interfere with the π-conjugated structure. Functionalizing GO with tannic acid (TA) can partially reinstate the π-conjugation and limit the amount of oxygen, resulting in enhanced electrical conductivity. Ultrasonic techniques were utilized to create WO3 NFs@TA-rGO, and a range of spectroscopic and microscopic methods were applied to examine the formation of the resulting WO3 NFs@TA-rGO nanocomposites. Under optimal conditions, modified sensors resulted in lower limits of detection (0.0055 μM) and good sensitivity (0.40 μA μM−1 cm−2). They also exhibited a broad linear range spanning from 0.009 to 568.6 μM. Fabricated sensors have significant anti-interference properties with high specificity and excellent storage stability (RSD = 4.3 %), reproducibility (RSD = 3.9 %), and repeatability (RSD = 3.3 %). Ultimately, the sensor's efficacy was confirmed through the successful detection of ACE in biological samples (with recoveries ranging from 99.1 to 99.6 %). Lastly, this study highlights the substantial potential of ACE detection and extends its applications in biomedical diagnostics and pharmaceutical research.

Alliums as Potential Antioxidants and Anticancer Agents.

The genus Allium plants, including onions, garlic, leeks, chives, and shallots, have long been recognized for their potential health benefits, particularly in oxidative and cancer prevention. Among them, onions and garlic have been extensively studied, unveiling promising biological activities that are indicative of their potential as potent antioxidant and anticancer agents. Research has revealed a rich repository of bioactive compounds in Allium species, highlighting their antioxidative properties and diverse mechanisms that target cancer cells. Compounds such as allicin, flavonoids, and organosulfur compounds (OSCs) exhibit notable antioxidant and anticancer properties, affecting apoptosis induction, cell cycle arrest, and the inhibition of tumor proliferation. Moreover, their antioxidant and anti-inflammatory attributes enhance their potential in cancer therapy. Studies exploring other Allium species beyond onions and garlic have revealed similar biological activities, suggesting a broad spectrum of natural products that could serve as promising candidates for developing novel anticancer treatments. Understanding the multifaceted potential of Allium plants will pave the way for innovative strategies in oxidative and cancer treatment and prevention, offering new avenues for pharmaceutical research and dietary interventions. Therefore, in this review, we compile an extensive analysis of the diversity of various Allium species, emphasizing their remarkable potential as effective agents.

Production of 5-fluorouracil-loaded PLGA nanoparticles with toroidal microfluidic system and optimization of process variables by design of experiments

In recent decades, microfluidics has presented new opportunities for the production of nanoparticles (NPs). However, to achieve rapid clinical translation, the production of PLGA NPs in a single microfluidic channel for both the pharmaceutical research and industry without the need for scaling is still limited. The aim of this study was to accomplish the production of reproducible and stable 5-FU loaded Poly(lactic-co-glycolic acid) (PLGA) NPs, using an innovative toroidal microfluidic system, for cancer therapy. The toroidal microfluidic system enabled the production of spherical NPs ranging from 100 to 150 nm by adjusting both the TFR within the range of 5–15 mL/min and FRR between 1:3 and 1:7. A systematic assessment of critical process variables (total flow rate; TFR, flow rate ratio; FRR) for the production of PLGA NPs was conducted using Design of Experiment (DoE). The NPs, which exhibit a uniform size distribution, remained stable even after centrifugation and storage for 3 months at 4 °C. The encapsulation efficiency of drug and the concentration of NPs were not affected by changing process parameters. The effective 5-FU encapsulation into NPs resulted in a controlled in vitro drug release. Due to the controlled release profile of the 5-FU loaded PLGA NPs, the formulation was a promising candidate for mitigating the toxic side effects of free 5-FU and improving cancer treatment. In conclusion, toroidal microfluidic system enables high-volume production of stable PLGA NPs, both with and without 5-FU.

