A real-world pharmacovigilance study of FDA Adverse Event Reporting System (FAERS) events for Bruton's tyrosine kinase inhibitors (BTKis) single and its combination therapy.

BACKGROUND: Bruton's tyrosine kinase inhibitors (BTKis) are targeted treatments for B-cell tumors but have significant side effects. This study assesses and contrasts the side effects of BTKis alone and its four combination therapies. RESEARCH DESIGN AND METHODS: The reporting odds ratio (ROR) was used to analyze the data on three BTKis monotherapies and combinations of ibrutinib with rituximab, obinutuzumab, venetoclax, and lenalidomide in the FDA Adverse Event Reporting System (FAERS) database up to December 2022. RESULTS: We analyzed the top 20 PTs for each treatment regimen. In monotherapies, atrial fibrillation (ROR (95% CI): 9.88 (9.47-10.32)) in zanubrutinib and rash (6.97 (5.42-8.98)) in acalabrutinib had higher associations. In combinations, infection (6.86 (6.11-7.70)), atrial fibrillation (27.96 (22.61-34.58)) and myelosuppression (10.09 (8.89-11.46)) were vital signals when ibrutinib was combined with obinutuzumab, and pyrexia (4.22 (2.57-6.93)) had a high signal value when combined with lenalidomide. Hemorrhage had a lower signal value when combined with venetoclax compared to ibrutinib alone (2.50 (2.18-2.87) vs 3.60 (3.52-3.68)). CONCLUSIONS: The ibrutinib-obinutuzumab combo has the highest risk of infection, atrial fibrillation, and myelosuppression, and the ibrutinib-lenalidomide combo has the highest risk of pyrexia. However, the ibrutinib-venetoclax combo has a lower risk of hemorrhage than monotherapy.

Association between methotrexate-induced Stevens-Johnson syndrome/toxic epidermal necrolysis and furosemide: a real-world disproportionality analysis.

BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and life-threatening skin adverse reactions that are usually induced by drugs. This study aimed to assess the association between methotrexate and SJS/TEN when combined with furosemide. RESEARCH DESIGN AND METHODS: Data on suspicious, interactions (PS, SS, I) from the FDA Adverse Event Reporting System database for 2016-2021 were analyzed using the reporting odds ratio (ROR), information component (IC), proportional reporting ratio (PRR) and the Medications and Health Care Products Regulatory Agency (MHRA). RESULTS: We identified 28 case reports of TEN associated with the combination of furosemide and methotrexate and 10 reports of SJS associated with furosemide and methotrexate. The association of methotrexate with SJS/TEN was more significant in the entire data set when combined with furosemide than when methotrexate was not combined with furosemide. The association of methotrexate with SJS/TEN remained significant when furosemide was combined with methotrexate in a tumor-based disease context. After sensitivity analysis of the entire dataset as well as all antineoplastic drug datasets, consistent results were observed for TEN. CONCLUSIONS: Our study confirmed a significant association between methotrexate and SJS/TEN when combined with furosemide, with an increased risk of SJS/TEN.

Synergistic anticancer activity of cisplatin combined with tannic acid enhances apoptosis in lung cancer through the PERK-ATF4 pathway.

BACKGROUND: Cisplatin (CDDP) is a common anticancer drug whose side effects limit its clinical applications. Tannins (TA) are plant-derived polyphenols that inhibit tumor growth in different types of cancer. Here, we evaluated the anticancer effect of TA combined with CDDP on lung cancer cell lines (GLC-82 and H1299) and investigated the underlying molecular mechanism of endoplasmic reticulum (ER) stress-induced apoptosis. METHODS: Cell lines were treated with CDDP, TA, and CDDP + TA, and the effect of the combination was assessed using MTT assay and observed under light and fluorescence microscopes. Cell apoptosis was detected by flow cytometry, and the levels of ERS apoptosis pathway related genes were valuated by qRT-PCR and western blotting. The effects of the drug combination on the tumors of nude mice injected with H1299 cells were investigated, and the expression of key factors in the ER stress apoptotic pathway was investigated. RESULTS: The combination of CDDP and TA significantly inhibited lung cancer cell viability indicating a synergistic antitumoral effect. The mRNA and protein expression levels of key ER stress factors in the CDDP + TA group were considerably higher than those in the CDDP and TA groups, the tumor volume in tumor-bearing mice was the smallest, and the number of apoptotic cells and the protein expression levels of the key ER stress in the combination group were considerably higher. CONCLUSIONS: The combination of TA and CDDP may produce synergistic antitumoral effects mediated by the PERK-ATF4-CHOP apoptotic axis, suggesting a novel adjuvant treatment for lung cancer.

