Combination Drug Research Articles

Co-Delivery of Tim-3 Monoclonal Antibody and Sorafenib to Enhance Chemoimmunotherapy of Liver Cancer by Using Silicon Nanosystem

In this study, mesoporous silica nanosystem (ST/SNs) was designed to co-deliver Tim-3 mAb and sorafenib (SF) for combined chemoimmunotherapy of liver cancer. The outer shell of ST/SNs is composed of Tim-3 mAb modified with metalloproteinase 2 (MMP2)-sensitive peptide, which acts as a “gating molecule” in the blood circulation to prevent drug release, and responds to Tim-3 mAb under the action of MMP2 in the tumor microenvironment Shedding enables Tim-3 mAb and SF-triggered drug release for heterotargeted cell delivery to T cells/tumor cells. In vivo tumor inhibition experiments showed that ST/SNs significantly improved tumor inhibition in tumor-bearing mice compared with sequential administration of free SF and Tim-3 mAb. At the same time, ST/SNs significantly up-regulated the expression of anti-tumor cytokines IFN-γ and IL-12 in mouse serum and the proportion of CD3+CD4+ and CD3+CD8+ cells in the tumor, showing a good immune regulation ability. In addition, at the administered dose, the blank vector exhibited low cytotoxicity and hemolysis, and no obvious hemolysis was observed. Provincial People’s Hospital. In conclusion, this study provides a promising chemoimmunotherapy combination drug combination for clinical liver cancer treatment, and provides a potential drug carrier for chemoimmunotherapy combination therapy.

Enhancing chemotherapeutic efficacy: Niosome-encapsulated Dox-Cis with MUC-1 aptamer.

Cancer remains a formidable global health challenge, currently affecting nearly 20 million individuals worldwide. Due to the absence of universally effective treatments, ongoing research explores diverse strategies to combat this disease. Recent efforts have concentrated on developing combined drug regimens and targeted therapeutic approaches. This study aimed to investigate the anticancer efficacy of a conjugated drug system, consisting of doxorubicin and cisplatin (Dox-Cis), encapsulated within niosomes and modified with MUC-1 aptamers to enhance biocompatibility and target specific cancer cells. The chemical structure of the Dox-Cis conjugate was characterized using Fourier Transform Infrared Spectroscopy (FTIR) and Liquid Chromatography Quadrupole Time-of-Flight Mass Spectrometry (LC-Q-TOF/MS). The zeta potential and morphological parameters of the niosomal vesicles were determined through Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM). In vitro assessments of cell viability and apoptosis were conducted on MUC-1 positive HeLa cells and MUC-1 negative U87 cells. The findings confirmed the successful conjugation of Dox and Cis within the niosomes. The Nio/Dox-Cis/MUC-1 formulation demonstrated enhanced efficacy compared to the individual drugs and their unencapsulated combination in both cell lines. Notably, the Nio/Dox-Cis/MUC-1 formulation exhibited greater effectiveness on HeLa cells (38.503 ± 1.407) than on U87 cells (46.653 ± 1.297). The study underscores the potential of the Dox-Cis conjugate as a promising strategy for cancer treatment, particularly through platforms that facilitate targeted drug delivery to cancer cells. This targeted approach could lead to more effective and personalized cancer therapies.

Efficacy and Safety of Metformin and Atorvastatin Combination Therapy vs. Monotherapy with Either Drug in Type 2 Diabetes Mellitus and Dyslipidemia Patients (ATOMIC): Double-Blinded Randomized Controlled Trial.