Deciphering the adsorption and sensing performance of Al24N24 and B24N24 nanoclusters as a drug delivery system for nitrosourea anticancer drug: A DFT insight

Nanomaterials for drug detection are crucial in pharmaceutical research, especially in cancer therapy applications like nitrosourea. The purpose of this work was to examine the sensitivity of Al24N24 and B24N24 nanocages for the detection of nitrosourea by using density functional theory (DFT). Different analyses were performed such as adsorption energy (Eads) studies, frontier molecular orbitals (FMOs), natural bond orbitals (NBO), global indices of reactivity, UV-Vis studies, molecular electrostatic potential (MEP), non-covalent interaction (NCI), quantum theory of atoms in molecules (QTAIM) and sensor mechanism. The adsorption of nitrosourea on Al24N24 shows the highest values of adsorption energies with the value of −59.239, −55.986, and −51.019 kcal/mol for O/6m-AN, plan/6m-AN, and plan/8m-AN respectively. On the other hand, B24N24 complexes show fewer adsorption energies with the notable presence in plan/6m-BN, O/4m-BN, and plan/8m-BN that have the values of −11.064, −10.983, and −10.064 kcal/mol respectively. The energy gap of Al24N24 and B24N24 complexes decrease from 4.120 eV and 6.493 eV respectively for bare nanocage showing the potential of using these cages for nitrosourea (NUr) detection. FMOs studies reveal that among all designed complexes the lowest energy gap is present in O/4m-AN having a value of 2.913 eV. Moreover, global indices of reactivity suggest the increase in softness for Al24N24 complexes from 0.2427 eV for bare nanocage to 0.3433 eV for O/4m-AN. Similarly, the softness for B24N24 complexes also increases from 0.1540 eV for bare cage to 0.3012 eV for O/B-BN. Sensitivities for NUr in O/B-BN, O/4m-BN, plan/6m-BN and plan/8m-BN are 0.896, 0.870, 0.834 and 0.815 respectively. Moreover, the recovery time of NUr drug from BN nanocage is also very short as 7.53 × 10-12 s for O/N-BN. Topological analysis predict the non-covalent nature of interaction present between AN and BN nanocages. The electrical conductivity values are increased after the adsorption process. The highest electrical conductivity is present in AN complexes such as 4.41 × 1012 S/m for O/4m-AN due to low energy gap of 2.91 eV. The sensor mechanism reflects the high values of sensitivity for B24N24 complexes due to narrow energy gaps. Thus, B24N24 could be a fine candidate for the detection of nitrosourea and as a drug delivery vehicle for nitrosourea to treat cancer.

Microneedles: An Efficient Technique to Increase Transdermal Drug Delivery System.

Transdermal Drug Delivery Systems (TDDS) have gained attention as a viable substitute for traditional drug administration methods because of their controlled release capabilities and non-invasive design. Microneedles are a new and effective technology that has attracted a lot of attention recently to enhance the capabilities of TDDS further. The study on microneedles and their potential to improve transdermal medication delivery is thoroughly reviewed in this review article. The study initiates by clarifying the difficulties linked to traditional medication delivery techniques and the benefits provided by transdermal channels. The article then explores the development of microneedle technology, outlining the several kinds of microneedles-solid, hollow, and dissolving-as well as their uses. Because of their special capacity to penetrate the skin's protective layer painlessly and their ability to distribute drugs precisely and precisely, microneedles are a highly useful instrument in pharmaceutical research. The materials, geometry, and manufacturing processes that affect the design and creation of microneedles are critically analyzed and presented. The manuscript delves into the latest developments in microneedle technology, encompassing the utilization of biodegradable polymers, smart materials, and sensing components for in-the-- moment monitoring. This analysis concludes by highlighting the noteworthy advancements in the field of microneedles and their potential to transform transdermal drug delivery systems. This thorough knowledge seeks to further the current discussion in pharmaceutical research, encouraging creativity and opening the door for the creation of safer, more effective drug delivery systems.

Unveiling Impurities: A Comprehensive RP-HPLC Method for Accurate Atorvastatin Impurity Analysis in Pharmaceuticals Using Accuracy Profile Approach.