Anaphylaxis associated with intracavernous penile injection of prostaglandin E1 in combination with papaverine and phentolamine / Anafilaxia associada à injeção intracavernosa peniana de prostaglandina E1 em combinação com papaverina e fentolamina

Total radical prostatectomy for advanced prostate cancer may lead to sexual impotence, since it is associated with severe erectile dysfunction. A widely recommended treatment for this disabling condition is intracavernous penile injection of a mixture of prostaglandin E1, papaverine, and phentolamine. To our knowledge, we present the first case of anaphylaxis associated with intracavernous penile injection of prostaglandin E1 in combination with papaverine and phentolamine.

A prostatectomia radical total para câncer de próstata avançado pode levar à impotência sexual, associada a uma disfunção erétil grave. Um tratamento amplamente recomendado para esta condição incapacitante é a injeção intracavernosa no pênis de uma mistura de prostaglandina E1, papaverina e fentolamina. Até onde sabemos, estamos apresentando o primeiro caso de anafilaxia associada à injeção intracavernosa peniana de prostaglandina E1 em combinação com papaverina e fentolamina.

Microscopic Raman illustrating antitumor enhancement effects by the combination drugs of γ-secretase inhibitor and cisplatin on osteosarcoma cells.

By using Raman microspectroscopy, it aims to elucidate the cellular variations caused by the combination drug of γ-secretase inhibitor (DAPT) and cisplatin in osteosarcoma (OS) cells. Illustrated by the obtained results of spectral analysis, the intracellular composition significantly changed after combined drug actions compared to the solo DAPT treatment, indicating the synergistic effect of DAPT combined with cisplatin on OS cells. Meanwhile, multivariate curve resolution-alternating least squares (MCR-ALS) algorithm was utilized to address the biochemical constitution changes in all investigated groups including the untreated (UT), DAPT (40D) and combined drug (40D + 20C) treated cells. K-means cluster and univariate imaging were both utilized to visualize the changes in subcellular morphology and biochemical distribution. The presented study provides a unique understanding on the cellular responses to DAPT combined with cisplatin from the natural biochemical perspectives, and laids an experimental foundation for exploring the therapeutic strategies of other combined anticancer drugs in cancer cell model.

Neuroprotection against supra-lethal 'stroke in a dish' insults by an anti-excitotoxic receptor antagonist cocktail.

The goal of this study was to identify cocktails of drugs able to protect cultured rodent cortical neurons against increasing durations of oxygen-glucose deprivation (OGD). As expected, a cocktail composed of an NMDA and AMPA receptor antagonists and a voltage gated Ca2+ channel blocker (MK-801, CNQX and nifedipine, respectively) provided complete neuroprotection against mild OGD. Increasingly longer durations of OGD necessitated increasing the doses of MK-801 and CNQX, until these cocktails ultimately failed to provide neuroprotection against supra-lethal OGD, even at maximal drug concentrations. Surprisingly, supplementation of any of these cocktails with blockers of TRPM7 channels for increasing OGD durations was not neuroprotective, unless these blockers possessed the ability to inhibit NMDA receptors. Supplementation of the maximally effective cocktail with other NMDA receptor antagonists augmented neuroprotection, suggesting insufficient NMDAR blockade by MK-801. Substitution of MK-801 in cocktails with high concentrations of a glycine site NMDA receptor antagonist caused the greatest improvements in neuroprotection, with the more potent SM-31900 superior to L689,560. Substitution of CQNX in cocktails with AMPA receptor antagonists at high concentrations also improved neuroprotection, particularly with the combination of SYM2206 and NBQX. The most neuroprotective cocktail was thus composed of SM-31900, SYM2206, NBQX, nifedipine and the antioxidant trolox. Thus, the cumulative properties of antagonist potency and concentration in a cocktail dictate neuroprotective efficacy. The central target of supra-lethal OGD is excitotoxicity, which must be blocked to the greatest extent possible to minimize ion influx.

A review on epidermal growth factor receptor's role in breast and non-small cell lung cancer.

