Investigation on vitamin E succinate based intelligent hyaluronic acid micelles for overcoming drug resistance and enhancing anticancer efficacy.

Abstract: Multidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports […]

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PEGylated lipid bilayer coated mesoporous silica nanoparticles co-delivery of paclitaxel and curcumin leads to increased tumor site drug accumulation and reduced tumor burden.

Abstract: Homogeneous PEGylated lipid bilayer coated highly ordered MSNs (PLMSNs) which were systematically optimized and characterized to co-encapsulate paclitaxel (Tax) and curcumin (Cur) were verified to manifest prolonged and enhanced […]

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Glycyrrhetinic acid-modified graphene oxide mediated siRNA delivery for enhanced liver-cancer targeting therapy.

Abstract: Graphene oxide (GO) has attracted huge attention in biomedical field in recent years. However, limited attempts have been invested in utilizing GO on active targeted delivery for gene therapy […]

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Combination of cyclodextrin complexation and iontophoresis as a promising strategy for the cutaneous delivery of aluminum-chloride phthalocyanine in photodynamic therapy.

Abstract: Topical application of aluminum-chloride phthalocyanine (AlClPc) is a challenge because of the drug’s extremely low solubility, which prevents its absorption into deeper skin layers and causes molecule aggregation, reducing […]

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Design, synthesis, biological evaluation and molecular docking study of arylcarboxamido piperidine and piperazine-based hydroxamates as potential HDAC8 inhibitors with promising anticancer activity.

Abstract: HDAC8 has been established as one of the vital targets as far as the cancer is concerned. Different compounds having potential HDAC inhibitory activity have been approved by USFDA. […]

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BRD4 PROTAC as a novel therapeutic approach for the treatment of vemurafenib resistant melanoma: Preformulation studies, formulation development and in vitro evaluation.

Abstract: Limited therapeutic interventions and development of resistance to targeted therapy within few months of therapy pose a great challenge in the treatment of melanoma. Current work was aimed to […]

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Natural compounds as potential adjuvants to cancer therapy: preclinical evidence.

Traditional chemotherapy is being considered due to hindrances caused by systemic toxicity. Currently the administration of multiple chemotherapeutic drugs with different biochemical/molecular targets, known as combination chemotherapy, has attained numerous benefits like efficacy enhancement and amelioration of adverse effects that has been broadly applied to various cancer types. Additionally, seeking natural-based alternatives with less toxicity has become more important. Experimental evidence suggests that herbal extracts such as Solanum nigrum and Claviceps purpurea and isolated herbal compounds (e.g., curcumin, resveratrol, and matairesinol) combined with antitumoral drugs have the potential to attenuate resistance against cancer therapy and to exert chemoprotective actions. Plant products are not free of risks: herb adverse effects, including herb drug interactions, should be carefully considered.

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Improvement of antimalarial activity of a 3-alkylpiridine alkaloid analog by replacing the pyridine ring to a thiazole-containing heterocycle: Mode of action, mutagenicity profile, and Caco-2 cell-based permeability.

The development of new antimalarial drugs is urgent to overcome the spread of resistance to the current treatment. Herein we synthesized the compound 3, a hit-to?lead optimization of a thiazole based on the most promising 3-alkylpyridine marine alkaloid analog. Compound 3 was tested against Plasmodium falciparum and has shown to be more potent than its precursor (IC50 values of 1.55 and 14.7??M, respectively), with higher selectivity index (74.7) for noncancerous human cell line. This compound was not mutagenic and showed genotoxicity only at concentrations four-fold higher than its IC50. Compound 3 was tested in vivo against Plasmodium berghei NK65 strain and inhibited the development of parasite at 50?mg/kg. In silico and UV-vis approaches determined that compound 3 acts impairing hemozoin crystallization and confocal microscopy experiments corroborate these findings as the compound was capable of diminishing food vacuole acidity. The assay of uptake using human intestinal Caco-2 cell line showed that compound 3 is absorbed similarly to chloroquine, a standard antimalarial agent. Therefore, we present here compound 3 as a potent new lead antimalarial compound.

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Pemetrexed-conjugated hyaluronan for the treatment of malignant pleural mesothelioma.

Pemetrexed (PMX) is a multi-targeted antifolate drug used for the treatment of malignant pleural mesothelioma (MPM) and non-small cell lung cancer. Hyaluronan (HA) in blood is well known as a disease marker of MPM. We synthesized PMX-conjugated hyaluronan (HA-ADH-PMX) for the first time to develop a novel anticancer chemotherapeutic agent. HAs with different molecular weights (76 and 130?kDa) were first derivatized with adipic dihydrazide (ADH) and then conjugated to PMX. The obtained HA-ADH-PMX retained inhibitory activity against folate metabolism enzymes; thymidylate synthase was inhibited to the same extent as native PMX, whereas the inhibition constant against dihydrofolate reductase was 3.3% for 76?kDa HA-ADH-PMX and 12% for 130?kDa HA-ADH-PMX when compared with that of native PMX. The in vitro cytotoxicity of HA-ADH-PMX from both molecular weights against MPM cell lines was lower than that of native PMX. On the other hand, intrapleural administration of 76?kDa HA-ADH-PMX resulted in a survival rate of MPM model mice comparable to that with native PMX, suggesting the potential for future MPM therapy.

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Clinical Pearls in Medical Toxicology: Updates Ranging From Decontamination to Elimination.