Accurate determination of active pharmaceutical ingredients and impurities is essential for ensuring the safety and effectiveness of medications. This study focuses on the validation of a high-performance liquid chromatography (HPLC) method for quantifying Atorvastatin and its impurities, addressing a critical aspect of pharmaceutical analysis. The primary objective is to conduct a comprehensive validation study for the HPLC method, covering specificity assessment, response function establishment, and a detailed analysis of precision, trueness, and tolerance intervals. The emphasis is on demonstrating the method's precision, accuracy, and stability-indicating capabilities across various concentrations and compounds. The HPLC method is validated through rigorous assessments, including specificity, response function establishment, and analyses of precision, trueness, and tolerance intervals. Induced degradation experiments are conducted to explore Atorvastatin's behavior under extreme conditions. Insights into the compound's synthesis and degradation pathways are provided through a proposed mechanism for intramolecular esterification. The results affirm the precision, accuracy, and stability-indicating capabilities of the validated HPLC method. The method effectively differentiates between Atorvastatin and its impurities, showcasing its suitability for pharmaceutical quality control. The validated HPLC method emerges as a robust and reliable tool for Atorvastatin analysis, contributing significantly to pharmaceutical research and quality control. Its application ensures the safety and efficacy of medications, reinforcing its role in pharmaceutical analysis. This study not only validates a crucial HPLC method for Atorvastatin analysis but also provides insights into the compound's behavior under extreme conditions and its synthesis and degradation pathways. The validated method serves as a cornerstone in pharmaceutical research and quality control, ensuring medication safety and efficacy.

Selective nitrogen insertion into aryl alkanes

Molecular structure-editing through nitrogen insertion offers more efficient and ingenious pathways for the synthesis of nitrogen-containing compounds, which could benefit the development of synthetic chemistry, pharmaceutical research, and materials science. Substituted amines, especially nitrogen-containing alkyl heterocyclic compounds, are widely found in nature products and drugs. Generally, accessing these compounds requires multiple steps, which could result in low efficiency. In this work, a molecular editing strategy is used to realize the synthesis of nitrogen-containing compounds using aryl alkanes as starting materials. Using derivatives of O-tosylhydroxylamine as the nitrogen source, this method enables precise nitrogen insertion into the Csp2-Csp3 bond of aryl alkanes. Notably, further synthetic applications demonstrate that this method could be used to prepare bioactive molecules with good efficiency and modify the molecular skeleton of drugs. Furthermore, a plausible reaction mechanism involving the transformation of carbocation and imine intermediates has been proposed based on the results of control experiments.

'Comprehensive review of emerging drug targets in traumatic brain injury (TBI): challenges and future scope.

Traumatic brain injury (TBI) is a complex brain problem that causes significant morbidity and mortality among people of all age groups. The complex pathophysiology, varied symptoms, and inadequate treatment further precipitate the problem. Further, TBI produces several psychiatric problems and other related complications in post-TBI survival patients, which are often treated symptomatically or inadequately. Several approaches, including neuroprotective agents targeting several pathways of oxidative stress, neuroinflammation, cytokines, immune system GABA, glutamatergic, microglia, and astrocytes, are being tried by researchers to develop effective treatments or magic bullets to manage the condition effectively. The problem of TBI is therefore treated as a challenge among pharmaceutical scientists or researchers to develop drugs for the effective management of this problem. The goal of the present comprehensivereview is to provide an overview of the several pharmacological targets, processes, and cellular pathways that researchers are focusing on, along with an update on their current state.

Glucagon-Like Peptide-1 Receptor Agonists and Risk for Suicidal Ideation and Behaviors in U.S. Older Adults With Type 2 Diabetes : A Target Trial Emulation Study.