Epithelial growth factor receptor (EGFR) is a cell surface transmembrane receptor that mediates the tyrosine signaling pathway to carry the extracellular messages inside the cell and thereby alter the function of nucleus. This leads to the generation of various protein products to up or downregulate the cellular function. It is encoded by cell erythroblastosis virus oncogene B1, so called C-erb B1/ERBB2/HER-2 gene that acts as a proto-oncogene. It belongs to the HER-2 receptor-family in breast cancer and responds best with anti-Herceptin therapy (anti-tyrosine kinase monoclonal antibody). HER-2 positive breast cancer patient exhibits worse prognosis without Herceptin therapy. Similar incidence and prognosis are reported in other epithelial neoplasms like EGFR + lung non-small cell carcinoma and glioblastoma (grade IV brain glial tumor). Present study highlights the role and connectivity of EGF with various cancers via signaling pathways, cell surface receptors mechanism, macromolecules, mitochondrial genes and neoplasm. Present study describes the EGFR associated gene expression profiling (in breast cancer and NSCLC), relation between mitrochondrial genes and carcinoma, and several in vitro and in vivo models to screen the synergistic effect of various combination treatments. According to this study, although clinical studies including targeted treatments, immunotherapies, radiotherapy, TKi-EGFR combined targeted therapy have been carried out to investigate the synergism of combination therapy; however still there is a gap to apply the scenarios of experimental and clinical studies for further developments. This review will give an idea about the transition from experimental to most advanced clinical studies with different combination drug strategies to treat cancer.

A convergent synthetic platform for dual anticancer drugs functionalized by reduced graphene nanocomposite delivery for hepatocellular cancer.

Hepatocellular carcinoma (HCC) is widespread cancer with a high degree of morbidity and mortality in individuals worldwide and a serious concern for its resistance to present chemotherapy drugs. In this investigation, the combination of cisplatin (CPT) and metformin (MET) to kill the HepG2 and caco-2 cells was developed into a new pH-responding magnetic nanocomposite based on reduced graphene oxide. Polyhydroxyethyl methacrylic (PHEA) was then linked employing grafting from approach to the reduced graphene oxide by ATRP polymerization (Fe3O4@rGO-G-PSEA). FT-IR, SEM, XRD, DLS, and TGA analyses evaluated physicochemical characteristics of the nanocomposite. In addition, the cellular uptake property of the nanocomposites was examined by the HepG2 cells. The outcomes of cell viability results indicate that the nanoparticles loaded with MET&CPT showed the lowest concentration rate of HepG2 and Caco-2 cells compared to the drug-loaded single nanocomposite groups and free drugs. The histological analysis has demonstrated relatively safe and does not produce different stress such as swelling and inflammation of the mice organs. Our results show the enhancement in cytotoxicity in HepG2 and Cocoa-2 cells by MET and CPT graphene oxide-based nanocomposite by promoting apoptotic response. Moreover, Fe3O4@rGO-G-PSEA showed potent in vivo antitumor efficacy but showed no adverse toxicity to normal tissues. Together, this study can provide insight into how surface embellishment may tune these nanocomposites' tumor specificity and provide the basis for developing anticancer efficacy.

Development of new combination anti-leishmanial complexes: Triphenyl Sb(V) mono-hydroxy mono-quinolinolates.

In seeking to develop single entity combination anti-Leishmanial complexes six heteropletic organometallic Sb(V) hydroxido quinolinolate complexes of general formula [SbPh3(C9H4NORR')(OH)] have been synthesised and characterised, derived from a series of halide substituted quinolinols (8-hydroxyquinolines). Single crystal X-ray diffraction on all the complexes show a common distorted six-coordinate octahedral environment at the Sb(V) centre, with the aryl groups and nitrogen atom of quinolinolate ligand bonding in the equatorial planes, with the two oxygen atoms (hydroxyl and quinolinolate) occupying the axial plane in an almost linear configuration. Each complex was tested for their anti-promastigote activity and mammalian cytotoxicity and a selectivity indices established. The complexes displayed excellent anti-promastigote activity (IC50: 2.03-3.39 µM) and varied mammalian cytotoxicity (IC50: 12.7-46.9 µM), leading to a selectivity index range of 4.52-16.7. All complexes displayed excellent anti-amastigote activity with a percentage infection range of 2.25%-9.00%. All complexes performed substantially better than the parent quinolinols and comparable carboxylate complexes [SbPh3(O2CRR')2] indicating the synergistic role of the Sb(V) and quinolinol moieties in increasing parasite mortality. Two of the complexes [SbPh3(C9H4NOBr2)(OH)] 4, [SbPh3(C9H4NOI2)(OH)] 5, provide an ideal combination of high selective and good activity towards the leishmanial amastigotes and offer the potential as good lead compounds.