It is well known that a large number of patients with diabetes also have dyslipidemia, which significantly increases the risk of cardiovascular disease (CVD). This study aimed to evaluate the efficacy and safety of combination drugs consisting of metformin and atorvastatin, widely used as therapeutic agents for diabetes and dyslipidemia. This randomized, double-blind, placebo-controlled, parallel-group and phase III multicenter study included adults with glycosylated hemoglobin (HbA1c) levels >7.0% and <10.0%, low-density lipoprotein cholesterol (LDL-C) >100 and <250 mg/dL. One hundred eighty-five eligible subjects were randomized to the combination group (metformin+atorvastatin), metformin group (metformin+atorvastatin placebo), and atorvastatin group (atorvastatin+metformin placebo). The primary efficacy endpoints were the percent changes in HbA1c and LDL-C levels from baseline at the end of the treatment. After 16 weeks of treatment compared to baseline, HbA1c showed a significant difference of 0.94% compared to the atorvastatin group in the combination group (0.35% vs. -0.58%, respectively; P<0.0001), whereas the proportion of patients with increased HbA1c was also 62% and 15%, respectively, showing a significant difference (P<0.001). The combination group also showed a significant decrease in LDL-C levels compared to the metformin group (-55.20% vs. -7.69%, P<0.001) without previously unknown adverse drug events. The addition of atorvastatin to metformin improved HbA1c and LDL-C levels to a significant extent compared to metformin or atorvastatin alone in diabetes and dyslipidemia patients. This study also suggested metformin's preventive effect on the glucose-elevating potential of atorvastatin in patients with type 2 diabetes mellitus and dyslipidemia, insufficiently controlled with exercise and diet. Metformin and atorvastatin combination might be an effective treatment in reducing the CVD risk in patients with both diabetes and dyslipidemia because of its lowering effect on LDL-C and glucose.

Determination of Tetracaine and Oxymetazoline in Drugs and Saliva via Potentiometric Sensor Arrays Based on Fluoropolymer/Polyaniline Composites

AbstractA growing interest in dental practice in intranasal anesthesia using tetracaine and oxymetazoline dictates the need for their simultaneous determination in combination drugs and human saliva. Potentiometric multisensory systems based on perfluorosulfonic acid membranes, including polyaniline‐modified ones, were developed for these purposes. A change in the distribution of the sensor sensitivity to the related analytes was achieved by variation of the conditions for concentration polarization at the membrane interface with a studied solution due to a change in the intrapore volume, nature, and availability of the sorption centers, as well as the hydrophilicity of the membrane surface that were specified by the conditions for their synthesis and subsequent hydrothermal treatment. Reversibility of the analyte sorption using the chosen conditions for regeneration provided long‐term stable work of both the sensors and the calibration equations established by multivariate linear regression. The membrane modification promoted their resistance to fouling. The relative errors of the simultaneous tetracaine and oxymetazoline determination in the combination drug solutions were no greater than 7% and 11%, while in the artificial saliva solutions, they were 15% and 17%, respectively, when an array of the cross‐sensitive sensors based on the composite membranes prepared by different methods was used. The analysis errors were reduced to 3%–6% when analyzing the drug and to 0.2%–6% when analyzing the artificial saliva if an array was organized with the sensors based on the membrane with the dopant and the membrane without it, due to the decreasing correlation between their responses.

The use of the combined drug «Urolife-Next» for recurrent lower urinary tract infections: clinical and microbiological aspects

The use of the combined drug «Urolife-Next» for recurrent lower urinary tract infections: clinical and microbiological aspects

New Strategies for Responding to SARS-CoV-2: The Present and Future of Dual-Target Drugs.

The 2019 coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in millions of deaths, posing a serious threat to public health and safety. Rapid mutations of SARS-CoV-2 and complex interactions among multiple targets during infection pose a risk of expiry for small molecule inhibitors. This suggests that the traditional concept of "one bug, one drug" could be ineffective in dealing with the coronavirus. The dual-target drug strategy is expected to be the key to ending coronavirus infections. However, the lack of design method and improper combination of dual-targets poses obstacle to the discovery of new dual-target drugs. In this Perspective, we summarized the profiles concerning drug design methods, structure-activity relationships, and pharmacological parameters of dual-target drugs for the treatment of COVID-19. Importantly, we underscored how target combination and rational drug design illuminate the development of dual-target drugs for SARS-CoV-2.

