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Polymer microcapsules containing cyanoacrylates have represented a promising option to develop self-healing biomaterials. This study aims to develop an electrospray method for the preparation of capsules using poly(methyl methacrylate) (PMMA) as the encapsulant and ethyl 2-cyanoacrylate (EC) as the encapsulate. It also aims to study the effect of the electrospray process parameters on the size and morphology of the capsules. The capsules were characterized using Fourier-transform infrared (FTIR) spectroscopy, thermogravimetric analysis (TGA), and field-emission scanning electron microscopy (FE-SEM). Moreover, the effects of electrospray process parameters on the size were investigated by Taguchi experimental design. FTIR and TGA approved the presence of both PMMA and EC without further reaction. FE-SEM micrograph demonstrated that an appropriate choice of solvents, utilizing an appropriate PMMA:EC ratio and sufficient PMMA concentration are critical factors to produce capsules dominantly with an intact and spherical morphology. Utilizing various flow rates (0.3-0.5 ml/h) and applied voltage (18-26 kV), capsules were obtained with a 600-1000 nm size range. At constantly applied voltages, the increase in flow rate increased the capsule size up to 40% (ANOVA, p ≤ 0.05), while at constant flow rates, the increase in applied voltage reduced the average capsule size by 3.4-26% (ANOVA, p ≤ 0.05). The results from the Taguchi design represented the significance of solution flow rate, applied voltage, and solution concentration. It was shown that the most effective parameter on the size of capsules is flow rate. This research demonstrated that electrospray can be utilized as a convenient method for the preparation of sub-micron PMMA capsules containing EC. Furthermore, the morphology of the capsules is dominated by solvents, PMMA concentration, and PMMA:EC ratio, while the average size of the capsules can be altered by adjusting the flow rate and applied voltage of the electrospray process.
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The addition of darolutamide, an androgen receptor signalling inhibitor, to therapy with docetaxel has recently been approved as a strategy to treat metastatic prostate cancer. OATP1B3 is an SLC transporter that is highly expressed in prostate cancer and is responsible for the accumulation of substrates, including docetaxel, into tumours. Given that darolutamide inhibits OATP1B3 in vitro, we sought to characterise the impact of darolutamide on docetaxel pharmacokinetics. We investigated the influence of darolutamide on OATP1B3 transport using in vitro and in vivo models. We assessed the impact of darolutamide on the tumour accumulation of docetaxel in a patient-derived xenograft (PDX) model and on an OATP1B biomarker in patients. Darolutamide inhibited OATP1B3 in vitro at concentrations higher than the reported Cmax. Consistent with these findings, in vivo studies revealed that darolutamide does not influence the pharmacokinetics of Oatp1b substrates, including docetaxel. Docetaxel accumulation in PDX tumours was not decreased in the presence of darolutamide. Metastatic prostate cancer patients had similar levels of OATP1B biomarkers, regardless of treatment with darolutamide. Consistent with a low potential to inhibit OATP1B3-mediated transport in vitro, darolutamide does not significantly impede the transport of Oatp1b substrates in vivo or in patients. Our findings support combined treatment with docetaxel and darolutamide, as no OATP1B3 transporter based drug-drug interaction was identified.
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Docetaxel , Neoplasias da Próstata , Pirazóis , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto , Ensaios Antitumorais Modelo de Xenoenxerto , Humanos , Masculino , Docetaxel/farmacologia , Docetaxel/farmacocinética , Animais , Camundongos , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Pirazóis/farmacologia , Pirazóis/farmacocinética , Interações Medicamentosas , Linhagem Celular Tumoral , Células HEK293RESUMO
We report the results of 24 women, 50% (N = 12) with hormone receptor-positive breast cancer and 50% (N = 12) with advanced triple-negative breast cancer, treated with entinostat + nivolumab + ipilimumab from the dose escalation (N = 6) and expansion cohort (N = 18) of ETCTN-9844 ( NCT02453620 ). The primary endpoint was safety. Secondary endpoints were overall response rate, clinical benefit rate, progression-free survival and change in tumor CD8:FoxP3 ratio. There were no dose-limiting toxicities. Among evaluable participants (N = 20), the overall response rate was 25% (N = 5), with 40% (N = 4) in triple-negative breast cancer and 10% (N = 1) in hormone receptor-positive breast cancer. The clinical benefit rate was 40% (N = 8), and progression-free survival at 6 months was 50%. Exploratory analyses revealed that changes in myeloid cells may contribute to responses; however, no correlation was noted between changes in CD8:FoxP3 ratio, PD-L1 status and tumor mutational burden and response. These findings support further investigation of this treatment in a phase II trial.