A major concern has recently emerged about a potential link between glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and increased risk for suicidal ideation and behaviors based on International Classification of Diseases codes. To investigate the association between GLP-1 RAs, compared with sodium-glucose cotransporter-2 inhibitors (SGLT2is) or dipeptidyl peptidase-4 inhibitors (DPP4is), and risk for suicidal ideation and behaviors in older adults with type 2 diabetes (T2D). Two target trial emulation studies comparing propensity score (PS)-matched cohorts for GLP-1 RAs versus SGLT2is and GLP-1 RAs versus DPP4is. U.S. national Medicare administrative data from January 2017 to December 2020. Older adults (≥66 years) with T2D; no record of suicidal ideation or behaviors; and a first prescription for a GLP-1 RA, SGLT2i, or DPP4i. The primary end point was a composite of suicidal ideation and behaviors. New GLP-1 RA users were matched 1:1 on PS to new users of an SGLT2i or DPP4i in each pairwise comparison. A Cox proportional hazards regression was used to estimate the hazard ratio (HR) and 95% CIs within matched groups. This study included 21 807 pairs of patients treated with a GLP-1 RA versus an SGLT2i and 21 402 pairs of patients treated with a GLP-1 RA versus a DPP4i. The HR of suicidal ideation and behaviors associated with GLP-1 RAs relative to SGLT2is was 1.07 (95% CI, 0.80 to 1.45; rate difference, 0.16 [CI, -0.53 to 0.86] per 1000 person-years); the HR relative to DPP4is was 0.94 (CI, 0.71 to 1.24; rate difference, -0.18 [CI, -0.92 to 0.57] per 1000 person-years). Low event rate; imprecise estimates; unmeasured confounders, such as body mass index; and potential misclassification of outcomes. Among Medicare beneficiaries with T2D, this study found no clear increased risk for suicidal ideation and behaviors with GLP-1 RAs, although estimates were imprecise and a modest adverse risk could not be ruled out. American Foundation for Pharmaceutical Education, Pharmaceutical Research and Manufacturers of America Foundation, National Institute on Aging, and National Institute of Diabetes and Digestive and Kidney Diseases.

On-Demand Thio-Succinimide Hydrolysis for the Assembly of Stable Protein-Protein Conjugates.

Chemical post-translational protein-protein conjugation is an important technique with growing applications in biotechnology and pharmaceutical research. Maleimides represent one of the most widely employed bioconjugation reagents. However, challenges associated with the instability of first- and second-generation maleimide technologies are yet to be fully addressed. We report the development of a novel class of maleimide reagents that can undergo on-demand ring-opening hydrolysis of the resulting thio-succinimide. This strategy enables rapid post-translational assembly of protein-protein conjugates. Thio-succinimide hydrolysis, triggered upon application of chemical, photochemical, or enzymatic stimuli, allowed homobifunctional bis-maleimide reagents to be applied in the production of stable protein-protein conjugates, with complete temporal control. Bivalent and bispecific protein-protein dimers constructed from small binders targeting antigens of oncological importance, PD-L1 and HER2, were generated with high purity, stability, and improved functionality compared to monomeric building blocks. The modularity of the approach was demonstrated through elaboration of the linker moiety through a bioorthogonal propargyl handle to produce protein-protein-fluorophore conjugates. Furthermore, extending the functionality of the homobifunctional reagents by temporarily masking reactive thiols included in the linker allowed the assembly of higher order trimeric and tetrameric single-domain antibody conjugates. The potential for the approach to be extended to proteins of greater biochemical complexity was demonstrated in the production of immunoglobulin single-domain antibody conjugates. On-demand control of thio-succinimide hydrolysis combined with the facile assembly of chemically defined homo- and heterodimers constitutes an important expansion of the chemical methods available for generating stable protein-protein conjugates.

Design, Synthesis and Antibacterial Assessment of Active (4-Arylazo-3-Methyl-2-Thienyl) 4-Antipyrine Ketones.

The chemicals formed from antipyrines are flexible organic building blocks that are employed in the development of pharmaceuticals. By diazotizing (4-arylazo-3-hydroxy-2-thienyl) 4-antipyrine ketones 1a, 1b and 1c and (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketones (2a, 2b and 2c) further replaced with six other coupling components, a broad spectrum of hybrid molecules have been created. Mass spectra, NMR, FTIR, and elemental analyses have all been used to confirm the structures of the synthesised compounds. The antimicrobial screening was investigated by agar well diffusion and diluting the broth technique against both Gram-negative and positive-tested bacterial strains. (3-methyl-5-(phenylamino)-4-(4-tolylazo)-2-thienyl) 4-antipyrine ketone (2a) was found to be superior to Ciprofloxacin against test strains: Acinetobacter sp (34.33±1.15 mm), Listeria monocytogenes (29.33±1.15 mm) and Streptococcus sp. (19.33±1.15 mm). Also, good to moderate activities were expressed as minimum inhibitory concentration (MIC) and minimum bacterial concentration (MBC) which were recorded at 9±1 to 59.67±4.51 μg/mL and 16±4 to >512 μg/mL, respectively, using compounds 2a, 2b, and 2c. MBC/MIC ratio showed, that only, 2a and 2b have a bactericidal effect but other antipyrines with bacteriostatic strength. To conclude, it was suggested that the use of these novel synthesized (4-arylazo-3-methyl-2-thienyl) 4-antipyrine ketone derivatives molecules as a new chemical class of antimicrobial agents to perform new drug discovery in pharmaceutical preparations and medicinal research.