Recent Progress in Multifunctional Stimuli-Responsive Combinational Drug Delivery Systems for the Treatment of Biofilm-Forming Bacterial Infections.

Drug-resistant infectious diseases pose a substantial challenge and threat to medical regimens. While adaptive laboratory evolution provides foresight for encountering such situations, it has inherent limitations. Novel drug delivery systems (DDSs) have garnered attention for overcoming these hurdles. Multi-stimuli responsive DDSs are particularly effective due to their reduced background leakage and targeted drug delivery to specific host sites for pathogen elimination. Bacterial infections create an acidic state in the microenvironment (pH: 5.0-5.5), which differs from normal physiological conditions (pH: 7.4). Infected areas are characterized by the overexpression of hyaluronidase, gelatinase, phospholipase, and other virulence factors. Consequently, several effective stimuli-responsive DDSs have been developed to target bacterial pathogens. Additionally, biofilms, structured communities of bacteria encased in a self-produced polymeric matrix, pose a significant challenge by conferring resistance to conventional antimicrobial treatments. Recent advancements in nano-drug delivery systems (nDDSs) show promise in enhancing antimicrobial efficacy by improving drug absorption and targeting within the biofilm matrix. nDDSs can deliver antimicrobials directly to the biofilm, facilitating more effective eradication of these resilient bacterial communities. Herein, this review examines challenges in DDS development, focusing on enhancing antibacterial activity and eradicating biofilms without adverse effects. Furthermore, advances in immune system modulation and photothermal therapy are discussed as future directions for the treatment of bacterial diseases.

Unravelling the role of tumor microenvironment responsive nanobiomaterials in spatiotemporal controlled drug delivery for lung cancer therapy.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

From Chips-in-Lab to Point-of-Care Live Cell Device: Development of a Microfluidic Device for On-Site Cell Culture and High-Throughput Drug Screening.

Live cell assays provide real-time data of cellular responses. In combination with microfluidics, applications such as automated and high-throughput drug screening on live cells can be accomplished in small devices. However, their application in point-of-care testing (POCT) is limited by the requirement for bulky equipment to maintain optimal cell culture conditions. In this study, we propose a POCT device that allows on-site cell culture and high-throughput drug screening on live cells. We first observe that cell viabilities are substantially affected by liquid evaporation within the microfluidic device, which is intrinsic to the polydimethylsiloxane (PDMS) material due to its hydrophobic nature and nanopatterned surface. The unwanted PDMS-liquid-air interface in the cell culture environment can be eliminated by maintaining a persistent humidity of 95-100% or submerging the whole microfluidic device under water. Our results demonstrate that in the POCT device equipped with a water tank, both primary cells and cell lines can be maintained for up to 1 week without the need for external cell culture equipment. Moreover, this device is powered by a standard alkali battery and can automatically screen over 5000 combinatorial drug conditions for regulating neural stem cell differentiation. By monitoring dynamic variations in fluorescent markers, we determine the optimal doses of platelet-derived growth factor and epidermal growth factor to suppress proinflammatory S100A9-induced neuronal toxicities. Overall, this study presents an opportunity to transform lab-on-a-chip technology from a laboratory-based approach to actual point-of-care devices capable of performing complex experimental procedures on-site and offers significant advancements in the fields of personalized medicine and rapid clinical diagnostics.

Evolving the Role of Black Race in Hypertension Therapeutics.