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Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Ipilimumab , Nivolumabe , Piridinas , Receptor ErbB-2 , Humanos , Feminino , Pessoa de Meia-Idade , Piridinas/administração & dosagem , Piridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Nivolumabe/uso terapêutico , Nivolumabe/administração & dosagem , Adulto , Receptor ErbB-2/metabolismo , Benzamidas/uso terapêutico , Benzamidas/administração & dosagem , Idoso , Ipilimumab/uso terapêutico , Ipilimumab/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Intervalo Livre de ProgressãoRESUMO
This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10-4), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2high group of pbDMG patients = 2.88 (1.12-7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.
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A rapid, sensitive, and simple UHPLC-MS/MS method for the determination of the PARP inhibitor talazoparib in mouse plasma was developed and validated using [13C,2H4]-talazoparib as an internal standard (IS). The assay procedure involved extraction of talazoparib and the IS from plasma using a single-step deproteination and separation of the analytes was achieved on an ACQUITY UPLC RP18 HSS T3 column with a mobile phase gradient at a flow rate of 0.4 mL/min in a run time of 5 min. The calibration curve was linear (r2 > 0.99) over the concentration range of 0.5-100 ng/mL, and 10-fold dilution of samples could be accurately quantitated. The matrix effect and mean extraction recovery for talazoparib were between 93.7-109% and 87.7-105%, respectively. Precision and percent bias of quality control samples were always less than ±15%, indicating reproducibility and accuracy of the method. Talazoparib demonstrated bench-top stability at room temperature for 6 h, auto-sampler and reinjection stability at 4 °C for at least 24 h, and no significant degradation was observed after three freeze-thaw cycles. The developed method was successfully applied to pharmacokinetic studies involving serial blood sampling after oral administration of talazoparib to wild-type mice and animals with a genetic deficiency of the efflux transporters ABCB1 (P-gp) and ABCG2 (BCRP). Together, our results demonstrate the successful development of a suitable analytical method for talazoparib in mouse plasma and suggest that mice are a useful model to evaluate transporter-mediated drug-drug interactions involving therapy with talazoparib.
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Introduction: Statins are known to have anticoagulation and anti-inflammatory effects. This study aimed to investigate the effect of Rosuvastatin in reduction of post thrombotic syndrome (PTS) following deep vein thrombosis (DVT). Methods: In this randomized clinical trial, patients who were diagnosed with DVT of lower extremity were randomly assigned to 4 treatment groups: group 1: Warfarin, group 2: Warfarin + Rosuvastatin, group 3: Rivaroxaban, and group 4: Rivaroxaban + Rosuvastatin. The treatments were followed for 3 months and prevalence of PTS (as primary outcome), as well as the changes in serum levels of D-dimer and C reactive protein (CRP), and the extent of thrombosis before and after the intervention (as secondary outcomes) were compared between groups. Results: 182 patients with the mean age of 55.22 ± 4.1 years finished the trial period (51.64% male). There was no significant difference between the groups regarding the baseline characteristics. Based on the Brandjes score, 31 (17.03%) patients had PTS at the end of the study. The occurrence of PTS was significantly lower in the groups taking statins (p<0.0001). Although the change in the mean difference of legs circumference before and after intervention, were significant in all groups (p < 0.05), the differences was more prominent in groups 2 and 4 (p < 0.0001). After 3 months of taking medication, decrease of CRP was more prominent in the statin groups (p = 0.001), and most cases with normal CRP were in statin groups. Among the patients with the serum D-dimer level above 10000 ng/mL, patients in the statin groups experienced significantly more reduction in D-dimer levels than the other groups (p<0.001). Conclusion: Rosuvastatin administration in combination with rivaroxaban or warfarin significantly reduces the level of inflammatory factors including CRP and D-dimer, compared to patients receiving anticoagulants alone. Rosuvastatin administration can significantly reduce the incidence of PTS and cause a difference in the size of the lower limbs within 3 months.