Quantification of abemaciclib and metabolites: evolution of bioanalytical methods supporting a novel oncolytic agent.

Aim: Bioanalytical methods undergo many revisions and modifications throughout drug development to meet the objectives of the study and development program. Results: Validated LC-MS/MS methodology used to quantify abemaciclib and four metabolites in human plasma is described. The method, initially validated to support the first-in-human study, was successfully modified to include additional metabolites as in vitro and in vivo information about the activity and abundance of human metabolites became available. Consistent performance of the method over time was demonstrated by an incurred sample reanalysis passing rate exceeding 95%, across clinical studies. An overview of the numerous methods involved during the development of abemaciclib, including the quantification of drugs evaluated as combination regimens and used as substrates during drug-drug interaction studies, is presented. Conclusion: Robust bioanalytical methods need to be designed with the flexibility required to support the evolving study objectives associated with registration and post-registration trials.

Antifungal In Vitro Activity of Pilosulin- and Ponericin-Like Peptides from the Giant Ant Dinoponera quadriceps and Synergistic Effects with Antimycotic Drugs.

Venoms from ants comprise a rich source of bioactive peptides, including antimicrobial peptides. From the proteome and peptidome of the giant ant Dinoponera quadriceps venom, members of five known classes of antimicrobial peptides were disclosed (e.g., dermaseptin-, defensin-, ICK-, pilosulin- and ponericin-like types). Based on comparative analysis, these family members have structural determinants that indicate they could display antimicrobial activities. In previous works, pilosulin- and ponericin-like peptides were demonstrated to be active against bacteria, fungi, and parasites. Herein, the antifungal activity of ponericin- and pilosulin-like peptides were assessed, aiming at the expansion of the knowledge about AMPs in predatory ants and the development of new microbicide strategies to deal with difficult-to-treat fungal infections. Synthetic pilosulin- (Dq-2562, Dq-1503, and Dq-1319) and ponericin-like (Dq-3162) peptides were evaluated for their fungicide and fungistatic activities against different species of Candida, including a drug-resistant clinical strain. The MICs and MLCs were determined for all peptides individually and in combination with general antifungal drugs by the microdilution method. The time-kill kinetic curves were set up by means of a luminescent reagent, of which the light signal is proportional to the number of viable cells. The candicidal synergism observed by the combination of subinhibitory concentrations of peptides and general antimycotic drugs were quantified by the checkerboard test and fluorescent dye permeation assay. The influence of ergosterol on the antifungal activity was verified by supplementation of culture medium. The pilosulin- (Dq-2562 and Dq-1503) and ponericin-like (Dq-3162) were the most active peptides, displaying a broad spectrum of antifungal activity in vitro, with MICs in the range of 0.625 to 10 µM. The combination of peptides and conventional antimycotic drugs displayed a synergistic reduction in the MIC values of individual peptides and drugs, while soluble ergosterol in the culture medium increased the MICs. The fungicide and fungistatic activity of the individual peptides and peptides in combination with antimycotics were time-dependent with a rapid onset of action and long-lasting effect, which involved membrane disruption as an underlying mechanism of their action. Altogether, pilosulin- and ponericin-like peptides from the giant ant D. quadriceps venom display a broad-spectrum of candicidal activity, what allows their inclusion in the row of the antifungal peptides and gives support for further studies on the development of strategies to fight candidiasis.

Mutual Enhancement of Opioid and Adrenergic Receptors by Combinations of Opioids and Adrenergic Ligands Is Reflected in Molecular Complementarity of Ligands: Drug Development Possibilities.

