Pill-burden and its association with treatment burden among patients with advanced stages of chronic kidney disease

Introduction: Chronic kidney disease (CKD) is associated with multimorbidity and high treatment burden. Pill-burden is one component of the overall treatment burden. However, little is known about its magnitude and contribution to the overall treatment burden among patients with advanced stages of CKD. This study aimed to quantify the magnitude of pill-burden in dialysis-dependent vs. non-dialysis-dependent advanced-stage CKD patients and its association with treatment burden. Methods: This was a cross-sectional study for the assessment of pill-burden and treatment burden among non-dialysis and hemodialysis (HD)-dependent CKD patients. Pill-burden was quantified as "number of pills/patient/week" through electronic medical record, while treatment burden was assessed using the "Treatment Burden Questionnaire (TBQ)". Furthermore, oral and parenteral medication burden was also quantified. Data were analyzed using both descriptive and inferential analysis, including Mann - Whitney U test and two-way between groups analysis of variance (ANOVA). Results: Among the 280 patients included in the analysis, the median (IQR) number of prescribed chronic medications was 12 (5.7) oral and 3 (2) parenteral medications. The median (IQR) pill-burden was 112 (55) pills/week. HD patients experienced higher pill-burden than non-dialysis patients [122 (61) vs. 109 (33) pills/week]; however, this difference did not reach statistical significance (p = 0.81). The most commonly prescribed oral medications were vitamin D (90.4%), sevelamer carbonate (65%), cinacalcet (67.5%), and statins (67.1%). Overall, patients who had high pill-burden (≥112 pills/week) had significantly higher perceived treatment burden compared to low pill-burden patients (<112 pills/week) [47(36.2) vs. 38.5(36.7); p = 0.0085]. However, two-way ANOVA showed that dialysis status is the significant contributor to the treatment-burden in the high overall pill-burden group (p < 0.01), the high oral-medication-burden group (p < 0.01), and the high parenteral-medication-burden group (p = 0.004). Conclusions: Patients with advanced CKD experienced a high pill-burden, which increases the treatment burden; however, the dialysis status of the patient is the main factor affecting the overall treatment burden. Future intervention studies should target this population with an aim to reduce polypharmacy, pill-burden, and treatment burden, which may ultimately improve CKD patients' quality of life.The authors would like to acknowledge Qatar University for the funding provided for the study. This manuscript is part of an MSc dissertation submitted to Qatar University and related abstracts were presented and published as part of the 56th European Renal Association - European Dialysis and Transplant Association (ERA-EDTA) Congress, Budapest, Hungary, 13-16 June 2019. The study received funding from Qatar University (grant number: QUCG- CPH-22/23-592 and QUST-CPH-SPR/2017-19). The content of this paper is the sole responsibility of the authors.Scopu

Topical Delivery of Diacetyl Boldine in a Microemulsion Formulation for Chemoprotection against Melanoma

This study aimed to develop a microemulsion formulation for topical delivery of Diacetyl Boldine (DAB) and to evaluate its cytotoxicity against melanoma cell line (B16BL6) in vitro. Using a pseudo-ternary phase diagram, the optimal microemulsion formulation region was identified, and its particle size, viscosity, pH, and in vitro release characteristics were determined. Permeation studies were performed on excised human skin using Franz diffusion cell assembly. The cytotoxicity of the formulations on B16BL6 melanoma cell lines was evaluated by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide) assay. Two formulation compositions were selected based on the higher microemulsion area of the pseudo-ternary phase diagrams. The formulations showed a mean globule size of around 50&thinsp;nm and a polydispersity index of &lt;0.2. The ex vivo skin permeation study demonstrated that the microemulsion formulation exhibited significantly higher skin retention levels than the DAB solution in MCT oil (Control, DAB-MCT). Furthermore, the formulations showed substantially higher cytotoxicity toward B16BL6 cell lines than the control formulation (p &lt; 0.001). The half-maximal inhibitory concentrations (IC50) of F1, F2, and DAB-MCT formulations against B16BL6 cells were calculated to be 1 &micro;g/mL, 10 &micro;g/mL, and 50 &micro;g/mL, respectively. By comparison, the IC50 of F1 was 50-fold lower than that of the DAB-MCT formulation. The results of the present study suggest that microemulsion could be a promising formulation for the topical administration of DAB

Screening of Apoptosis Pathway-Mediated Anti-Proliferative Activity of the Phytochemical Compound Furanodienone against Human Non-Small Lung Cancer A-549 Cells