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A simple LC-MS/MS method for the quantitative determination of the norepinephrine analogue meta-iodobenzyl-guanidine (mIBG) was developed and validated for mouse plasma and tissues, including salivary gland and heart. The assay procedure involved a one-step solvent extraction of mIBG and the internal standard N-(4-fluorobenzyl)-guandine from plasma or tissue homogenates with acetonitrile. An Accucore aQ column was used to separate analytes using a gradient elution with a total run time of 3.5 min. Validation studies with quality control samples processed on consecutive days revealed values for intra-day and inter-day precision of < 11.3%, with values for accuracy ranging 96.8-111%. Linear responses were observed over the entire calibration curves range (up to 100 ng/mL), and the lower limit of quantification was 0.1 ng/mL, using sample volumes of 5 µL. The developed method was successfully applied to evaluate the plasma pharmacokinetics and tissue distribution of mIBG in wild-type mice and animals lacking the organic cation transporters OCT1, OCT2, OCT3, and/or MATE1 to further understand mechanisms contributing to drug distribution and elimination and causes of inter-individual pharmacokinetic variability.
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3-Iodobenzilguanidina , Espectrometria de Massas em Tandem , Ratos , Camundongos , Animais , Espectrometria de Massas em Tandem/métodos , Cromatografia Líquida , Ratos Sprague-Dawley , Cromatografia Líquida de Alta Pressão/métodos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: PURPOSE: This study intended to investigate the prevalence of anemia and its associated factors among patients with type 2 diabetes mellitus (T2DM) in Gorgan, Iran. METHODS: This cross-sectional study was conducted on 415 (109 men) patients with T2DM referred to the referral diabetes clinic of Sayad Shirazi Hospital in Gorgan in 2021. Demographic information, anthropometric indices, past medical history, and some laboratory data on cell counts, serum blood glucose, HbA1c, creatinine, lipid/iron profiles, and urinary albumin were collected. The univariable and multivariable logistic regression analysis was applied to compute odds ratios (ORs) and 95% confidence intervals (CI) for potential associated factors, using SPSS version 21. The multivariable Model was adjusted for obesity, Hb A1c, T2DM duration, using glucose-lowering drugs (GLDs), chronic kidney disease (CKD), albuminuria, hypertriglyceridemia, and hypercholesterolemia. RESULTS: The prevalence of anemia was 21.5% [95%CI: 17.6-25.7] among our total participants. The corresponding values for men and women were 20.2 (13.1-29.0) and 21.9 (17.4-27.0), respectively.The adjusted model revealed that obesity (OR, 1.94 [95% CI, 1.17-3.23]), T2DM duration for more than five years (OR, 3.12 [1.78-5.47]), albuminuria (OR, 6.37 [3.13-10.91]), chronic kidney disease (OR, 4.30 [ 2.83-7.29]) and hypertriglyceridemia (OR, 1.72 [ 1.21-2.77]) were significantly associated with prevalent anemia among patients with T2DM. Moreover, using insulin separately or in combination with oral GLDs associated positively with the prevalence of anemia with ORs of 2.60 [1.42-6.42] and 1.87 [1.30-4.37] , respectively. CONCLUSION: Anemia had a high prevalence among patients with T2DM in the north of Iran (about 22%), which is associated with obesity, hypertriglyceridemia, duration of T2DM, and diabetic kidney disease.
