Effectiveness Of Drugs Research Articles

Exploring the Recent Pioneering Developments of Small Molecules in Antimalarial Drug Armamentarium: A Chemistry Prospective Appraisal.

Malaria is a very destructive and lethal parasitic disease that causes significant mortality worldwide, resulting in the loss of millions of lives annually. It is an infectious disease transmitted by mosquitoes, which is caused by different species of the parasite protozoan belonging to the genus Plasmodium. The uncontrolled intake of antimalarial drugs often employed in clinical settings has resulted in the emergence of numerous strains of plasmodium that are resistant to these drugs, including multidrug-resistant strains. This resistance significantly diminishes the effectiveness of many primary drugs used in the treatment of malaria. Hence, there is an urgent need for developing unique classes of antimalarial drugs that function with distinct mechanisms of action. In this context, the design and development of hybrid compounds that combine pharmacophoric properties from different lead molecules into a single unit gives a unique perspective towards further development of malaria drugs in the next generation. In recent years, the field of medicinal chemistry has made significant efforts resulting in the discovery and synthesis of numerous small novel compounds that exhibit potent antimalarial properties, while also demonstrating reduced toxicity and desirable efficacy. In light of this, we have reviewed the progress of hybrid antimalarial agents from 2021 up to the present. This manuscript presents a comprehensive overview of the latest advancements in the medicinal chemistry pertaining to small molecules, with a specific focus on their potential as antimalarial agents. As possible antimalarial drugs that might target both the dual stage and multi-stage stages of the parasite life cycle, these small hybrid molecules have been studied. This review explores a variety of physiologically active compounds that have been described in the literature in order to lay a strong foundation for the logical design and eventual identification of antimalarial drugs based on lead frameworks.

The Effect of Neuropsychiatric Drugs on the Oxidation-Reduction Balance in Therapy.

The effectiveness of available neuropsychiatric drugs in the era of an increasing number of patients is not sufficient, and the complexity of neuropsychiatric disease entities that are difficult to diagnose and therapeutically is increasing. Also, discoveries about the pathophysiology of neuropsychiatric diseases are promising, including those initiating a new round of innovations in the role of oxidative stress in the etiology of neuropsychiatric diseases. Oxidative stress is highly related to mental disorders, in the treatment of which the most frequently used are first- and second-generation antipsychotics, mood stabilizers, and antidepressants. Literature reports on the effect of neuropsychiatric drugs on oxidative stress are divergent. They are starting with those proving their protective effect and ending with those confirming disturbances in the oxidation-reduction balance. The presented publication reviews the state of knowledge on the role of oxidative stress in the most frequently used therapies for neuropsychiatric diseases using first- and second-generation antipsychotic drugs, i.e., haloperidol, clozapine, risperidone, olanzapine, quetiapine, or aripiprazole, mood stabilizers: lithium, carbamazepine, valproic acid, oxcarbazepine, and antidepressants: citalopram, sertraline, and venlafaxine, along with a brief pharmacological characteristic, preclinical and clinical studies effects.

Drug Survival, Safety, and Effectiveness of Secukinumab for up to 5 Years in Patients with Psoriasis and Psoriatic Arthritis: A Long-Term Real-Life Experience.

the selective IL-17 inhibitor secukinumab has demonstrated efficacy and safety in the treatment of moderate-severe psoriasis in recent years. evaluate effectiveness and drug survival (DS) of secukinumab in patients with psoriasis for up to 5 years. This is a retrospective study on a monocentric cohort of patients with psoriasis on secukinumab evaluating the achievement of PASI100, PASI90, and PASI ≤ 3 and DS analysis up to 260 weeks. DS multivariate analysis was carried out considering sex, age, age of onset of the disease, obesity, cardiovascular comorbidities, diabetes, involvement of difficult-to-treat sites, psoriatic arthritis, treatment-naïve status, and mean baseline PASI. At baseline, we evaluated 255 patients on secukinumab. PASI100 was reached by 41.7% and 70.6% of patients at weeks 16 and 260, respectively. PASI90 showed a similar trend with 46.5% of patients achieving it at week 16 and 88.2% at week 260. Non-obese patients showed a faster response than patients with obesity in achieving PASI100, PASI90, and PASI ≤ 3, with significant differences at 28 weeks [55% vs. 40% (p = 0.033), 64% vs. 49% (p = 0.038), and 76% vs. 62% (p = 0.036), respectively]. The estimated DS for secukinumab was 84.3% at 12 and 48% at 60 months. Obesity and smoking habits were associated with a higher risk of discontinuation in multivariate models (HR 1.6 CI 1.05-2.45, p = 0.028; HR 1.48 CI 1.01-2.17, p = 0.043, respectively). Secukinumab showed effectiveness for up to 5 years of treatment, with a high DS and achievement of PASI100, PASI90, and PASI < 3 at these time points. Only obesity reduced the response and maintenance of DS.

