Differential effects of two phosphodiesterase 4 inhibitors against lipopolysaccharide-induced neuroinflammation in mice.

BACKGROUND: Several phosphodiesterase 4 (PDE4) inhibitors have emerged as potential therapeutics for central nervous system (CNS) diseases. This study investigated the pharmacological effects of two selective PDE4 inhibitors, roflumilast and zatolmilast, against lipopolysaccharide-induced neuroinflammation. RESULTS: In BV-2 cells, the PDE4 inhibitor roflumilast reduced the production of nitric oxide and tumor necrosis factor-α (TNF-α) by inhibiting NF-κB phosphorylation. Moreover, mice administered roflumilast had significantly reduced TNF-α, interleukin-1ß (IL-1ß), and IL-6 levels in plasma and brain tissues. By contrast, zatolmilast, a PDE4D inhibitor, showed no anti-neuroinflammatory effects in vitro or in vivo. Next, in vitro and in vivo pharmacokinetic studies of these compounds in the brain were performed. The apparent permeability coefficients of 3 µM roflumilast and zatolmilast were high (> 23 × 10-6 cm/s) and moderate (3.72-7.18 × 10-6 cm/s), respectively, and increased in a concentration-dependent manner in the MDR1-MDCK monolayer. The efflux ratios were < 1.92, suggesting that these compounds are not P-glycoprotein substrates. Following oral administration, both roflumilast and zatolmilast were slowly absorbed and eliminated, with time-to-peak drug concentrations of 2-2.3 h and terminal half-lives of 7-20 h. Assessment of their brain dispositions revealed the unbound brain-to-plasma partition coefficients of roflumilast and zatolmilast to be 0.17 and 0.18, respectively. CONCLUSIONS: These findings suggest that roflumilast, but not zatolmilast, has the potential for use as a therapeutic agent against neuroinflammatory diseases.

Evaluation of the potential herb-drug interaction between Bojungikki-tang and PD-L1 immunotherapy in a syngeneic mouse model.

Atezolizumab (a PD-L1 inhibitor) has shown remarkable efficacy and tolerability in various cancer types. Despite its efficacy and safety, atezolizumab monotherapy has limitations, such as acquired resistance and adverse events. Bojungikki-tang (BJIKT) is an herbal decoction widely prescribed in Asian countries and used to treat cancer-related symptoms including fatigue, appetite loss, gastrointestinal disorders, and other side effects from cancer therapy. Due to its immunomodulatory effects, Bojungikki-tang has been investigated as a combined treatment with anticancer agents. We evaluated the potential drug-drug interaction (DDI) between Bojungikki-tang and the anti-PD-L1 antibody based on the Food and Drug Administration (FDA) guidelines. In the study, we conducted an in vivo drug-drug interaction study using a syngeneic mouse model of CMT-167 in C57BL/6. We then determined the antibody concentrations to evaluate the pharmacokinetic (PK) drug-drug interaction and measured variable biomarkers related to therapeutic efficacy and immune response. The pharmacodynamic (PD) drug-drug interaction study investigated changes in response between anti-PD-L1 antibody monotherapy and combination therapy. Using the pharmacokinetic and pharmacodynamic data, we conducted a statistical analysis to assess drug-drug interaction potential. In the presence of Bojungikki-tang, the pharmacokinetic characteristics of the anti-PD-L1 antibody were not changed. This study suggested that combination treatment with Bojungikki-tang and atezolizumab is a safe treatment option for non-small cell lung cancer. Clinical studies are warranted to confirm this finding.

Application of physiologically-based pharmacokinetic model approach to predict pharmacokinetics and drug-drug interaction of rivaroxaban: A case study of rivaroxaban and carbamazepine.