Black race has been used to guide antihypertensive drug selection for Black patients based on predominant between race (same drug) and intra-race (different drugs) blood pressure (BP) response patterns. Accordingly, thiazide diuretics and calcium antagonists have been recommended over renin-angiotensin system (RAS) inhibitors (angiotensin-receptor blockers, angiotensin-converting enzyme inhibitors) and beta blockers for Black patients. Current antihypertensive drug prescribing reflects historical guidance as calcium antagonists and thiazide diuretics are prescribed more and RAS blockers less in Black than White patients. Hypertension control rates in Blacks, lag those for Whites despite their greater use of combination drug therapy and lesser use of monotherapy. This is also true across drug regimens containing any of the 4 recommended classes for initial therapy as well as for evidence-based combination drug therapy (calcium antagonist or thiazide diuretic + RAS blocker) regimens for which there is no known racial disparity in BP response. Current recommendations acknowledge the need for combination drug therapy in most, especially in Black patients. One exemplary comprehensive hypertension control program achieved >80% control rates in Black and White patients with minimal racial disparity while utilizing a race-agnostic therapeutic algorithm. Black patients manifest robust, if not outsized, BP responses to diet/lifestyle modifications. Importantly, race neither appears to be a necessary nor sufficient consideration for the selection of effective drug therapy. Accordingly, we urge the initiation of adequately intense race-agnostic drug therapy coupled with greater emphasis on diet/lifestyle modifications for Black patients as the cornerstone of a race-informed approach to hypertension therapeutics.

BACTERIOLOGICAL PROFILE AND ANTIBIOGRAM OF GRAM-NEGATIVE BACILLI ISOLATED FROM ENDOTRACHEAL TUBE SECRETIONS AND TRACHEAL ASPIRATES FROM PATIENTS ON MECHANICAL VENTILATION: A HOSPITAL-BASED CROSS-SECTIONAL STUDY

Objective: Nosocomial infections have become a serious threat to mortality and morbidity among hospitalized patients. Major risk factor among critically ill patients is excessive use of invasive devices like Endotracheal tube (ET) and tracheal intubation. The development of biofilm and their subsequent dislodgement aids in lung colonization and may cause Ventilator-associated pneumonia (VAP) [1]. Methods: Present study was conducted on ET tube tips and Tracheal aspirates received in microbiological laboratory from various ICU’s (Medical, surgical and pediatric) in Andhra Medical College, Visakhapatnam over a period of one year from September 2022 to August 2023. A total of 116 samples were processed according to standard protocols and Antibiotic Susceptible Testing (AST) was performed by Kirby-Bauer disc diffusion method on Mueller-Hinton agar as per CLSI guidelines. Results: In total, 116 samples were processed. ET tube tips were 76/116 and tracheal aspirates were 40/116, with males (69/116) outnumbered females (47/116). Out of a total of 116 samples, 72 (62%) were culture-positive and 44 (38%) were sterile. Acinetobacter spp. was the most common pathogen among 72 culture positives (31/72, 43%), followed by Klebsiella spp. (20/72, 28%), Pseudomonas spp. (13/72, 18%) and Escherichia coli (8/72, 11%). A total of 11 (11/72, 15%) GNB were found as multi-drug resistant. The multi-drug resistant GNB isolated were Acinetobacter (6/72), Klebsiella (3/72) and Pseudomonas (2/72). Meropenem is the most susceptible antibiotic, followed by Piperacillin-Tazobactam. Conclusion: It was concluded from this study that most commonly isolated pathogen was Acinetobacter spp. Most of these isolates were sensitive to Carbapenem and BLBLI combination drugs. Microbial persistence and impaired response to the treatment were more frequent, when multi-drug resistant organisms were present. Hence a local combined antibiotic approach, based on bacteriological profile and AST is essential to initiate empirical therapy which will minimize the bacterial colonization and prevent the incidences of VAP.