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Anemia , Diabetes Mellitus Tipo 2 , Hipertrigliceridemia , Insuficiência Renal Crônica , Masculino , Humanos , Feminino , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/epidemiologia , Prevalência , Estudos Transversais , Irã (Geográfico)/epidemiologia , Albuminúria/etiologia , Albuminúria/complicações , Insuficiência Renal Crônica/epidemiologia , Obesidade/complicações , Obesidade/epidemiologia , Anemia/epidemiologia , Anemia/etiologia , Hipertrigliceridemia/complicações , Fatores de RiscoRESUMO
Oxaliplatin-induced peripheral neurotoxicity (OIPN) is a debilitating side effect that afflicts ~90% of patients that is initiated by OCT2-dependent uptake of oxaliplatin in DRG neurons. The antidepressant drug duloxetine has been used to treat OIPN, although its usefulness in preventing this side effect remains unclear. We hypothesized that duloxetine has OCT2-inhibitory properties and can be used as an adjunct to oxaliplatin-based regimens to prevent OIPN. Transport studies were performed in cells stably transfected with mouse or human OCT2 and in isolated mouse DRG neurons ex vivo. Wild-type and OCT2-deficient mice were used to assess effects of duloxetine on hallmarks of OIPN, endogenous OCT2 biomarkers, and the pharmacokinetics of oxaliplatin, and the translational feasibility of a duloxetine-oxaliplatin combination was evaluated in various models of colorectal cancer. We found that duloxetine potently inhibited the OCT2-mediated transport of several xenobiotic substrates, including oxaliplatin, in a reversible, concentration-dependent manner, and independent of species and cell context. Furthermore, duloxetine restricted access of these substrates to DRG neurons ex vivo and prevented OIPN in wild-type mice to a degree similar to the complete protection observed in OCT2-deficient mice, without affecting the plasma levels of oxaliplatin. Importantly, the uptake and cytotoxicity of oxaliplatin in tumor cell lines in vitro and in vivo were not negatively influenced by duloxetine. The observed OCT2-targeting properties of duloxetine, combined with the potential for clinical translation, provide support for its further exploration as a therapeutic candidate for studies aimed at preventing OIPN in cancer patients requiring treatment with oxaliplatin. Significance: We found that duloxetine has potent OCT2-inhibitory properties and can diminish excessive accumulation of oxaliplatin into DRG neurons. In addition, pre-treatment of mice with duloxetine prevented OIPN without significantly altering the plasma pharmacokinetics and antitumor properties of oxaliplatin. These results suggest that intentional inhibition of OCT2-mediated transport by duloxetine can be employed as a prevention strategy to ameliorate OIPN without compromising the effectiveness of oxaliplatin-based treatment.
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Antineoplásicos , Síndromes Neurotóxicas , Doenças do Sistema Nervoso Periférico , Humanos , Camundongos , Animais , Oxaliplatina/efeitos adversos , Antineoplásicos/toxicidade , Cloridrato de Duloxetina/farmacologia , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Síndromes Neurotóxicas/tratamento farmacológicoRESUMO
Gilteritinib, an FDA-approved tyrosine kinase inhibitor approved for the treatment of relapsed/refractory FLT3-mutated acute myeloid leukemia, is primarily eliminated via CYP3A4-mediated metabolism, a pathway that is sensitive to the co-administration of known CYP3A4 inhibitors, such as itraconazole. However, the precise mechanism by which itraconazole and other CYP3A-modulating drugs affect the absorption and disposition of gilteritinib remains unclear. In the present investigation, we demonstrate that pretreatment with itraconazole is associated with a significant increase in the systemic exposure to gilteritinib in mice, recapitulating the observed clinical drug-drug interaction. However, the plasma levels of gilteritinib were only modestly increased in CYP3A-deficient mice and not further influenced by itraconazole. Ensuing in vitro and in vivo studies revealed that gilteritinib is a transported substrate of OATP1B-type transporters, that gilteritinib exposure is increased in mice with OATP1B2 deficiency, and that the ability of itraconazole to inhibit OATP1B-type transport in vivo is contingent on its metabolism by CYP3A isoforms. These findings provide new insight into the pharmacokinetic properties of gilteritinib and into the molecular mechanisms underlying drug-drug interactions with itraconazole.
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Itraconazol , Leucemia Mieloide Aguda , Camundongos , Animais , Itraconazol/farmacologia , Citocromo P-450 CYP3A/genética , Inibidores do Citocromo P-450 CYP3A/farmacologia , Compostos de Anilina/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologiaRESUMO
Targeted therapies have significantly altered the landscape of available cancer therapies across all diagnoses and patient populations, and supportive care therapies have steadily improved throughout the years to make therapy more tolerable for patients. Even so, these therapies have varied efficacy and toxicity among patients with cancer, and pharmacogenomics presents an opportunity to identify which patients are most at risk of toxicities and most likely to benefit from them. While the field of pharmacogenomics in targeted cancer therapy is still growing, we review current knowledge, hypotheses, and clinical practices in this chapter, along with a brief review of pharmacogenomics in supportive therapies in cancer treatment.