Translocation of Antimicrobial Peptides across Model Membranes: The Role of Peptide Chain Length.

Cushioned lipid bilayers are structures consisting of a lipid bilayer supported on a solid substrate with an intervening layer of soft material. They offer possibilities for studying the behavior and interactions of biological membranes more accurately under physiological conditions. In this work, we continue our studies of cushion formation induced by histatin 5 (24Hst5), focusing on the effect of the length of the peptide chain. 24Hst5 is a short, positively charged, intrinsically disordered saliva peptide, and here, both a shorter (14Hst5) and a longer (48Hst5) peptide variant were evaluated. Experimental surface active techniques were combined with coarse-grained Monte Carlo simulations to obtain information about these peptides. Results show that at 10 mM NaCl, both the shorter and the longer peptide variants behave like 24Hst5 and a cushion below the bilayer is formed. At 150 mM NaCl, however, no interaction is observed for 24Hst5. On the contrary, a cushion is formed both in the case of 14Hst5 and 48Hst5, and in the latter, an additional thick, diffuse, and highly hydrated layer of peptide and lipid molecules is formed, on top of the bilayer. Similar trends were observed from the simulations, which allowed us to hypothesize that positively charged patches of the amino acids lysine and arginine in all three peptides are essential for them to interact with and translocate over the bilayer. We therefore hypothesize that electrostatic interactions are important for the interaction between the solid-supported lipid bilayers and the peptide depending on the linear charge density through the primary sequence and the positively charged patches in the sequence. The understanding of how, why, and when the cushion is formed opens up the possibility for this system to be used in the research and development of new drugs and pharmaceuticals.

Antioxidant, Anti-Inflammatory, Anti-Diabetic, and Pro-Osteogenic Activities of Polyphenols for the Treatment of Two Different Chronic Diseases: Type 2 Diabetes Mellitus and Osteoporosis.

Polyphenols are natural bioactives occurring in medicinal and aromatic plants and food and beverages of plant origin. Compared with conventional therapies, plant-derived phytochemicals are more affordable and accessible and have no toxic side effects. Thus, pharmaceutical research is increasingly inclined to discover and study new and innovative natural molecules for the treatment of several chronic human diseases, like type 2 diabetes mellitus (T2DM) and osteoporosis. These pathological conditions are characterized by a chronic inflammatory state and persistent oxidative stress, which are interconnected and lead to the development and worsening of these two health disorders. Oral nano delivery strategies have been used to improve the bioavailability of polyphenols and to allow these natural molecules to exert their antioxidant, anti-inflammatory, anti-diabetic, and pro-osteogenic biological activities in in vivo experimental models and in patients. Polyphenols are commonly used in the formulations of nutraceuticals, which can counteract the detrimental effects of T2DM and osteoporosis pathologies. This review describes the polyphenols that can exert protective effects against T2DM and osteoporosis through the modulation of specific molecular markers and pathways. These bioactives could be used as adjuvants, in combination with synthetic drugs, in the future to develop innovative therapeutic strategies for the treatment of T2DM and osteoporosis.

Harnessing policy to promote inclusive medical product evidence: development of a reference standard and structured audit of clinical trial diversity policies

ObjectiveTo develop a reference standard based on US Food and Drug Administration and stakeholder guidance for pharmaceutical companies' policies on diversity in clinical trials and to assess these policies.DesignDevelopment of...