Rivaroxaban (RIV; Xarelto; Janssen Pharmaceuticals, Beerse, Belgium) is one of the direct oral anticoagulants. The drug is a strong substrate of cytochrome P450 (CYP) enzymes and efflux transporters. This study aimed to develop a physiologically-based pharmacokinetic (PBPK) model for RIV. It contained three hepatic metabolizing enzyme reactions (CYP3A4, CYP2J2, and CYP-independent) and two active transporter-mediated transfers (P-gp and BCRP transporters). To illustrate the performance of the developed RIV PBPK model on the prediction of drug-drug interactions (DDIs), carbamazepine (CBZ) was selected as a case study due to the high DDI potential. Our study results showed that CBZ significantly reduces the exposure of RIV. The area under the concentration-time curve from zero to infinity (AUCinf ) of RIV was reduced by 35.2% (from 2221.3 to 1438.7 ng*h/ml) and by 25.5% (from 2467.3 to 1838.4 ng*h/ml) after the first dose and at the steady-state, respectively, whereas the maximum plasma concentration (Cmax ) of RIV was reduced by 37.7% (from 266.3 to 166.1 ng/ml) and 36.4% (from 282.3 to 179.5 ng/ml), respectively. The developed PBPK model of RIV could be paired with PBPK models of other interested perpetrators to predict DDI profiles. Further studies investigating the extent of DDI between CBZ and RIV should be conducted in humans to gain a full understanding of their safety and effects.

Evaluation for Potential Drug-Drug Interaction of MT921 Using In Vitro Studies and Physiologically-Based Pharmacokinetic Models.

MT921 is a new injectable drug developed by Medytox Inc. to reduce submental fat. Cholic acid is the active pharmaceutical ingredient, a primary bile acid biosynthesized from cholesterol, endogenously produced by liver in humans and other mammals. Although individuals treated with MT921 could be administered with multiple medications, such as those for hypertension, diabetes, and hyperlipidemia, the pharmacokinetic drug-drug interaction (DDI) has not been investigated yet. Therefore, we studied in vitro against drug-metabolizing enzymes and transporters. Moreover, we predicted the potential DDI between MT921 and drugs for chronic diseases using physiologically-based pharmacokinetic (PBPK) modeling and simulation. The magnitude of DDI was found to be negligible in in vitro inhibition and induction of cytochrome P450s and UDP-glucuronosyltransferases. Organic anion transporting polypeptide (OATP)1B3, organic anion transporter (OAT)3, Na+-taurocholate cotransporting polypeptide (NTCP), and apical sodium-dependent bile acid transporter (ASBT) are mainly involved in MT921 transport. Based on the result of in vitro experiments, the PBPK model of MT921 was developed and evaluated by clinical data. Furthermore, the PBPK model of amlodipine was developed and evaluated. PBPK DDI simulation results indicated that the pharmacokinetics of MT921 was not affected by the perpetrator drugs. In conclusion, MT921 could be administered without a DDI risk based on in vitro study and related in silico simulation. Further clinical studies are needed to validate this finding.

Clinical Benefits of Oral Anticoagulant Use in Cancer Patients at Increased Risk for Venous Thromboembolism per Khorana Index.

BACKGROUND: Cancer patients are at increased risk for venous thromboembolism (VTE) due to cancer-induced hypercoagulability. However, current guidelines do not routinely recommend prophylactic use of oral anticoagulants to prevent VTE in cancer patients. OBJECTIVE: To evaluate the efficacy and safety of novel oral anticoagulants (NOACs) versus no anticoagulant use (no-use) and, additionally, differential effects between NOACs and warfarin, in VTE and adverse bleeding prevention among cancer patients, in consideration of risk stratification by gender, high-risk chemotherapy exposure, and Khorana index. METHODS: This national health insurance data-based study with a 180-day follow-up enrolled cancer patients with or without oral anticoagulant use in 2017. The primary outcome was VTE risk in oral anticoagulant users vs non-users. Four propensity score-matched comparison pairs were designed: use vs no-use, NOAC vs no-use, warfarin vs no-use, and NOAC vs warfarin. A logistic regression model was used to investigate between-group differences in VTE and bleeding risk. RESULTS: When compared to no-use, NOACs showed substantial effects in preventing VTE complications (OR=0.40, p<0.001), primarily deep vein thrombosis (DVT) events (OR=0.38, p<0.001), in both male and female cancer patients as well as those with a Khorana score ≥1. Adverse bleeding risk was comparable or lower in NOAC-receiving female patients (p=0.13) and male patients (p=0.04), respectively. In contrast, no protective effects were found with warfarin compared to no-use in controlling thrombosis and adverse bleeding risk. In a head-to-head comparison of NOACs versus warfarin, DVT risk in those patients exposed to high-risk chemotherapy was significantly decreased with NOAC use (OR=0.19, p=0.03). CONCLUSION: NOACs can be a promising thromboprophylactic option in both male and female cancer patients with VTE risk.