Innovative eco-friendly stability-indicating HPLC-PDA method for simultaneous determination of the emerging antiviral drugs against COVID-19 infection molnupiravir and favipiravir; degradation kinetic studies along with LC-MS based structure elucidation

The adoption of the principles of green chemistry in analytical procedures lowers the negative influence on both people and the environment, which presently has become the key goal. Additionally, the need for advanced analytical techniques for the simultaneous determination of antiviral combinations is highly recommended, one of those novel combinations that recently proved effective emerging antiviral drugs in the treatment of SARS-COV-2 is molnupiravir (MOL) and favipiravir (FAV). Therefore, the establishment of simple and precise stability-indicating HPLC-PDA method for their simultaneous determination is crucial for the probable co-formulation. The stability of MOL was studied along with FAV after forced degradation of both under different stress conditions Separation of MOL, FAV, and their corresponding degradation products was achieved by simple isocratic HPLC-PDA method using a mobile phase comprised of 25.0 mM phosphate buffer (pH 3.0 ± 0.05) − methanol (70:30, v/v) at flow rate 1.0 mL/min. A Zorbax C18 (250 × 4.6 mm, 5 μm; Agilent Technologies, USA) column was used for the separation of the components and the column oven was maintained at 30 °C, the selected wavelength for detection of both analytes and their degradation products was 230.0 nm. The method was linear over the range of 1.0 – 200.0 µg/mL for both MOL and FAV. MOL was found to be susceptible to all forced degradation conditions, namely, acid, alkali, oxidative, thermal, and photodegradation while FAV was susceptible only to acid, alkali, and oxidative degradation. The probable degradation mechanisms were assumed through the evaluation of the MS1 fragmentation pattern of the degradation products, also studying the kinetic behavior of the degradation reactions. Furthermore, the greenness profile for the proposed method was evaluated utilizing the new Complementary Green Analytical Procedure Index method (ComplexGAPI), and analytical greenness (AGREE) metrics with a score of the later one equals to 0.61 that indicated the greenness evaluation of the method. In addition, the new blue applicability grade index (BAGI) which is complementary to the green metrics showed a score of 85.0 that presents a good applicability potential of the method. The proposed method is the first sustainable, stability-indicating method developed for the simultaneous determination of this potential combination that would help in manufacturing both drugs in a fixed-dose drug combination.

The Variation in the Traits Ameliorated by Inhibitors of JAK1/2, TGF-β, P-Selectin, and CXCR1/CXCR2 in the Gata1low Model Suggests That Myelofibrosis Should Be Treated by These Drugs in Combination.

Studies conducted on animal models have identified several therapeutic targets for myelofibrosis, the most severe of the myeloproliferative neoplasms. Unfortunately, many of the drugs which were effective in pre-clinical settings had modest efficacy when tested in the clinic. This discrepancy suggests that treatment for this disease requires combination therapies. To rationalize possible combinations, the efficacy in the Gata1low model of drugs currently used for these patients (the JAK1/2 inhibitor Ruxolitinib) was compared with that of drugs targeting other abnormalities, such as p27kip1 (Aplidin), TGF-β (SB431542, inhibiting ALK5 downstream to transforming growth factor beta (TGF-β) signaling and TGF-β trap AVID200), P-selectin (RB40.34), and CXCL1 (Reparixin, inhibiting the CXCL1 receptors CXCR1/2). The comparison was carried out by expressing the endpoints, which had either already been published or had been retrospectively obtained for this study, as the fold change of the values in the corresponding vehicles. In this model, only Ruxolitinib was found to decrease spleen size, only Aplidin and SB431542/AVID200 increased platelet counts, and with the exception of AVID200, all the inhibitors reduced fibrosis and microvessel density. The greatest effects were exerted by Reparixin, which also reduced TGF-β content. None of the drugs reduced osteopetrosis. These results suggest that future therapies for myelofibrosis should consider combining JAK1/2 inhibitors with drugs targeting hematopoietic stem cells (p27Kip1) or the pro-inflammatory milieu (TGF-β or CXCL1).

Suppression of CTC1 inhibits hepatocellular carcinoma cell growth and enhances RHPS4 cytotoxicity.