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Antineoplásicos , Neoplasias , Antineoplásicos/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , FarmacogenéticaRESUMO
Pharmacogenetic testing in patients with cancer requiring cytotoxic chemotherapy offers the potential to predict, prevent, and mitigate chemotherapy-related toxicities. While multiple drug-gene pairs have been identified and studied, few drug-gene pairs are currently used routinely in the clinical status. Here we review what is known, theorized, and unknown regarding the use of pharmacogenetic testing in cancer.
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Neoplasias , Farmacogenética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Testes FarmacogenômicosRESUMO
Dofetilide is a rapid delayed rectifier potassium current inhibitor widely used to prevent the recurrence of atrial fibrillation and flutter. The clinical use of this drug is associated with increases in QTc interval, which predispose patients to ventricular cardiac arrhythmias. The mechanisms involved in the disposition of dofetilide, including its movement in and out of cardiomyocytes, remain unknown. Using a xenobiotic transporter screen, we identified MATE1 (SLC47A1) as a transporter of dofetilide and found that genetic knockout or pharmacological inhibition of MATE1 in mice was associated with enhanced retention of dofetilide in cardiomyocytes and increased QTc prolongation. The urinary excretion of dofetilide was also dependent on the MATE1 genotype, and we found that this transport mechanism provides a mechanistic basis for previously recorded drug-drug interactions of dofetilide with various contraindicated drugs, including bictegravir, cimetidine, ketoconazole, and verapamil. The translational significance of these observations was examined with a physiologically-based pharmacokinetic model that adequately predicted the drug-drug interaction liabilities in humans. These findings support the thesis that MATE1 serves a conserved cardioprotective role by restricting excessive cellular accumulation and warrant caution against the concurrent administration of potent MATE1 inhibitors and cardiotoxic substrates with a narrow therapeutic window.
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Antiarrítmicos , Fibrilação Atrial , Animais , Antiarrítmicos/farmacologia , Humanos , Camundongos , Fenetilaminas/farmacologia , Sulfonamidas/uso terapêuticoRESUMO
INTRODUCTION: Members of the solute carrier family of organic anion transporting polypeptides are responsible for the cellular uptake of a broad range of endogenous compounds and xenobiotics in multiple tissues. In particular, the polymorphic transporters OATP1B1 and OATP1B3 are highly expressed in the liver and have been identified as critical regulators of hepatic elimination. As these transporters are also expressed in cancer cells, the function alteration of these proteins have important consequences for an individual's susceptibility to certain drug-induced side effects, drug-drug interactions, and treatment efficacy. AREAS COVERED: In this mini-review, we provide an update of this rapidly emerging field, with specific emphasis on the direct contribution of genetic variants in OATP1B1 and OATP1B3 to the transport of anticancer drugs, the role of these carriers in regulation of their disposition and toxicity profiles, and recent advances in attempts to integrate information on transport function in patients to derive individualized treatment strategies. EXPERT OPINION: Based on currently available data, it appears imperative that different aspects of disease, physiology, and drugs of relevance should be evaluated along with an individual's genetic signature, and that tools such as biomarker levels can be implemented to achieve the most reliable prediction of clinically relevant pharmacodynamic endpoints.