The Chameleon Strategy-A Recipe for Effective Ligand Screening for Viral Targets Based on Four Novel Structure-Binding Strength Indices.

The RNA viruses SARS-CoV, SARS-CoV-2 and MERS-CoV encode the non-structural Nsp16 (2'-O-methyltransferase) that catalyzes the transfer of a methyl group from S-adenosylmethionine (SAM) to the first ribonucleotide in mRNA. Recently, it has been found that breaking the bond between Nsp16 and SAM substrate results in the cessation of mRNA virus replication. To date, only a limited number of such inhibitors have been identified, which can be attributed to a lack of an effective "recipe". The aim of our study was to propose and verify a rapid and effective screening protocol dedicated to such purposes. We proposed four new indices describing structure-binding strength (structure-binding affinity, structure-hydrogen bonding, structure-steric and structure-protein-ligand indices) were then applied and shown to be extremely helpful in determining the degree of increase or decrease in binding affinity in response to a relatively small change in the ligand structure. After initial pre-selection, based on similarity to SAM, we limited the study to 967 compounds, so-called molecular chameleons. They were then docked in the Nsp16 protein pocket, and 10 candidate ligands were selected using the novel structure-binding affinity index. Subsequently the selected 10 candidate ligands and 8 known inhibitors and were docked to Nsp16 pockets from SARS-CoV-2, MERS-CoV and SARS-CoV. Based on the four new indices, the best ligands were selected and a new one was designed by tuning them. Finally, ADMET profiling and molecular dynamics simulations were performed for the best ligands. The new structure-binding strength indices can be successfully applied not only to screen and tune ligands, but also to determine the effectiveness of the ligand in response to changes in the target viral entity, which is particularly useful for assessing drug effectiveness in the case of alterations in viral proteins. The developed approach, the so-called chameleon strategy, has the capacity to introduce a novel universal paradigm to the field of drugs design, including RNA antivirals.

Evaluating the Efficacy of Omalizumab in Severe Cedar Seasonal Allergic Rhinitis in Japan.

Traditional treatments for cedar seasonal allergic rhinitis include second-generation antihistamines, nasal corticosteroids, and sublingual immunotherapy (SLIT). Omalizumab (Xolair®), an anti-immunoglobulin E (IgE) monoclonal antibody, is an additional option for severe cases unresponsive to existing therapies. Numerous studies have demonstrated the therapeutic effectiveness of omalizumab for cedar seasonal allergic rhinitis; however, most reported results after only up to four weeks of follow-up. Therefore, this study evaluates the clinical efficacy of omalizumab throughout one whole cedar pollen season. Subjects and methods: This study included patients from our department and the Otorhinolaryngology Department of Minami Osaka Hospital between 2021 and 2023 who were ≥ 12 years old and had serum total IgE levels of 30-1,500 IU/mL, a baseline weight of 30-150 kg, and persistent severe nasal symptoms despite conventional treatments. Patients taking oral steroids at the time of enrollment or had fewer than two omalizumab doses were excluded. Forty-six patients (26 males, 20 females; mean age, 19.1 ± 11.2 years) met these criteria and received subcutaneous omalizumab every 2 or 4 weeks based on their IgE levels and weight. Symptoms were assessed at baseline and 4, 8, and 12 weeks post-administration using the Total Nasal Symptom Score (TNSS) and the Japanese Standard Quality of Life Questionnaire (JRQLQ No. 1) for allergic rhinitis. Results: Thirty-six patients were followed up for 8 weeks and 13 for 12 weeks. TNSS significantly improved from 6.6 to 4.5 at 4 weeks, 4.2 at 8 weeks, and 4.1 at 12 weeks (p<0.05). Nasal discharge, sneezing, nasal obstruction, itchy eyes, and tearfulness showed significant improvements (p<0.05). Quality of life scores improved in daily activities, sleep, and physical health from week 4 to week 12. Discussion: Consistent with previous findings, omalizumab significantly improved nasal and ocular symptoms and quality of life in patients with severe cedar seasonal allergic rhinitis. Despite many patients discontinuing the drug after eight weeks due to high costs, the drug's effectiveness in preventing symptom recurrence suggests potential long-term benefits. Combining omalizumab with SLIT showed no significant differences in outcomes; however, further pharmacoeconomic studies are warranted to evaluate cost-effectiveness. Conclusion: Omalizumab proved to be an effective treatment for severe cedar seasonal allergic rhinitis, providing significant symptom relief and quality of life improvements. Further studies should investigate its long-term efficacy and safety, including potential adverse effects and the development of anti-omalizumab antibodies.