Pharmacokinetics of eperisone following oral administration in healthy Korean volunteers.

Eperisone is an oral muscle relaxant used to treat musculoskeletal diseases, which exhibits high pharmacokinetic (PK) variability in bioequivalence studies. The aim of this study was to characterize the PKs of eperisone following its oral administration to Korean volunteers through the conduct of a noncompartmental and population analysis. A total of 360 concentration-time measurements collected on two separate occasions from 15 healthy volunteers during a bioequivalent study of eperisone 50 mg (Murex® ) were used in the PK analysis. Noncompartmental analysis was performed using WinNonLinTM and population analysis was performed using NONMEM® . The possible influence of thirty demographic and pathophysiological characteristics on the PKs of eperisone were explored. Based on noncompartmental analysis mean eperisone elimination half-life, apparent clearance (CL/F), and apparent volume of distribution were estimated to be 3.81 h, 39.24 × 103  l/h × 103  L, respectively. During population PK modeling a two-compartment model with first-order absorption rate constant (typical population K a  = 1.5 h-1 ) and first-order elimination (typical population CL/F and apparent volume of distribution in the central compartment [V c /F] = 30.8 × 103  l/h and 86.2 × 103  l, respectively) best described the PKs of eperisone. Interindividual variability in CL/F and V c /F were estimated to be 87.9% and 130.3%, respectively and interoccasion variability in CL/F and V c /F were estimated to be 23.8% and 30.8%, respectively. Aspartate aminotransferase level and smoking status were identified as potential covariates that may influence the CL/F of eperisone. This is the first study to develop a disposition model for eperisone and investigate the potential influence of covariate factors on it PK variability.

Molecular design of anticancer drugs from marine fungi derivatives.

Heat shock protein 90 (Hsp90) is one of the most potential targets in cancer therapy. We have demonstrated using a combination of molecular docking and fast pulling of ligand (FPL) simulations that marine fungi derivatives can be possible inhibitors, preventing the biological activity of Hsp90. The computational approaches were validated and compared with previous experiments. Based on the benchmark of available inhibitors of Hsp90, the GOLD docking package using the ChemPLP scoring function was found to be superior over both Autodock Vina and Autodock4 in the preliminary estimation of the ligand-binding affinity and binding pose with the Pearson correlation, R = -0.62. Moreover, FPL calculations were also indicated as a suitable approach to refine docking simulations with a correlation coefficient with the experimental data of R = -0.81. Therefore, the binding affinity of marine fungi derivatives to Hsp90 was evaluated. Docking and FPL calculations suggest that five compounds including 23, 40, 46, 48, and 52 are highly potent inhibitors for Hsp90. The obtained results enhance cancer therapy research.

Chondroitin sulfate-hybridized zein nanoparticles for tumor-targeted delivery of docetaxel.

Chondroitin sulfate-hybridized zein nanoparticles (zein/CS NPs) were developed for targeted delivery of docetaxel, which exhibited mean diameters of 157.8 ± 3.6 nm and docetaxel encapsulation efficiency of 64.2 ± 1.9 %. Docetaxel was released from the NPs in a sustained manner (∼72 h), following first-order kinetics. The zein/CS NPs showed improved colloidal stability, maintaining the initial size in serum for 12 h. The pre-treatment of CS reduced the uptake efficiency of the NPs by 23 % in PC-3 cells, suggesting the involvement of CD44-mediated uptake mechanism. The NPs showed 2.79-fold lower IC50 values than free docetaxel. Enhanced tumor accumulation of the NPs was confirmed in PC-3 xenograft mice by near-infrared fluorescence imaging (35.3-fold, versus free Cy5.5). The NPs exhibited improved pharmacokinetic properties (9.5-fold longer terminal half-life, versus free docetaxel) and anti-tumor efficacy comparable to Taxotere with negligible systemic toxicity, suggesting zein/CS NPs could be a promising nanoplatform for targeted cancer therapy.