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Antineoplásicos , Transportadores de Ânions Orgânicos , Antineoplásicos/efeitos adversos , Humanos , Transportador 1 de Ânion Orgânico Específico do Fígado/genética , Proteínas de Membrana Transportadoras/metabolismo , Transportadores de Ânions Orgânicos/genética , Transportadores de Ânions Orgânicos/metabolismo , Transportadores de Ânions Orgânicos Sódio-Independentes/metabolismo , Membro 1B3 da Família de Transportadores de Ânion Orgânico Carreador de Soluto/genéticaRESUMO
Venetoclax, a BCL-2 inhibitor used to treat certain hematological cancers, exhibits low oral bioavailability and high interpatient pharmacokinetic variability. Venetoclax is commonly administered with prophylactic antifungal drugs that may result in drug interactions, of which the underlying mechanisms remain poorly understood. We hypothesized that antifungal drugs may increase venetoclax exposure through inhibition of both CYP3A-mediated metabolism and OATP1B-mediated transport. Pharmacokinetic studies were performed in wild-type mice and mice genetically engineered to lack all CYP3A isoforms, or OATP1B2 that received venetoclax alone or in combination with ketoconazole or micafungin. In mice lacking all CYP3A isoforms, venetoclax AUC was increased by 1.8-fold, and pretreatment with the antifungal ketoconazole further increased venetoclax exposure by 1.6-fold, despite the absence of CYP3A. Ensuing experiments demonstrated that the deficiency of OATP1B-type transporters is also associated with increases in venetoclax exposure, and that many antifungal drugs, including micafungin, posaconazole, and isavuconazole, are inhibitors of this transport mechanism both in vitro and in vivo. These studies have identified OATP1B-mediated transport as a previously unrecognized contributor to the elimination of venetoclax that is sensitive to inhibition by various clinically-relevant antifungal drugs. Additional consideration is warranted when venetoclax is administered together with agents that inhibit both CYP3A-mediated metabolism and OATP1B-mediated transport.
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Oral anticancer drugs suffer from significant variability in pharmacokinetics and pharmacodynamics partially due to limited bioavailability. The limited bioavailability of anticancer drugs is due to both pharmaceutical limitations and physiological barriers. Pharmacokinetic boosting is a strategy to enhance the oral bioavailability of a therapeutic drug by inhibiting physiological barriers through an intentional drug-drug interaction (DDI). This type of strategy has proven effective across several therapeutic indications including anticancer treatment. Pharmacokinetic boosting could improve anticancer drugs lacking or with otherwise unacceptable oral formulations through logistic, economic, pharmacodynamic and pharmacokinetic benefits. Despite these benefits, pharmacokinetic boosting strategies could result in unintended DDIs and are only likely to benefit a limited number of targets. Highlighting this concern, pharmacokinetic boosting has mixed results depending on the boosted drug. While pharmacokinetic boosting did not significantly improve certain drugs, it has resulted in the commercial approval of boosted oral formulations for other drugs. Pharmacokinetic boosting to improve oral anticancer therapy is an expanding area of research that is likely to improve treatment options for cancer patients.
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Antineoplásicos/farmacocinética , Interações Medicamentosas , Neoplasias/tratamento farmacológico , Administração Oral , Antineoplásicos/administração & dosagem , Disponibilidade Biológica , HumanosRESUMO
A mesoporous silica aerogel (SiA) with a high specific surface area was synthesized through the sol-gel process and subsequently modified with two different silane-based modifiers to reveals the effect of microstructure and surface modification on the fracture mechanics of a dental composite. The synthesized and modified aerogel were characterized using field-emission scanning electron microscopy (FESEM), nitrogen adsorption-desorption, and Fourier-transform infrared spectroscopy (FTIR). The prepared aerogels were then incorporated within methacrylate-based dental composites with the filler content of 0-35 wt%. Flexural modulus (FM) and Flexural strength (FS) were evaluated by the three-point bending test. The fracture toughness (FT) of the composites was evaluated by single edge V-notched beam (SEVNB) flexure test, while FESEM was employed to investigate the fracture surface morphology of the composites. Furthermore, the wettability of the composites was assessed according to the sessile drop method. The characterization of synthesized aerogels revealed the formation of SiA with a surface area of 550-560 m2/g and porosity of 77%, while FTIR results confirmed the successful modification. Statistical analysis (ANOVA, p≤0.05, and n = 5) revealed that FM significantly enhanced (from 1.43 GPa to 2.66 GPa) as filler content increased over 0-30 wt%, and FS improved (from 80 to 95 MPa) as filler content increased over 0-15 wt%. Furthermore, the modification of aerogels improved both fracture characteristics and the wettability of the composites. The FT evaluations and fractography analysis revealed that the mesoporous structure of the fillers mainly dominated the filler-matrix adhesion strength at the same filler content.