Pandemic and Pregnancy: Impact of COVID-19 Medication on Pregnant Women Outcomes

Abstract: The devastating outcomes of the Coronavirus disease 2019 (COVID-19) outbreak have traumatized the world, as they are highly infectious and mainly attack the respiratory tract. Although pregnant women are not at a higher risk of infection, it may result in more severe consequences than in the general population. Treatment of pregnant women with COVID-19 is challenging for doctors, as they need to consider the safety of both the mother and fetus. In addition, there is a lack of knowledge regarding the safety, effectiveness, and possible adverse outcomes of drugs used in COVID-19 pregnant women because they are generally excluded from clinical trials. We briefly reviewed the pathophysiology of drugs currently used in the treatment of COVID-19 in pregnant women and excluded drugs contraindicated during pregnancy. The safety of these drugs is derived from small case studies or clinical trials on other diseases. This article may be useful to physicians, researchers, and people interested in treating COVID-19.

A novel degradable PEG superparamagnetic iron oxide capsule coupled with a polyphenolic nano-enzymatic conjugate (PSPM-NE), to treat ROS-driven cardiovascular-diseases, tested in atherosclerosis as a model disease, and hypothesizing autoimmunity as an atheroma's trigger.

Cardiovascular diseases account for a significant portion of the worldwide mortality rate. This aroused interest among the specialised scientific community, seeking for solutions based on non-clinical and clinical investigations, to shed light onto the physio-pathology of cardiovascular impairment. It is proven challenging managing chronic cardiovascular illnesses like atherosclerosis, arrhythmias, and diverse cardiomyopathies. In certain cases, there is no approved treatment. In other cases, the need for combining therapeutic components, when dealing with co-morbidities, may increase the risk of toxicity-driven cardiovascular impairment. In this case, because the risk of cardiac events correlates with the QT prolongation rates, the QT or QTc interval prolongation has become an important biomarker to access drug-related cardio-toxicity. Several approaches have been found in the current literature, aiming at improving physiological acceptance, i.e., to reduce toxicity. Nanotechnology has increasingly appeared as a promising ally to modulate active substances, preserving cardiovascular function and optimising drug effectiveness, i.e., acting as a cardio-protective mechanism, leveraging the effects of drug-driven cardio-toxicity. In this manuscript, the author combines plant active compounds and nanotechnological strategies, e.g., nano-encapsulation, nano-enzymes, magnetically driven nano-delivery systems, applied in regenerative medicine, and assesses their effects on the cardiovascular system, e.g., as cardio-protective factors, reducing cardio-toxicity. The aim is to propose a new strategy to tackle atherosclerosis initiation and progression, in a drug design that targets ROS-removal and reduces inflammation, using auto-immunity biomarkers to select key atheroma-related signalling cascades. To analyse physiological phenomena related to atherosclerosis initiation and progression, the author proposes both experimental observations and a new haemorheological computational model of arterial constriction. The results of such analysis are used as motivators in the design of the here presented strategy to tackle atheroma. This novel design is based on degradable polyethylene glycol (PEG) superparamagnetic iron oxide capsule coupled with a polyphenolic nano-enzymatic conjugate (PSPM-NE).

Patient-derived mini-colons enable long-term modeling of tumor-microenvironment complexity.