Although DNA repair mechanisms function to maintain genomic integrity, in cancer cells these mechanisms may negatively affect treatment efficiency. The strategy of targeting cancer cells via inhibiting DNA damage repair has been successfully used in breast and ovarian cancer using PARP inhibitors. Unfortunately, such strategies have not yet yielded results in liver cancer. Hepatocellular carcinoma (HCC), the most common type of liver cancer, is a treatment-resistant malignancy. Despite the development of guided therapies, treatment regimens for advanced HCC patients still fall short of the current need and significant problems such as cancer relapse with resistance still exist. In this paper, we targeted telomeric replication protein CTC1, which is responsible for telomere maintenance. CTC expression was analyzed using tumor and matched-tissue RNA-sequencing data from TCGA and GTEx. In HCC cell lines, q-RT-PCR and Western blotting were used to detect CTC1 expression. The knock-down of CTC1 was achieved using lentiviral plasmids. The effects of CTC1 silencing on HCC cells were analyzed by flow cytometry, MTT, spheroid and colony formation assays. CTC1 is significantly downregulated in HCC tumor samples. However, CTC1 protein levels were higher in sorafenib-resistant cell lines compared to the parental groups. CTC1 inhibition reduced cell proliferation in sorafenib-resistant HCC cell lines and diminished their spheroid and colony forming capacities. Moreover, these cells were more sensitive to single and combined drug treatment with G4 stabilizer RHPS4 and sorafenib. Our results suggest that targeting CTC1 might be a viable option for combinational therapies designed for sorafenib resistant HCC patients.

A novel CAF-cancer cell crosstalk-related gene prognostic index based on machine learning: prognostic significance and prediction of therapeutic response in head and neck squamous cell carcinoma

BackgroundCancer-associated fibroblast (CAF)-cancer cell crosstalk (CCCT) plays an important role in tumor microenvironment shaping and immunotherapy response. Current prognostic indexes are insufficient to accurately assess immunotherapy response in patients with head and neck squamous cell carcinoma (HNSCC). This study aimed to develop a CCCT-related gene prognostic index (CCRGPI) for assessing the prognosis and response to immune checkpoint inhibitor (ICI) therapy of HNSCC patients.MethodsTwo cellular models, the fibroblast-cancer cell indirect coculture (FCICC) model, and the fibroblast-cancer cell organoid (FC-organoid) model, were constructed to visualize the crosstalk between fibroblasts and cancer cells. Based on a HNSCC scRNA-seq dataset, the R package CellChat was used to perform cell communication analysis to identify gene pairs involved in CCCT. Least absolute shrinkage and selection operator (LASSO) regression was then applied to further refine the selection of these gene pairs. The selected gene pairs were subsequently subjected to stepwise regression to develop CCRGPI. We further performed a comprehensive analysis to determine the molecular and immune characteristics, and prognosis associated with ICI therapy in different CCRGPI subgroups. Finally, the connectivity map (CMap) analysis and molecular docking were used to screen potential therapeutic drugs.ResultsFCICC and FC-organoid models showed that cancer cells promoted the activation of fibroblasts into CAFs, that CAFs enhanced the invasion of cancer cells, and that CCCT was somewhat heterogeneous. The CCRGPI was developed based on 4 gene pairs: IGF1-IGF1R, LGALS9-CD44, SEMA5A-PLXNA1, and TNXB-SDC1. Furthermore, a high CCRGPI score was identified as an adverse prognostic factor for overall survival (OS). Additionally, a high CCRGPI was positively correlated with the activation of the P53 pathway, a high TP53 mutation rate, and decreased benefit from ICI therapy but was inversely associated with the abundance of various immune cells, such as CD4+ T cells, CD8+ T cells, and B cells. Moreover, Ganetespib was identified as a potential drug for HNSCC combination therapy.ConclusionsThe CCRGPI is reliable for predicting the prognosis and immunotherapy response of HSNCC patients and may be useful for guiding the individualized treatment of HNSCC patients.