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Dióxido de SilícioRESUMO
Medication reconciliation based on complete medication histories has been introduced to minimize medication errors and its associated healthcare costs in the transitions of care. In this study, to evaluate the routine process of medication reconciliation in an academic medical center, medication history taken at the time of admission by physicians and the first order prescribed in the hospital was compared to a comprehensive reconciliation form filled by a pharmacist using direct interview of the patients and caregivers, patient's insurance records and medication packages they brought from home. Two hundred and fifty-seven patients admitted in the internal wards of an academic medical center between June and September 2019 were investigated. In 6% of the patients, drug history was not included in the medical history form. Other patients were using 8.59 drugs in average, with a mean of 3.55 medication discrepancies in the history-taking process. Most commonly occurring errors were drug omissions (2.23 per patient on average) and incorrect frequency (0.96 per patient on average). There was a mean of 0.7 potentially harmful discrepancies for each patient. The mean number of drug discrepancies in new prescriptions from the hospital was 1.25, and almost half of patients had a potentially harmful discrepancies reordered in the hospital. There was no statistically meaningful relationship between patients' gender, physicians' gender, or the time of history taking and the total number of medication errors. History of ischemic heart disease was significantly associated with higher number of medication errors (p = 0.05). The results suggest that the medication reconciliation process in this academic center is inefficient. Using a systematic approach in medication reconciliation and gathering the best possible medication history, with a pharmacist who has better understanding of drugs' potential interactions and harmful errors can improve this process and prevent such errors in the future.
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Reconciliação de Medicamentos , Farmacêuticos , Centros Médicos Acadêmicos , Hospitais , Humanos , Medicina Interna , Reconciliação de Medicamentos/métodos , Admissão do Paciente , Fatores de RiscoRESUMO
The membrane transport of many cationic prescription drugs depends on facilitated transport by organic cation transporters of which several members, including OCT2 (SLC22A2), are sensitive to inhibition by select tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs may differentially interact with the renal transporter MATE1 (SLC47A1) and influence the elimination and toxicity of the MATE1 substrate oxaliplatin. Interactions with FDA-approved TKIs were evaluated in transfected HEK293 cells, and in vivo pharmacokinetic studies were performed in wild-type, MATE1-deficient, and OCT2/MATE1-deficient mice. Of 57 TKIs evaluated, 37 potently inhibited MATE1 function by >80% through a non-competitive, reversible, substrate-independent mechanism. The urinary excretion of oxaliplatin was reduced by about 2-fold in mice with a deficiency of MATE1 or both OCT2 and MATE1 (p < 0.05), without impacting markers of acute renal injury. In addition, genetic or pharmacological inhibition of MATE1 did not significantly alter plasma levels of oxaliplatin, suggesting that MATE1 inhibitors are unlikely to influence the safety or drug-drug interaction liability of oxaliplatin-based chemotherapy.
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Drug resistance and relapse are common challenges in acute myeloid leukemia (AML), particularly in an aggressive subset bearing internal tandem duplications (ITDs) of the FLT3 receptor (FLT3-ITD+). The tyrosine kinase inhibitor gilteritinib is approved for the treatment of relapse/refractory AML with FLT3 mutations, yet resistance to gilteritinib remains a clinical concern, and the underlying mechanisms remain incompletely understood. Using transcriptomic analyses and functional validation studies, we identified the calcium-binding proteins S100A8 and S100A9 (S100A8/A9) as contributors to gilteritinib resistance in FLT3-ITD+ AML. Exposure of FLT3-ITD+ AML cells to gilteritinib increased S100A8/A9 expression in vivo and in vitro and decreased free calcium levels, and genetic manipulation of S100A9 was associated with altered sensitivity to gilteritinib. Using a transcription factor screen, we identified the transcriptional corepressor BCL6, as a regulator of S100A9 expression and found that gilteritinib decreased BCL6 binding to the S100A9 promoter, thereby increasing S100A9 expression. Furthermore, pharmacological inhibition of BCL6 accelerated the growth rate of gilteritinib-resistant FLT3-ITD+ AML cells, suggesting that S100A9 is a functional target of BCL6. These findings shed light on mechanisms of resistance to gilteritinib through regulation of a target that can be therapeutically exploited to enhance the antileukemic effects of gilteritinib.