Existing organoid models fall short of fully capturing the complexity of cancer because they lack sufficient multicellular diversity, tissue-level organization, biological durability and experimental flexibility. Thus, many multifactorial cancer processes, especially those involving the tumor microenvironment, are difficult to study ex vivo. To overcome these limitations, we herein implemented tissue-engineering and microfabrication technologies to develop topobiologically complex, patient-specific cancer avatars. Focusing on colorectal cancer, we generated miniature tissues consisting of long-lived gut-shaped human colon epithelia ('mini-colons') that stably integrate cancer cells and their native tumor microenvironment in a format optimized for real-time, high-resolution evaluation of cellular dynamics. We demonstrate the potential of this system through several applications: a comprehensive evaluation of drug effectivity, toxicity and resistance in anticancer therapies; the discovery of a mechanism triggered by cancer-associated fibroblasts that drives cancer invasion; and the identification of immunomodulatory interactions among different components of the tumor microenvironment. Similar approaches should be feasible for diverse tumor types.

Preparation and Characterization of Dutasteride Nanoparticles as Oral Fast-Dissolving Film

Background: Dutasteride, is a drug whose mechanism of action is inhibition of the enzyme 5-alpha reductase. It has been approved for use in the treatment of benign prostatic hyperplasia. Dutasteride has low solubility and high permeability, which classifies it as Biopharmaceutics classification system class II, according to the Biopharmaceutics Classification System. It has a water solubility of only 0.038 ng/mL and a slow dissolving rate, resulting in its exclusive availability in the market as a formulation contained within soft gelatin capsules. Objective: The aim of this study involves two parts. First, is the enhancement of dutasteride dissolution rate, by the creation of dutasteride nanosuspension, and second is the enhancement of patient compliance by the transformation of this nanosuspension to oral fast-dissolving film, which is characterized by its fast disintegration, stability, and ease of administration. Methods: The solvent anti/solvent precipitation method was used to formulate dutasteride nanosuspension. In addition, dutasteride nanoparticles oral fast dissolving films were prepared by using the solvent casting method. To compare the in vitro release patterns of pure dutasteride film and selected dutasteride nanoparticles film, the statistical analysis for the dissolution investigation was conducted using the model-independent technique (employing similarity factor f2) utilizing a DD solver. The selected dutasteride nanoparticle film was supposed to be the test material, while the pure dutasteride film was supposed to serve as the reference. Results: dutasteride nanosuspension demonstrated a high enhancement of the dissolution rate. In addition, the prepared dutasteride nanoparticles oral fast-dissolving film exhibited a further increase in the rate of dissolution and fast disintegration, and the administration is easy, all of these properties making it a promising dosage form. Conclusion: Nanosuspension is an excellent approach for enhancing the solubility, dissolution rate, and effectiveness of drugs with limited aqueous solubility such as dutasteride. In addition, the oral fast-dissolving film can be considered a promising dosage form that will increase patient compliance due to its high dissolution rate, fast disintegration, and easy administration.

Screening olfaction under dupilumab in chronic rhinosinusitis with nasal polyps.

Chronic rhinosinusitis with nasal polyps (CRSwNP) frequently leads to olfactory dysfunction. This study aimed to assess the impact of dupilumab on CRSwNP patients, focusing on olfactory outcomes and potential correlations with other clinical factors. CRSwNP patients eligible for dupilumab therapy received subcutaneous Dupixent® injections every two weeks (300mg/2ml dupilumab). The 12-item Sniffin' Sticks Test (SST-12), fractional exhaled nitric oxide (FeNO) and Nasal Polyp Score (NPS) were assessed at baseline and after one, three, and six months. Patients also completed the Sino-Nasal Outcome Test (SNOT-22) weekly. 26 CRSwNP patients were included. After one month, dupilumab led to substantial reductions in FeNO, SNOT scores, andNPS, whereas SST-12 scores improved significantly only after three months. A shift toward normosmia occurred, with 81% achieving normosmia after six months, and a drop in anosmia prevalence to 9.5%. Significant negative correlations between olfaction (SST-12) and polyp severity (NPS) at baseline and after six months were found, while no significant correlations were observed between SST-12 and FeNO or SNOT scores. Age did not correlate with olfaction. Dupilumab demonstrated efficacy in restoring olfaction in CRSwNP patients. Reaching normosmia in over 80% ofpatients after six months of treatment underscores the drug's effectiveness in managing this challenging symptom.

