P-glycoprotein Inhibition Exacerbates Paclitaxel Neurotoxicity in Neurons and Cancer Patients.

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Paclitaxel-induced peripheral neuropathy (PIPN) is a common and dose-limiting adverse event. The role of P-glycoprotein (P-gp) in the neuronal efflux of paclitaxel was assessed using a translational approach. SH-SY5Y cells […]

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Activation of the Met receptor attenuates doxorubicin-induced cardiotoxicity in vivo and in vitro.

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Doxorubicin anti-cancer therapy is associated with cardiotoxicity, resulting from DNA damage response (DDR). Hepatocyte growth factor (HGF) protects cardiomyocytes from injury, but its administration is hampered by low biodistribution. In […]

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Cannabidiol protects against high glucose-induced oxidative stress and cytotoxicity in cardiac voltage-gated sodium channels.

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Cardiovascular complications are the major cause of mortality in diabetic patients. However, the molecular mechanisms underlying diabetes-associated arrhythmias are unclear. We hypothesized that high glucose, could adversely affect Nav1.5, the […]

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Bilirubin enhances the activity of ASIC channels to exacerbate neurotoxicity in neonatal hyperbilirubinemia in mice.

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Neonatal hyperbilirubinemia is a common clinical condition that can lead to brain encephalopathy, particularly when concurrent with acidosis due to infection, ischemia, and hypoxia. The prevailing view is that acidosis […]

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Protective effect of cilastatin against diclofenac-induced nephrotoxicity in mice through interaction with diclofenac acyl glucuronide via OATs.

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Diclofenac is a widely used nonsteroidal anti-inflammatory drug. However, adverse effects in the kidney limit the clinical application of diclofenac. The present study was aimed to evaluate the potential effect […]

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An application of machine learning in pharmacovigilance: estimating likely patient genotype from phenotypical manifestations of fluoropyrimidine toxicity.

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Dihydropyrimidine dehydrogenase (DPD) deficient patients might only become aware of their genotype after exposure to dihydropyrimidines, if testing is performed. Case reports to pharmacovigilance databases might only contain phenotypical manifestations […]

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ALPHA-TOCOPHERYL SUCCINATE IMPROVES ENCAPSULATION, pH-SENSITIVITY, ANTITUMOR ACTIVITY AND REDUCES TOXICITY OF DOXORUBICIN-LOADED LIPOSOMES.

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Doxorubicin (DOX) plays an important role in cancer treatment; however, high cardiotoxicity and low penetration in solid tumors are the main limitations of its use. Liposomal formulations have been developed […]

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Proposed therapeutic range of treosulfan in reduced toxicity pediatric allogeneic hematopoietic stem cell transplant conditioning: results from a prospective trial.

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Treosulfan is given off-label in pediatric allogeneic hematopoietic stem cell transplant. This study investigated treosulfan’s pharmacokinetics (PK), efficacy and safety in a prospective trial. Pediatric patients (n=87) receiving treosulfan-fludarabine conditioning […]

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Disrupted hepatic pentose phosphate pathway directly participates in and indirectly promotes cyp3a-reduction: a new strategy for cyp3a-mediated drug hepatotoxicity.

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Hepatic CYP450s play an important role in drug-induced hepatotoxicity. They are altered not only in liver diseases but in many non-liver diseases, such as extra-hepatic tumours. Consequently, CYP450-mediated abnormal drug […]

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Synergistic Antibacterial Actions of Graphene Oxide and Antibiotics towards Bacteria and the Toxicological Effects of Graphene Oxide on Human Epidermal Keratinocytes.

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Abstract: Graphene oxide (GO) has displayed antibacterial activity that has been investigated in the past, however, information on synergistic activity of GO with conventional antibiotics is still lacking. The objectives […]

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Convection Enhanced Delivery of Anti-angiogenic and Cytotoxic Agents in Combination Therapy against Brain Tumour.

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Abstract: Convection enhanced delivery is an effective alternative to routine delivery methods to overcome the blood brain barrier. However, its treatment efficacy remains disappointing in clinic owing to the rapid […]

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

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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.

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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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LL1, a novel specific STAT3 inhibitor, displays anti-colorectal cancer activities in vitro and in vivo.

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Abstract: The signal transducer and activator of transcription 3 (STAT3) is associated with the development and progression of numerous types of human cancer, and STAT3 activation confers metastasis to cancer. […]

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Silence of miR-494 impairs neurotoxic Th1 shift via regulating STAT4-STAT4 cascade in ischemic stroke.

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Abstract: T helper cell 1 (Th1)-skewed neurotoxicity contributes to the poor outcome of stroke in rodents. Here we elucidate the mechanism of Th1/Th2 shift in acute ischemic stroke (AIS) patients […]

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

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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.

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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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DNL104, a centrally penetrant RIPK1 inhibitor, inhibits RIP1 kinase phosphorylation in a randomized phase I ascending dose study in healthy volunteers.

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Abstract: RIP kinase 1 regulates inflammation, cytokine release, and necroptotic cell death and is implicated in pathogenic cellular pathways in ALS, AD and MS. Inhibition of RIPK1 activity protects against […]

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Pharmacist Survey: Pharmacist Perception of Vancomycin Area Under the Curve Therapeutic Drug Monitoring.

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Abstract: Evidence suggests the standard vancomycin trough goal of 15 to 20 mg/L for serious Staphylococcus aureus infections is associated with acute kidney injury, whereas appropriate monitoring of 24-hour area […]

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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.

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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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Design, synthesis and anticancer evaluation of novel 1,3-benzodioxoles and 1,4-benzodioxines.

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Abstract: A new set of 1,3-benzodioxoles and 1,4-benzodioxines was designed and synthesized starting from gallic acid as anticancer agents. The antiproliferative effect of the target compounds was evaluated against a […]

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?-Estradiol Protects Against Acidosis-Mediated and Ischemic Neuronal Injury by Promoting ASIC1a (Acid-Sensing Ion Channel 1a) Protein Degradation.

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Abstract: Background and Purpose- Sex differences in the incidence and outcome of stroke have been well documented. The severity of stroke in women is, in general, significantly lower than that […]

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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.

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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.

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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.

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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.

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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.

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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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