Binding and displacement study of gentamicin, 5-fluorouracil, oxytetracycline and rolitetracycline with (BSA: Drug2) complex using spectroscopic and calorimetric techniques: Biophysical approach

Understanding of energetics of interactions between drug and protein is essential in pharmacokinetics and pharmacodynamics study. The binding affinity (K) helps in investigating how tightly or loosely drug is bound to protein. The binding, displacement, conformational change and stability study of drugs- gentamicin (GM), 5-fluorouracil (5FU), oxytetracycline (OTC) and rolitetracycline (RTC) with bovine serum albumin (BSA) has been carried out in presence of each other drug by fluorescence, UV–visible spectroscopy, molecular docking, circular dichroism techniques and thermal denaturation method. The site marker study and docking methods have confirmed that 5FU and GM are able to bind at site 1 and OTC and RTC at site II of BSA. The order of their binding affinities with BSA for the binary system were as GM <5FU < OTC < RTC with the order of 102 < 103 < 105 < 105–6 M−1. The displacement study has shown that higher affinity drug decreases the equilibrium constant of another drug already in bound state with BSA if both these drugs are having the same binding site. Therefore 5FU, GM (binding site 1) drugs were not able to displace OTC and RTC (binding site 2) and vice-versa as they are binding at two different sites. The binding constant values were found to be decreasing with increasing temperature for all the systems involved which suggests static or mixed type of quenching, however can only confirmed with the help of TCSPC technique. The ΔG0 (binding energy) obtained from docking method were in accordance with the ITC method. From molecular docking we have determined the amino acid residues involved in binding process for binary and ternary systems by considering first rank minimum binding energy confirmation. From CD it has been observed that RTC causes most conformational change in secondary and tertiary structure of BSA due to the presence of pyrrole ring. OTC-RTC with higher affinity showed highest melting temperature Tm values while low affinity drugs in (5FU-GM) combination showed lowest Tm value. 5FU showed large endothermic denaturation enthalpy ΔHd0 due to the presence of highly electronegative fluorine atom in the pyridine analogue.

Investigation of the synergistic effect mechanism underlying sequential use of palbociclib and cisplatin through integral proteomic and glycoproteomic analysis.

Chemoresistance largely hampers the clinical use of chemodrugs for cancer patients, combination or sequential drug treatment regimens have been designed to minimize chemotoxicity and resensitize chemoresistance. In this work, the cytotoxic effect of cisplatin was found to be enhanced by palbociclib pretreatment in HeLa cells. With the integration of liquid chromatography-mass spectrometry-based proteomic and N-glycoproteomic workflow, we found that palbociclib alone mainly enhanced the N-glycosylation alterations in HeLa cells, while cisplatin majorly increased the different expression proteins related to apoptosis pathways. As a result, the sequential use of two drugs induced a higher expression level of apoptosis proteins BAX and BAK. Those altered N-glycoproteins induced by palbociclib were implicated in pathways that were closely associated with cell membrane modification and drug sensitivity. Specifically, the top four frequently glycosylated proteins FOLR1, L1CAM, CD63, and LAMP1 were all associated with drug resistance or drug sensitivity. It is suspected that palbociclib-induced N-glycosylation on the membrane protein allowed the HeLa cell to become more vulnerable to cisplatin treatment. Our study provides new insights into the mechanisms underlying the sequential use of target drugs and chemotherapy drugs, meanwhile suggesting a high-efficiency approach that involves proteomic and N-glycoproteomic to facilitate drug discovery.

Vortioxetine improved schizophrenia-like behavioral deficits in a Poly I:C-induced maternal immune activation model of schizophrenia in rats.