A Review on Nanostructured Lipid Carriers as Promising Drug Delivery Vehicle to Target Various Cancers via Oral Route: A Step towards “Chemotherapy at Home”

Abstract: Oral drug administration is largely preferred owing to enhanced patient compliance, convenience of self-intake of dose, non-invasiveness, and low manufacturing cost. Cancer is a condition that starts with aberrant cell division at an uncontrolled rate. The clinical effectiveness of many anticancer drugs is limited by their physicochemical characteristics and physiological circumstances in the GI tract. Nanostructured lipid carriers have the potential to enhance the bio-availability of anticancer drugs by entrapping them. The NLCs, by virtue of their nanosize and their biocompatibility, can bypass the first-pass metabolism and be taken up by M cells of Peyer’s patches to deliver the drug to the deeper tumours. The proposed review highlights the potential of NLCs in oral drug delivery for the management of various cancers. It discusses various strategies, method of preparation, mechanism of uptake, and their applications in the treatment of cancer via oral delivery. Further, it explains the recent advances and future perspectives.

Therapeutic effectiveness of silver-containing drugs for various forms of mastitis in cows

Therapeutic effectiveness of silver-containing drugs for various forms of mastitis in cows

Comparative effectiveness of hormonal drugs from different manufacturers in synchronizing sexual heat in cows

Comparative effectiveness of hormonal drugs from different manufacturers in synchronizing sexual heat in cows

Three decades of research in lymphatic filariasis-lessons learned.

Lymphatic filariasis (LF), one of the 21 Neglected Tropical Diseases (NTD) which is the second leading cause for disability globally. Wuchereria Bancrofti, Brugia malayi and Brugia timori are the parasites causing this infection. World Health Assembly in 1997 declared LF to be eliminated and the Global Program to eliminate LF (GPELF) was launched by WHO in 2000 with the two strategies viz, 1) stop transmission of infection through Mass Drug Administration (MDA) and 2) to alleviate the suffering of the people affected with the disease through Morbidity Management and Disability Prevention (MMDP. The 'Filariasis research unit' recommended by WHO TDR and ICMR was established in Alappuzha, Kerala in 1989 for research studies related to LF. Over the last three decades 23 studies have been completed, which included different trials to find out the dose, effectiveness and safety of the various drugs used in preventive chemotherapy as single drug or combinations, for treatment of microfilaraemia,, various studies related to morbidity management in filarial disease, socio-economic aspects of filarial disability, Pharmacokinetic study of antifilarial drugs, Study on lymphatic filariasis in children, Studies on dignostics of LF, efficacy of drugs in management of lymphedema etc. In this article an attempt is made to explain the lessons learned from these studies and its importance in development of policy decision making for GPELF.

Antibiotic Potentiation Through Phytochemical-Based Efflux Pump Inhibitors to Combat Multidrug Resistance Bacteria.

Antimicrobial resistance development poses a significant danger to the efficacy of antibiotics, which were once believed to be the most efficient method for treating infections caused by bacteria. Antimicrobial resistance typically involves various mechanisms, such as drug inactivation or modification, drug target modification, drug uptake restriction, and drug efflux, resulting in decreased antibiotic concentrations within the cell. Antimicrobial resistance has been associated with efflux Pumps, known for their capacity to expel different antibiotics from the cell non-specifically. This makes EPs fascinating targets for creating drugs to combat antimicrobial resistance (AMR). The varied structures of secondary metabolites (phytomolecules) found in plants have positioned them as a promising reservoir of efflux pump inhibitors. These inhibitors act as modifiers of bacterial resistance and facilitate the reintroduction of antibiotics that have lost clinical effectiveness. Additionally, they may play a role in preventing the emergence of multidrug resistant strains. The objective of this review article is to discuss the latest studies on plant-based efflux pump inhibitors such as terpenoids, alkaloids, flavonoids, glycosides, and tetralones. It highlighted their potential in enhancing the effectiveness of antibiotics and combating the development of multidrug resistance. Efflux pump inhibitors (EPIs) derived from botanical sources, including compounds like lysergol, chanaoclavine, niazrin, 4-hydroxy-α-tetralone, ursolic acid, phytol, etc., as well as their partially synthesized forms, have shown significant potential as practical therapeutic approaches in addressing antimicrobial resistance caused by efflux pumps. Further, several phyto-molecules and their analogs demonstrated superior potential for reversing drug resistance, surpassing established agents like reserpine, niaziridin, etc. Conclusion: This review found that while the phyto-molecules and their derivatives did not possess notable antimicrobial activity, their combination with established antibiotics significantly reduced their minimum inhibitory concentration (MIC). Specific molecules, such as chanaoclavine and niaziridin, exhibited noteworthy potential in reversing the effectiveness of drugs, resulting in a reduction of the MIC of tetracycline by up to 16 times against the tested strain of bacteria. These molecules inhibited the efflux pumps responsible for drug resistance and displayed a stronger affinity for membrane proteins. By employing powerful EPIs, these molecules can selectively target and obstruct drug efflux pumps. This targeted approach can significantly augment the strength and efficacy of older antibiotics against various drug resistant bacteria, given that active drug efflux poses a susceptibility for nearly all antibiotics.