Crosstalk between opioid and adrenergic receptors is well characterized and due to interactions between second messenger systems, formation of receptor heterodimers, and extracellular allosteric binding regions. Both classes of receptors bind both sets of ligands. We propose here that receptor crosstalk may be mirrored in ligand complementarity. We demonstrate that opioids bind to adrenergic compounds with micromolar affinities. Additionally, adrenergic compounds bind with micromolar affinities to extracellular loops of opioid receptors while opioids bind to extracellular loops of adrenergic receptors. Thus, each compound type can bind to the complementary receptor, enhancing the activity of the other compound type through an allosteric mechanism. Screening for ligand complementarity may permit the identification of other mutually-enhancing sets of compounds as well as the design of novel combination drugs or tethered compounds with improved duration and specificity of action.

Delivery Systems as Vital Tools in Drug Repurposing.

The process of developing an old drug for new indications is now a widely accepted strategy of shortening drug development time, reducing drug costs, and improving drug availability, especially for rare and neglected diseases. In this mini-review, we highlighted the impact of drug delivery systems in the fulfillment of crucial aspects of drug repurposing such as (i) maximizing the repurposed drug effects on a new target, (ii) minimizing off-target effects, (iii) modulating the release profiles of drug at the site of absorption, (iv) modulating the pharmacokinetics/in vivo biodistribution of the repurposed drug, (v) targeting/modulating drug retention at the sites of action, and (vi) providing a suitable platform for therapeutic application of combination drugs.

Analysis of adverse reactions of penicillin combined with chloramphenicol and tetracycline / 中国基层医药

Objective@#To investigate the occurrence and characteristics of adverse reactions of penicillin combined with chloramphenicol and tetracycline, so as to provide a reliable basis for the rational clinical application of penicillin, chloramphenicol and tetracycline antibiotics.@*Methods@#From January 2017 to July 2018, 200 cases with adverse reactions of combined use of penicillin, chloramphenicol, tetracycline in Yiwu Central Hospital were chosen.The clinical data of 200 cases of drug adverse reactions report were retrospectively analyzed.The gender distribution, age distribution, dosage, clinical manifestation, adverse reactions involving system, time, unreasonable drug adverse reactions happen were analyzed.@*Results@#Among the 200 adverse reactions, 51.50% cases were male and 48.50% were female, and the difference was not statistically significant(χ2=0.360, P>0.05). The age distribution of 200 cases of adverse reactions was concentrated in people aged less than 14 and more than 60, accounting for 36.50% and 41.00%, respectively.The main routes of administration of 200 adverse reactions were intravenous injection, intramuscular injection and oral administration, accounting for 38.00%, 32.50% and 29.50%, respectively.The clinical manifestations of adverse reactions in 200 cases were mainly anaphylactic shock, bone marrow suppression and dizziness, accounting for 20.00%, 18.50% and 11.50%, respectively.The adverse reactions of 200 cases mainly involved hematopoietic system, nervous system, systemic damage and skin system, accounting for 36.00%, 24.50%, 20.00% and 18.00%, respectively.The adverse reactions of 200 cases occurred within 30 min after medication, accounting for 69.50%.The unreasonable medication of 200 cases of adverse reactions mainly included unreasonable course of medication, unreasonable timing of administration, unreasonable solvent selection, unreasonable dosage and repeated medication.@*Conclusion@#Penicillin, chloramphenicol, tetracycline class of antimicrobial agents combined application has more adverse reactions, the adverse reaction throughout children and the elderly, many involving the hematopoietic system, nervous system, clinical need according to penicillin, chloramphenicol, tetracycline class of antimicrobial agents combined use of the laws and characteristics of adverse reactions in the aftermath of the targeted pharmaceutical intervention, so as to promote clinical rational drug use.

Analysis of adverse reactions of penicillin combined with chloramphenicol and tetracycline / 中国基层医药