Several studies provide clear evidence that exposure to various infections during pregnancy are linked with an increased risk for schizophrenia. In preclinical studies, administration of polyinosinic-polycytidylic acid (Poly I:C) in pregnant rodents can induce maternal immune activation leading to impairments in brain function in the offspring. The aim of this study was to investigate the effect of vortioxetine, a multimodal selective serotonin reuptake inhibitor (SSRI), in the pathophysiology of Poly I:C-induced schizophrenia-like model in rats. For this purpose, Poly I:C (8 mg/kg, ip) was injected into pregnant animals 14 days after mating, and tail blood was taken for determination of IL-6 levels after 2 h. At postnatal days 83-86, behavioral tests were performed. Our results revealed that Poly I:C caused impairments in prepulse inhibition, novel object recognition, social interaction, and open-field tests. Chronic administration of vortioxetine (2.5, 5, and 10 mg/kg, ip, postnatal days 69-83) caused significant improvements in these deficits. Overall, our findings indicate that vortioxetine may provide new therapeutic approaches for the treatment of schizophrenia. We think that increased serotonergic activity in frontal brain regions may provide the ameliorative effect of vortioxetine, especially on negative and cognitive symptoms. Therefore, it will be useful to determine the efficacy of vortioxetine with combined drugs with further studies.

Pharmaceutical care for patients with headaches: pharmacists' statements and pharmacy practice

Relevance. According to the World Health Organization, headaches are one of the most common symptoms of nervous system diseases. Pharmacists play an important role in communicating with headache patients, as well as in rationally directing self-treatment.Aim. Using the questionnaire and patient’s simulation method, comparing the results of these studies, to evaluate the quality of pharmaceutical care for patients with headaches.Material and methods. An anonymous survey was conducted among 153 pharmacists. Three different trained simulated patients (SP) allegedly suffering from headaches visited 101 pharmacies. The results were recorded visually and on a voice recorder. The commercial segment of the Russian pharmaceutical market for analgesics was analyzed.Results. The leaders in sales in ATC-subgroups were the following INN: Ibuprofen, Paracetamol+Naproxen+Caffeine+Drotaverine+ Pheniramine. Corresponding trade names are most often recommended based on the results of questionnaires and simulated patient methodology (SPM). Prescription drugs (13.1 %/14.9 % in SPM) that shouldn’t be recommended in the pharmacy and combination drugs (87.6 %/91.1 % in SPM) were frequently mentioned. A similar number of INN (20/23) and trade names (52/53) were named. The average number of trade names recommended by one pharmacist was higher in the SPM. In SPM the patient was asked very few questions and almost no information about the drug was specified.Conclusion. The real involvement of pharmacists in the provision of pharmaceutical care to patients with cephalgia appears to be much lower, in contrast to the stated results of the questionnaire. In real pharmacy practice, the approach to interaction with a patient with headache and counselling is formal and requires standardization: the development of protocols, standards and algorithms for interaction with patients with headache based on clinical guidelines.

CTF-DDI: Constrained tensor factorization for drug–drug interactions prediction

Computational approaches for predicting drug–drug interactions (DDI) can significantly facilitate combination therapy and drug discovery. Existing similarity-based methods often overlook simple yet valuable structural information or ignore multiple relationships from biological entities (e.g., target proteins and enzymes). Meanwhile, matrix factorization-based methods can alleviate the inherent sparsity issues in DDI data. However, this line of work usually only considers the original association information of DDI pairs. To address these issues, we proposed a novel tensor factorization strategy with effective constraint terms (CTF-DDI) for potential DDI prediction. Specifically, we first obtained drug features by constructing specific similarity matrices based on drug structure and drug-related biological associations. Then, a novel constrained tensor factorization (CTF) module was designed to further reconstruct drug similarity by introducing Hessian and L2,1 regularization as constraints. Finally, we trained a deep neural network to extract nonlinear features for DDI prediction. Experimental results on two benchmark datasets demonstrated that the proposed CTF-DDI model outperforms classical tensor factorization and deep learning models. Furthermore, ablation and case studies validated the performance of CTF-DDI in DDI prediction. The source code of CTF-DDI is available at https://github.com/angelfacedac/CTF_DDI.