Expanding the Role of Chiral Drugs and Chiral Nanomaterials as a Potential Therapeutic Tool.

Chirality, the property of molecules having mirror-image forms, plays a crucial role in pharmaceutical and biomedical research. This review highlights its growing importance, emphasizing how chiral drugs and nanomaterials impact drug effectiveness, safety, and diagnostics. Chiral molecules serve as precise diagnostic tools, aiding in accurate disease detection through unique biomolecule interactions. The article extensively covers chiral drug applications in treating cardiovascular diseases, CNS disorders, local anesthesia, anti-inflammatories, antimicrobials, and anticancer drugs. Additionally, it explores the emerging field of chiral nanomaterials, highlighting their suitability for biomedical applications in diagnostics and therapeutics, enhancing medical treatments.

NEW STRATEGIES IN COMBATING FUNGAL PATHOGENS

Background. The relevance of the research is driven by the emerging trend of increasing resistance to existing drugs for the treatment of fungal infections. Addressing this issue is only possible by developing new formulations of antifungal agents or improving existing ones; studying the mechanisms of interaction of drugs with fungal cell walls and their exopolysaccharide matrices; refining delivery methods of antifungal agents, such as DectiSomes, for maximum effectiveness and minimizing side effects; expanding understanding of the immune response mechanisms to fungal infections and developing vaccines for the prevention of these diseases. The research aims to improve methods of diagnosis, treatment, and prevention of fungal infections to enhance the quality of life for patients and reduce the overall impact of these diseases on public health. Aim: To evaluate new treatment strategies for fungal infections to increase the effectiveness of antifungal agents, reduce their toxicity, and slow down the development of resistance. Materials and Methods: The materials for this study included publications of results from contemporary scientific research on the topic. The methods used for conducting the research were: a systematic approach and analysis, literary and critical analysis. Results. Prove the prospects for developing new strategies and techniques for antifungal therapy. By analyzing the results of clinical studies, including the assessment of the effectiveness of various antifungal drugs, it is possible to determine which ones are most effective under certain conditions and for specific types of fungal infections. New methodologies based on the principle of delivering or acting directly on the target area allow reducing the overall burden on the body. Better penetration of drugs into the skin and tissues allows for better control of fungal infection and accelerated healing process. Evaluating side reactions and patient tolerance levels to different drugs helps select antifungal agents that are the safest and most comfortable to use. Conclusion. Fungal infections continue to be a serious public health problem, and the development of new treatment and prevention methods is extremely important. Overall, research in these areas can help develop new therapeutic strategies that are more effective and safer for treating fungal infections, which pose a threat to humanity.

Unveiling the antibacterial potential of nature-inspired material for designing food-related coatings

The escalating challenge of antibiotic resistance has driven the innovation of new antibacterial and antifouling materials. Recent developments focus on nature-inspired topographical engineering and nanostructured surfaces to combat resistant bacteria. This review discusses these advances, emphasizing the potential of nanoantibiotics and biopolymers. Nanoantibiotics revitalize drug effectiveness by encapsulating them in nanoparticles, presenting a new strategy to fight pathogens. Biopolymers, eco-friendly and biodegradable, emerge as a sustainable alternative, with applications in food safety and beyond. The exploration of these materials signifies a leap in design, fabrication, and the possibility of cost-effective, large-scale production, highlighting a promising avenue for commercial applications to tackle antibiotic resistance and biofouling effectively.