Furanodienone (FDN), a major bioactive component of sesquiterpenes produced from Rhizoma Curcumae, has been repeatedly acknowledged for its intrinsic anticancer efficacy against different types of cancer. In this study, we aimed to investigate the cytotoxic potential of furanodienone against human lung cancer (NSCLC A549) cells in vitro, as well as its underlying molecular mechanisms in the induction of apoptosis. Herein, we found that FDN significantly inhibited the proliferation of A549 cells in a dose-dependent manner. In addition, treatment with FDN potentially triggered apoptosis in A549 cells via not only disrupting the nuclear morphology, but by activating capsase-9 and caspase-3 with concomitant modulation of the pro- and antiapoptotic gene expression as well. Furthermore, FDN revealed its competence in inducing cell cycle arrest at G0/G1 phase in A549 cells, which was associated with decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4), along with increased expression of CDK inhibitor p21Cip1. Intriguingly, FDN treatment efficiently downregulated the Wnt signaling pathway, which was correlated with increased apoptosis, as well as cell cycle arrest, in A549 cells. Collectively, FDN might represent a promising adjuvant therapy for the management of lung cancer

Cytotoxic and Apoptotic Effect of Rubus chingii Leaf Extract against Non-Small Cell Lung Carcinoma A549 Cells

Rubus chingii is a traditional Chinese medicinal herbal that has been used since ancient times for its great dietary and medicinal values. Recent reports have underscored the promising cytotoxic effect of R. chingii extracts against a wide variety of cancer cells. Therefore, in the current study, we aim to explore the anticancer potential of the Rubus chingii ethanolic leaf extract (RcL-EtOH) against non-small cell lung cancer A549 cells. RcL-EtOH efficiently exerted a cytotoxic effect against A549 cells in a dose dependent manner, whilst, it exhibited non-significant toxic effects on normal murine macrophage cells, signifying its safety against normal cells. The reduced viability of A549 cells was reaffirmed by the acridine orange/ethidium bromide double staining, which confirmed the induction of apoptosis in RcL-EtOH-treated A549 cells. In addition, RcL-EtOH instigated the dissipation of mitochondrial membrane potential (&Delta;&Psi;m) with mutual escalation in ROS generation in a dose-dependent manner. Furthermore, RcL-EtOH increased caspase-3, caspase-9 levels in A549 cells post-exposure to RcL-EtOH, which was concomitantly followed by altered mRNA expression of apoptotic (anti-apoptotic: Bcl-2, BclXL; pro-apoptotic: Bax, Bad). To sum up, the RcL-EtOH-instigated apoptotic cell death within A549 cells was assumed to be accomplished via targeting mitochondria, triggering increased ROS generation, with subsequent activation of caspase cascade and altering the expression of gene regulating apoptosis. Collectively, RcL-EtOH might represent a plausible therapeutic option for the management of lung cancer

Screening of Apoptosis Pathway-Mediated Anti-Proliferative Activity of the Phytochemical Compound Furanodienone against Human Non-Small Lung Cancer A-549 Cells

Furanodienone (FDN), a major bioactive component of sesquiterpenes produced from Rhizoma Curcumae, has been repeatedly acknowledged for its intrinsic anticancer efficacy against different types of cancer. In this study, we aimed to investigate the cytotoxic potential of furanodienone against human lung cancer (NSCLC A549) cells in vitro, as well as its underlying molecular mechanisms in the induction of apoptosis. Herein, we found that FDN significantly inhibited the proliferation of A549 cells in a dose-dependent manner. In addition, treatment with FDN potentially triggered apoptosis in A549 cells via not only disrupting the nuclear morphology, but by activating capsase-9 and caspase-3 with concomitant modulation of the pro- and antiapoptotic gene expression as well. Furthermore, FDN revealed its competence in inducing cell cycle arrest at G0/G1 phase in A549 cells, which was associated with decreased expression of cyclin D1 and cyclin-dependent kinase 4 (CDK4), along with increased expression of CDK inhibitor p21Cip1. Intriguingly, FDN treatment efficiently downregulated the Wnt signaling pathway, which was correlated with increased apoptosis, as well as cell cycle arrest, in A549 cells. Collectively, FDN might represent a promising adjuvant therapy for the management of lung cancer

Development of Chitosan-Coated PLGA-Based Nanoparticles for Improved Oral Olaparib Delivery: In Vitro Characterization, and In Vivo Pharmacokinetic Studies