Association of mitochondrial DNA content and displacement loop region sequence variations with cancer-related fatigue in breast cancer survivors receiving chemotherapy.

Cancer-related fatigue (CRF) is characterized by a lack of energy, and mitochondrial dysfunction is postulated to contribute to its etiology. This prospective cohort study assesses the self-reported fatigue levels of early-stage breast cancer patients using the validated Multi-Dimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) and blood samples drawn at three time points: before treatment, approximately 6 weeks, and 12 weeks after the initiation of chemotherapy. The aim of this study is to evaluate mitochondrial measures with CRF, over the course of chemotherapy using mitochondrial DNA (mtDNA content) and displacement loop (D-loop) region sequence variations at nucleotide positions 303, 489 and 514. The relative mtDNA copy number was determined via real-time quantitative polymerase chain reaction and compared between study time points and D-loop sequence variants. The association of mtDNA content with MFSI-SF total and sub-domain scores was analyzed in a sample of 155 patients (mean age ± SD: 51.7 ± 8.8 years). The median mtDNA content decreased over 12 weeks after the initiation of chemotherapy (p < 0.001). Baseline mtDNA content was lower for nucleotide position 303 in sequence variations than for the reference sequence (67.2 copies vs 79.1 copies, p = 0.03). Physical fatigue negatively correlated with mtDNA content in both unadjusted (ß = -0.0075, p = 0.048) and adjusted models (ß = -0.0062, p = 0.042), accounting for age, anxiety, insomnia, haemoglobin levels and body mass index. Our findings add to the literature indicating that mitochondrial function serves as an important target for mitigating CRF.

Chemotherapy-associated cognitive impairments in Korean cancer patients: Risk factors and functional outcome.

OBJECTIVE: To identify those experiencing significant self-reported cognitive decline over 2 time points during chemotherapy, examine the risk factors for cognitive decline, and examine differences between those with and without significant decline in functional limitations. METHODS: This secondary analysis used data from 163 cancer patients, collected from a Korean University hospital. Significant decline was determined by 15% or more reduction from baseline in the Functional Assessment of Cancer Therapy-Cognitive Function. Multivariate logistic regression was performed to estimate risk factors. Repeated-measures ANOVA and t tests tested differences in groups with and without cognitive decline in cognitive impairment and functional limitation. RESULTS: About 31% (n = 51) experienced significant cognitive decline. Groups with and without decline significantly differed in cognitive-impairment changes over time (F = 238.49, P < .001) and in functional limitations at follow-up (t test, P < .01). Those experiencing increased fatigue over time (odds = 0.94, P < .05) and those who underwent 2 or more cycles between time 1 and 2 (odds = 2.61; P < .05) had higher risk of significant decline over time during chemotherapy. CONCLUSION: Significant cognitive decline occurred during active chemotherapy; attention to cognitive impairment should be given in the early phase of chemotherapy.

Prediction of Methionine and Homocysteine levels in Zucker diabetic fatty (ZDF) rats as a T2DM animal model after consumption of a Methionine-rich diet.