Objective To investigate the occurrence and characteristics of adverse reactions of penicillin combined with chloramphenicol and tetracycline ,so as to provide a reliable basis for the rational clinical application of penicillin,chloramphenicol and tetracycline antibiotics.Methods From January 2017 to July 2018,200 cases with adverse reactions of combined use of penicillin ,chloramphenicol,tetracycline in Yiwu Central Hospital were chosen. The clinical data of 200 cases of drug adverse reactions report were retrospectively analyzed.The gender distribution, age distribution,dosage,clinical manifestation,adverse reactions involving system , time, unreasonable drug adverse reactions happen were analyzed.Results Among the 200 adverse reactions ,51.50% cases were male and 48.50%were female,and the difference was not statistically significant (χ2 ＝0.360,P＞0.05).The age distribution of 200 cases of adverse reactions was concentrated in people aged less than 14 and more than 60,accounting for 36.50%and 41.00%, respectively.The main routes of administration of 200 adverse reactions were intravenous injection , intramuscular injection and oral administration,accounting for 38.00%,32.50%and 29.50%,respectively.The clinical manifestations of adverse reactions in 200 cases were mainly anaphylactic shock ,bone marrow suppression and dizziness ,accounting for 20.00%,18.50% and 11.50%, respectively.The adverse reactions of 200 cases mainly involved hematopoietic system,nervous system,systemic damage and skin system ,accounting for 36.00%,24.50%,20.00% and 18.00%, respectively.The adverse reactions of 200 cases occurred within 30 min after medication,accounting for 69.50%.The unreasonable medication of 200 cases of adverse reactions mainly included unreasonable course of medication , unreasonable timing of administration,unreasonable solvent selection ,unreasonable dosage and repeated medication. Conclusion Penicillin,chloramphenicol ,tetracycline class of antimicrobial agents combined application has more adverse reactions,the adverse reaction throughout children and the elderly ,many involving the hematopoietic system , nervous system, clinical need according to penicillin , chloramphenicol, tetracycline class of antimicrobial agents combined use of the laws and characteristics of adverse reactions in the aftermath of the targeted pharmaceutical intervention,so as to promote clinical rational drug use.

Lowering blood pressure in primary care in Vienna (LOW-BP-VIENNA) : A cluster-randomized trial.

BACKGROUND: In Austria only 41% of patients with treated hypertension (HTN) have their blood pressure (BP) controlled. This study investigated a strategy to improve BP control in primary care. METHODS: General practitioners (GPs) were randomized to interventional care vs. standard care and included patients with uncontrolled office BP > 140/90 mm Hg. In interventional care, antihypertensive therapy was up-titrated using a single pill combination (olmesartan, amlodipine and/or hydrochlorothiazde) in 4­week intervals. In standard care, physicians were encouraged to treat according to the 2013 European Society of Cardiology guidelines for the management of arterial hypertension. The primary endpoint was the proportion of patients with controlled office BP < 140/90 mm Hg at 6 months. The main secondary endpoint was the improvement in 24 h ambulatory BP (ABPM, Clinicaltrials.gov NCT02377661). RESULTS: Between 2015-2017, 20 GPs contributed to patient recruitment. The trial was discontinued due to slow recruitment after inclusion of 139 eligible patients, 54 of whom were included in the interventional group. A significantly larger proportion of patients in interventional vs. standard care achieved the office BP target (67% ± 26% vs. 39% ± 29%, respectively, mean difference -27.9%, 95% confidence interval CI -54.0%; -1.7%, p = 0.038). The proportion of patients with controlled 24 h ABPM (<130/80 mm Hg) was similar between groups (49% ± 33% vs. 40% ± 34%, respectively, mean difference -8.8%, 95% CI -40.7%; 23.1%, p = 0.57). At baseline, pretreated patients received an average of 1.5 ± 0.8 vs. 1.7 ± 0.9 antihypertensive prescriptions. At 6 months, the respective BP reductions were achieved with 1.2 ± 0.5 prescriptions in interventional vs. 2.0 ± 1.0 in standard care (p < 0.01). CONCLUSION: In both groups statistically and clinically significant BP reductions were observed after 6 months. In the interventional care group, a larger proportion of patients achieved the office BP target compared to standard care. The 24 h ambulatory blood pressure levels were controlled in 44% of patients at 6 months, without significant differences between groups. The respective BP reductions were achieved with a significantly lower medication burden in interventional care.

Combined use of polypill components in patients with type 2 diabetes mellitus.