Olaparib (OLP) is an orally active poly (ADP-ribose) polymerase enzyme inhibitor, approved for treatment for the metastatic stage of prostate, pancreatic, breast and ovarian cancer. Due to its low bioavailability, an increase in dose and frequency is required to achieve therapeutic benefits, which also results in associated toxicity in patients. In the current study, OLP-loaded poly (d,l-lactide-co-glycolide) (PLGA) nanoparticles (NPs) (OLP-PLGA NPs) and a coating of OLP-PLGA NPs with chitosan (CS) (OLP-CS-PLGA NPs) were prepared successfully in order to improve the dissolution rate and bioavailability. The developed OLP-PLGA NPs were evaluated for hydrodynamic particle size (392 &plusmn; 5.3 nm), PDI (0.360 &plusmn; 0.03), ZP (&minus;26.9 &plusmn; 2.1 mV), EE (71.39 &plusmn; 5.5%) and DL (14.86 &plusmn; 1.4%), and OLP-CS-PLGA NPs, hydrodynamic particle size (622 &plusmn; 9.5 nm), PDI (0.321 &plusmn; 0.02), ZP (+36.0 &plusmn; 1.7 mV), EE (84.78 &plusmn; 6.3%) and DL (11.05 &plusmn; 2.6%). The in vitro release profile of both developed NPs showed a sustained release pattern. Moreover, the pharmacokinetics results exhibited a 2.0- and 4.75-fold increase in the bioavailability of OLP-PLGA NPs and OLP-CS-PLGA NPs, respectively, compared to normal OLP suspension. The results revealed that OLP-CS-PLGA NPs could be an effective approach to sustaining and improving the bioavailability of OLP

Amphotericin B-PEG Conjugates of ZnO Nanoparticles: Enhancement Antifungal Activity with Minimal Toxicity

Amphotericin B (AMB) is commonly used to treat life-threatening systemic fungal infections. AMB formulations that are more efficient and less nephrotoxic are currently unmet needs. In the current study, new ZnO-PEGylated AMB (ZnO-AMB-PEG) nanoparticles (NPs) were synthesized and their antifungal effects on the Candida spp. were investigated. The size and zeta potential values of AMB-PEG and ZnO-AMB-PEG NPs were 216.2 &plusmn; 26.9 to 662.3 &plusmn; 24.7 nm and &minus;11.8 &plusmn; 2.02 to &minus;14.2 &plusmn; 0.94 mV, respectively. The FTIR, XRD, and EDX spectra indicated that the PEG-enclosed AMB was capped by ZnO, and SEM images revealed the ZnO distribution on the surface NPs. In comparison to ZnO-AMB NPs and free AMB against C.albicans and C.neoformans, ZnO-AMB-PEG NPs significantly reduced the MIC and MFC. After a week of single and multiple dosage, the toxicity was investigated utilizing in vitro blood hemolysis, in vivo nephrotoxicity, and hepatic functions. ZnO-AMB-PEG significantly lowered WBC count and hematocrit concentrations when compared to AMB and ZnO-AMB. RBC count and hemoglobulin content, on the other hand, were unaltered. ZnO-AMB-PEG considerably lowered creatinine and blood urea nitrogen (BUN) levels when compared to AMB and ZnO-AMB. The difference in liver function indicators was determined to be minor by all formulae. These findings imply that ZnO-AMB-PEG could be utilized in the clinic with little nephrotoxicity, although more research is needed to determine the formulation&rsquo;s in vivo efficacy

Development of Sustained Release Baricitinib Loaded Lipid-Polymer Hybrid Nanoparticles with Improved Oral Bioavailability

Baricitinib (BTB) is an orally administered Janus kinase inhibitor, therapeutically used for the treatment of rheumatoid arthritis. Recently it has also been approved for the treatment of COVID-19 infection. In this study, four different BTB-loaded lipids (stearin)-polymer (Poly(d,l-lactide-co-glycolide)) hybrid nanoparticles (B-PLN1 to B-PLN4) were prepared by the single-step nanoprecipitation method. Next, they were characterised in terms of physicochemical properties such as particle size, zeta potential (ζP), polydispersity index (PDI), entrapment efficiency (EE) and drug loading (DL). Based on preliminary evaluation, the B-PLN4 was regarded as the optimised formulation with particle size (272 ± 7.6 nm), PDI (0.225), ζP (−36.5 ± 3.1 mV), %EE (71.6 ± 1.5%) and %DL (2.87 ± 0.42%). This formulation (B-PLN4) was further assessed concerning morphology, in vitro release, and in vivo pharmacokinetic studies in rats. The in vitro release profile exhibited a sustained release pattern well-fitted by the Korsmeyer–Peppas kinetic model (R2 = 0.879). The in vivo pharmacokinetic data showed an enhancement (2.92 times more) in bioavailability in comparison to the normal suspension of pure BTB. These data concluded that the formulated lipid-polymer hybrid nanoparticles could be a promising drug delivery option to enhance the bioavailability of BTB. Overall, this study provides a scientific basis for future studies on the entrapment efficiency of lipid-polymer hybrid systems as promising carriers for overcoming pharmacokinetic limitations