Addition of Polyphenols to Drugs: The Potential of Controlling "Inflammaging" and Fibrosis in Human Senescent Lung Fibroblasts In Vitro.

The combination of a polyphenol, quercetin, with dasatinib initiated clinical trials to evaluate the safety and efficacy of senolytics in idiopathic pulmonary fibrosis, a lung disease associated with the presence of senescent cells. Another approach to senotherapeutics consists of controlling inflammation related to cellular senescence or "inflammaging", which participates, among other processes, in establishing pulmonary fibrosis. We evaluate whether polyphenols such as caffeic acid, chlorogenic acid, epicatechin, gallic acid, quercetin, or resveratrol combined with different senotherapeutics such as metformin or rapamycin, and antifibrotic drugs such as nintedanib or pirfenidone, could present beneficial actions in an in vitro model of senescent MRC-5 lung fibroblasts. A senescent-associated secretory phenotype (SASP) was evaluated by the measurement of interleukin (IL)-6, IL-8, and IL-1β. The senescent-associated β-galactosidase (SA-β-gal) activity and cellular proliferation were assessed. Fibrosis was evaluated using a Picrosirius red assay and the gene expression of fibrosis-related genes. Epithelial-mesenchymal transition (EMT) was assayed in the A549 cell line exposed to Transforming Growth Factor (TGF)-β in vitro. The combination that demonstrated the best results was metformin and caffeic acid, by inhibiting IL-6 and IL-8 in senescent MRC-5 cells. Metformin and caffeic acid also restore cellular proliferation and reduce SA-β-gal activity during senescence induction. The collagen production by senescent MRC-5 cells was inhibited by epicatechin alone or combined with drugs. Epicatechin and nintedanib were able to control EMT in A549 cells. In conclusion, caffeic acid and epicatechin can potentially increase the effectiveness of senotherapeutic drugs in controlling lung diseases whose pathophysiological component is the presence of senescent cells and fibrosis.

Influence of regulatory peptides on neurogenic lower urinary tract dysfunction in multiple sclerosis. Data of one center

Objective: Cclinical evaluation of the effectiveness and safety of the effect of the regulatory polypeptide drug on neurogenic overactive bladder (OAB) in patients with multiple sclerosis (MS).Materials and methods: 41 patients with MS and urodynamically confirmed detrusor overactivity were included in a prospective, single-center, simple comparative clinical trial with sequential drug changes. The initial function of the lower urinary tract and its dynamic changes during therapy were studied by filling out a voiding diary and questionnaires using the EDSS, NBSS, SF-Qualiveen, I-QOL questionnaires. The control drug Solifenacin (patient group 1) is a specific competitive antagonist of muscarinic receptors of the M3 subtype, which causes detrusor contraction. The Study Drug (patient group 2) is a complex of regulatory polypeptides that have an organotropic effect on the bladder. Drug administration: control drug for 4 weeks, then an observation period of 4 weeks, after which - taking the Study Drug for 30 days. The results were monitored immediately after the end of taking the Study Drugs, after which they were compared with the initial data. Statistical analysis was carried out by the program “Statistica 10” (StatSoft Inc., USA), using non-parametric data analysis with median analysis, Wilcoxon test and Mann-Whitney U-test search. The results of differences were considered statistically significant if the probability of error was &lt;5% (p&lt;0.05).Results: Vvoiding diary: 14.6% and 24.4% of patients in groups 1 and 2, respectively, were freed from urinary incontinence; from nocturia —- 31.7% and 56.1% of patients for groups 1 and 2, respectively, the frequency of daily urination was normalized in 53.6% and 70.7% of patients in groups 1 and 2, respectively. NBSS questionnaire: decrease in the total questionnaire score by 29.2% and 47.4% for groups 1 and 2, respectively. SF-Qualiveen questionnaire: an increase in the overall assessment score by 42.3% for group 1 versus +66.5% for group 2. I-QOL questionnaire: improvement in quality of life by 56.0% and 80.4% for groups 1 and 2, respectively. The Study Drug has a higher safety profile compared to Solifenacin.Conclusion: Tthe effectiveness of the Study Drug in the correction of neurogenic OAB is higher in comparison with Solifenacin, which is reflected in a decrease in urgency, pollakiuria, the number of episodes of urinary incontinence and a significant improvement in the quality of life of these patients. The Study Drug demonstrates a high safety profile in the study.