Objectives A polypill containing aspirin, a statin and blood pressure (BP)-lowering agents has been proposed for the prevention of cardiovascular disease. To increase adherence and reduce the gaps between indicated and used therapy, a polypill might be of interest for patients with type 2 diabetes (T2DM). Our aim was to assess the prevalence of the combined use of polypill components in patients with T2DM over time. Methods The combined use of polypill components was assessed between 1996 and 2015 in patients with T2DM in the prospective SMART cohort ( n = 1828). The results were dichotomized into patients without ( n = 568) and with ( n = 1260) vascular disease. The patient characteristics associated with the use of polypill components were evaluated. Results In total, 19% of patients with T2DM without vascular disease received a statin and ≥2 BP-lowering agents ('cardiovascular polypill') and 13% received additional oral glucose-lowering therapy ('diabetic polypill'). Of the patients with T2DM with vascular disease, 42% received the combination of an antiplatelet agent, a statin and ≥2 BP-lowering agents ('cardiovascular polypill') and 30% received additional glucose-lowering therapy ('diabetic polypill'). The prevalence of the use of the cardiovascular and diabetic polypill combination has substantially increased between 1996 and 2015 to 36 and 32% in patients without vascular disease and to 67 and 57% in patients with vascular disease. Conclusions Patients with T2DM frequently use polypill components, often together with oral glucose-lowering agents, and this rate of use has increased steadily between 1996 and 2015. Introducing a cardiovascular or diabetic polypill for patients with T2DM seems to be highly relevant.

Cell- and Tissue-Based Proteome Profiling and Dual Imaging of Apoptosis Markers with Probes Derived from Venetoclax and Idasanutlin.

Venetoclax (ABT-199) and idasanutlin (RG7388) are efficient anticancer drugs targeting two essential apoptosis markers, Bcl-2 and MDM2, respectively. Recent studies have shown that the combination of these two drugs leads to remarkable enhancement of anticancer efficacy, both in vitro and in vivo. In an attempt to disclose the relationships of their protein targets, competitive affinity-based proteome profiling coupled with bioimaging was employed to characterize their protein targets in the same cancer cell line and tumor tissue. A series of protein hits, including ITPR1, GSR, RER1, PDIA3, Apoa1, and Tnfrsf17 were simultaneously identified by pull-down/LC-MS/MS with the two sets of affinity-based probes. Dual imaging was successfully carried out, with the simultaneous detection of Bcl-2 and MDM2 expression in various cancer cells. This could facilitate the novel diagnostic and therapeutic strategies of dual targeting of Bcl-2/MDM2.

Application of Combination High-Throughput Phenotypic Screening and Target Identification Methods for the Discovery of Natural Product-Based Combination Drugs.

Modern drug discovery efforts have had mediocre success rates with increasing developmental costs, and this has encouraged pharmaceutical scientists to seek innovative approaches. Recently with the rise of the fields of systems biology and metabolomics, network pharmacology (NP) has begun to emerge as a new paradigm in drug discovery, with a focus on multiple targets and drug combinations for treating disease. Studies on the benefits of drug combinations lay the groundwork for a renewed focus on natural products in drug discovery. Natural products consist of a multitude of constituents that can act on a variety of targets in the body to induce pharmacodynamic responses that may together culminate in an additive or synergistic therapeutic effect. Although natural products cannot be patented, they can be used as starting points in the discovery of potent combination therapeutics. The optimal mix of bioactive ingredients in natural products can be determined via phenotypic screening. The targets and molecular mechanisms of action of these active ingredients can then be determined using chemical proteomics, and by implementing a reverse pharmacokinetics approach. This review article provides evidence supporting the potential benefits of natural product-based combination drugs, and summarizes drug discovery methods that can be applied to this class of drugs.

Active Tumor-Targeted co-Delivery of Epigallocatechin Gallate and Doxorubicin in Nanoparticles for Combination Gastric Cancer Therapy.

The clinical treatment of gastric cancer is hampered by the development of anticancer drug resistance as well as the unfavorable pharmacokinetics, nontarget toxicity, and inadequate intratumoral accumulation of current chemotherapies. The polyphenol epigallocatechin gallate in combination with doxorubicin exhibits synergistic inhibition P-glycoprotein efflux pump activity and cancer cell growth. This study evaluated a potential activated nanoparticle delivery system comprising a hyaluronic acid complex with polyethylene glycol-conjugated gelatin containing encapsulated epigallocatechin gallate and low-dose doxorubicin, which may facilitate targeted drug administration to gastric cancer cells. We confirmed successful delivery of bioactive combination drugs and internalization into gastric cancer cells through CD44 ligand recognition and ensuing inhibition of cell proliferation via caspase-induced apoptosis and G2/M phase cell cycle arrest. Furthermore, the targeted nanoparticles significantly suppressed gastric tumor activity and reduced both tumor and heart tissue inflammatory reaction in vivo compared to systemic combination treatment.