Pill-burden and its association with treatment burden among patients with advanced stages of chronic kidney disease

Introduction: Chronic kidney disease (CKD) is associated with multimorbidity and high treatment burden. Pill-burden is one component of the overall treatment burden. However, little is known about its magnitude and contribution to the overall treatment burden among patients with advanced stages of CKD. This study aimed to quantify the magnitude of pill-burden in dialysis-dependent vs. non-dialysis-dependent advanced-stage CKD patients and its association with treatment burden. Methods: This was a cross-sectional study for the assessment of pill-burden and treatment burden among non-dialysis and hemodialysis (HD)-dependent CKD patients. Pill-burden was quantified as “number of pills/patient/week” through electronic medical record, while treatment burden was assessed using the “Treatment Burden Questionnaire (TBQ)”. Furthermore, oral and parenteral medication burden was also quantified. Data were analyzed using both descriptive and inferential analysis, including Mann – Whitney U test and two-way between groups analysis of variance (ANOVA). Results: Among the 280 patients included in the analysis, the median (IQR) number of prescribed chronic medications was 12 (5.7) oral and 3 (2) parenteral medications. The median (IQR) pill-burden was 112 (55) pills/week. HD patients experienced higher pill-burden than non-dialysis patients [122 (61) vs. 109 (33) pills/week]; however, this difference did not reach statistical significance (p = 0.81). The most commonly prescribed oral medications were vitamin D (90.4%), sevelamer carbonate (65%), cinacalcet (67.5%), and statins (67.1%). Overall, patients who had high pill-burden (≥112 pills/week) had significantly higher perceived treatment burden compared to low pill-burden patients (<112 pills/week) [47(36.2) vs. 38.5(36.7); p = 0.0085]. However, two-way ANOVA showed that dialysis status is the significant contributor to the treatment-burden in the high overall pill-burden group (p < 0.01), the high oral-medication-burden group (p < 0.01), and the high parenteral-medication-burden group (p = 0.004). Conclusions: Patients with advanced CKD experienced a high pill-burden, which increases the treatment burden; however, the dialysis status of the patient is the main factor affecting the overall treatment burden. Future intervention studies should target this population with an aim to reduce polypharmacy, pill-burden, and treatment burden, which may ultimately improve CKD patients’ quality of life

Enhanced Cytotoxic Activity of Docetaxel-Loaded Silk Fibroin Nanoparticles against Breast Cancer Cells

Despite decades of research, breast cancer therapy remains a great challenge. Docetaxel is an antimicrotubule agent that is effectively used for the treatment of breast cancer. However, its clinical use is significantly hampered by its low water solubility and systemic toxicity. The current study was designed to prepare docetaxel (DXL)-loaded silk-fibroin-based nanoparticles (SF-NPs) and to screen their potential antitumor activity against breast cancer cell lines. DXL-loaded SF-NPs were prepared using a nanoprecipitation technique and were evaluated for particle size, zeta potential, entrapment efficiency, and in vitro release profile. In addition, DXL-loaded SF-NPs were screened for in vitro cytotoxicity, cellular uptake, and apoptotic potential against MCF-7 and MDA-MB-231 breast cancer cell lines. The prepared DXL-loaded SF-NPs were 178 to 198 nm in diameter with a net negative surface charge and entrapment efficiency ranging from 56% to 72%. In vitro release studies exhibited a biphasic release profile of DXL from SF-NPs with sustained drug release for 72 h. In vitro cell studies revealed that entrapment of DXL within SF-NPs significantly improved cytotoxic potential against breast cancer cell lines, compared to the free drug, and enhanced cellular uptake of DXL by breast cancer cells. Furthermore, the accumulation in the G2/M phase was significantly higher in cells treated with DXL-loaded SF-NPs than in cells treated with free DXL. Collectively, the superior antitumor activities of DXL-loaded SF-NPs against breast cancer cells, compared to free DXL, could be ascribed to improved apoptosis and cell cycle arrest. Our results highlighted the feasibility of using silk fibroin nanoparticles as a nontoxic biocompatible delivery vehicle for enhanced therapeutic outcomes in breast cancer