Such as any field of medicine, it is imperative to stay current with the latest advances and treatment modalities in toxicology. With the absence of rigorous randomized controlled trials, many updated guidelines are created by expert consensus and/or case reports and clinical experience. Over the past 10 years, there have been several changes in the management of drug overdoses in light of new data available. Although this is not a comprehensive review of all available antidotes, this article will focus on several important interventions including the use of gastrointestinal decontamination, hyperinsulinemic-euglycemic therapy, methylene blue, intravenous lipid emulsion, hemodialysis, and extracorporeal membrane oxygenation.

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Drug-induced Shortening of the Electromechanical Window is an Effective Biomarker for in Silico Prediction of Clinical Risk of Arrhythmias.

Early identification of drug-induced cardiac adverse events is key in drug development. Human-based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug-induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study investigates the potential of a cellular surrogate for the electromechanical window (EMw) for prediction of pro-arrhythmic cardiotoxicity, and its underlying ionic mechanisms, using human-based computer models.In silico drug trials for 40 reference compounds were performed, testing up to 100-fold the therapeutic concentrations (EFTPCmax ) and using a control population of human ventricular action potential (AP) models, optimised to capture pro-arrhythmic ionic profiles. EMw was calculated for each model in the population as the difference between AP and Ca2+ -transient durations at 90%. Drug-induced changes in the EMw and occurrence of repolarisation abnormalities (RA) were quantified.Drugs with clinical risk of Torsade de Pointes arrhythmias induced a concentration-dependent EMw shortening, while safe drugs lead to increase or small change in EMw. Risk predictions based on EMw shortening achieved 90% accuracy at 10x EFTPCmax , whereas RA-based predictions required 100x EFTPCmax to reach the same accuracy. Due to its dependence on Ca2+ -transient, the EMw was also shown to be more sensitive than AP prolongation in distinguishing between pure hERG blockers and multichannel compounds also blocking the calcium current.The EMw is an effective biomarker for in silico predictions of drug-induced clinical pro-arrhythmic risk, particularly for compounds with multichannel blocking action.

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Evaluation and use of an anti-cynomolgus monkey CD79b surrogate antibody-drug conjugate to enable clinical development of polatuzumab vedotin.

Polatuzumab vedotin is an antibody-drug conjugate (ADC) being developed for non-Hodgkin’s lymphoma. It contains a humanized anti-CD79b IgG1 monoclonal antibody linked to mono-methyl auristatin E (MMAE), an anti-mitotic agent. Polatuzumab vedotin binds to human CD79b only. Therefore, a surrogate ADC that binds to cynomolgus monkey CD79b was used to determine CD79b-mediated pharmacological effects in the monkey, and to enable first-in-human clinical trials.Polatuzumab vedotin, the surrogate ADC, and the corresponding antibodies were evaluated in different assays in vitro and in animals. In vitro assessments included binding to peripheral blood mononuclear cells (PBMCs) from different species, binding to a human and monkey CD79b-expressing cell line, binding to human Fc?-receptors, and stability in plasma across species. In vivo, ADCs were assessed for anti-tumor activity in mice, pharmacokinetics/pharmacodynamics in monkeys, and toxicity in rats and monkeys.Polatuzumab vedotin and surrogate ADC bind with similar affinity to human and cynomolgus monkey B cells, respectively. Comparable in vitro plasma stability, in vivo anti-tumor activity, and mouse pharmacokinetics were also observed between the surrogate ADC and polatuzumab vedotin. In monkeys, only the surrogate ADC showed B-cell depletion and B-cell mediated drug disposition, but both ADCs showed similar MMAE-driven myelotoxicity, as expected.The suitability of the surrogate ADC for evaluation of CD79b-dependent pharmacology was demonstrated, and anti-tumor activity, pharmacokinetics/pharmacodynamics and toxicity data with both ADCs supported the entry of polatuzumab vedotin into clinical trials.

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Modulating the site-specific oral delivery of sorafenib using sugar-grafted nanoparticles for hepatocellular carcinoma treatment.

Abstract: Globally, one in six deaths is reported due to cancer suggesting the critical need for development of advanced treatment regimens. In this study, solid lipid nanoparticles (SLN) were prepared […]

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New isoniazid derivatives with improved pharmaco-toxicological profile: Obtaining, characterization and biological evaluation.

Abstract: Tuberculostatic drugs are the most common drug groups with global hepatotoxicity. Awareness of potentially severe hepatotoxic reactions is vital, as hepatic impairment can be a devastating and often fatal […]

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5-Hydrazinylethylidenepyrimidines effective against multidrug-resistant Acinetobacter baumannii: Synthesis and in vitro biological evaluation of antibacterial, radical scavenging and cytotoxic activities.

Abstract: Acinetobacter baumannii has emerged as an important nosocomial pathogen in recent years, with infectious outbreaks caused by multidrug-resistant strains increasing worldwide. Thus, new antibacterial treatments for multidrug-resistant A. baumannii […]

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Design and synthesis of new norfloxacin-1,3,4-oxadiazole hybrids as antibacterial agents against methicillin-resistant Staphylococcus aureus (MRSA).

Abstract: Toward the search of new antibacterial agents to control methicillin-resistant Staphylococcus aureus (MRSA), a class of new norfloxacin-1,3,4-oxadiazole hybrids were designed and synthesized. Antibacterial activities against drug-sensitive bacteria S. […]

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