BACKGROUND: Although alterations in the methionine metabolism cycle (MMC) have been associated with vascular complications of diabetes, there have not been consistent results about the levels of methionine and homocysteine in type 2 diabetes mellitus (T2DM). The aim of the current study was to predict changes in plasma methionine and homocysteine concentrations after simulated consumption of methionine-rich foods, following the development of a mathematical model for MMC in Zucker Diabetic Fatty (ZDF) rats, as a representative T2DM animal model. METHOD: The model building and simulation were performed using NONMEM® (ver. 7.3.0) assisted by Perl-Speaks-NONMEM (PsN, ver. 4.3.0). Model parameters were derived using first-order conditional estimation method with interactions permitted among the parameters (FOCE-INTER). NCA was conducted using Phoenix (ver. 6.4.0). For all tests, we considered a P-value < 0.05 to reflect statistical significance. RESULTS: Our model featured seven compartments that considered all parts of the cycle by applying non-linear mixed effects model. Conversion of S-adenosyl-L-homocysteine (SAH) to homocysteine increased and the metabolism of homocysteine was reduced under diabetic conditions, and consequently homocysteine accumulated in the elimination phase.Using our model, we performed simulations to compare the changes in plasma methionine and homocysteine concentrations between ZDF and normal rats, by multiple administrations of the methionine-rich diet of 1 mmol/kg, daily for 60 days. The levels of methionine and homocysteine were elevated approximately two- and three-fold, respectively, in ZDF rats, while there were no changes observed in the normal control rats. CONCLUSION: These results can be interpreted to mean that both methionine and homocysteine will accumulate in patients with T2DM, who regularly consume high-methionine foods.

Association of mitochondrial DNA content in peripheral blood with cancer-related fatigue and chemotherapy-related cognitive impairment in early-stage breast cancer patients: a prospective cohort study.

PURPOSE: Cancer-related fatigue (CRF) and chemotherapy-related cognitive impairment (CRCI) are reported to be associated with mitochondrial dysfunction. Hence, mitochondrial DNA (mtDNA) content, a biomarker of mitochondrial dysfunction, is hypothesized to correlate with the onset of CRF and CRCI. This study aims to evaluate the association between peripheral blood mtDNA content reduction and severity of CRF and CRCI in patients receiving chemotherapy. METHODS: This was a prospective cohort study. Early-stage breast cancer patients receiving anthracycline- or taxane-based chemotherapy were recruited. CRF was assessed using MFSI-SF, and CRCI was assessed using FACT-Cog and CANTAB at two timepoints: baseline (T1; prior to treatment) and 6 weeks after initiation of treatment (T2). mtDNA content was measured at both timepoints using real-time quantitative polymerase chain reaction. Multiple logistic regression was utilized to evaluate the association between mtDNA reduction and worsening of CRF and CRCI, adjusting for age, anxiety, insomnia, plasma cytokines concentrations, and other clinically important covariates. RESULTS: A total of 108 patients (age 52.0 ± 9.2 years; 82.4% Chinese; 64.8% receiving anthracycline-based chemotherapy) were recruited. Proportions of patients with worsening of CRF increased from the lower to the upper quartiles of mtDNA reduction (22.2, 33.3, 55.6, and 63.0% in quartiles 1, 2, 3, and 4, respectively, p = 0.001 for trend). Reduction of mtDNA content was significantly greater among those with worsening of CRF and CRCI compared to those without CRF [mean reduction (± SD): 36.5 (46.1) vs. 9.4 (34.5), p < 0.001]. After adjusting for covariates, every 1-unit reduction of the mtDNA content was associated with a 4% increased risk for worsening of CRF (95% CI, 1-6%; p = 0.009). CONCLUSIONS: This is the first study to show that the reduction of mtDNA content in peripheral blood is associated with the onset of CRF in patients receiving chemotherapy. Further validation studies are required to confirm the findings.

Psychometric properties and measurement equivalence of the Multidimensional Fatigue Syndrome Inventory- Short Form (MFSI-SF) amongst breast cancer and lymphoma patients in Singapore.

BACKGROUND: Currently, several fatigue measurement instruments are available to evaluate and measure cancer-related fatigue. Amongst them, Multidimensional Fatigue Syndrome Inventory-Short Form (MFSI-SF) is a self-reported instrument and a multidimensional scale that aims to capture the global, somatic, affective, cognitive and behavioural symptoms of fatigue. This study examines the psychometric properties and measurement equivalence of the English and Chinese versions of MFSI-SF in breast cancer and lymphoma patients in Singapore. METHODS: Patients were recruited from National Cancer Centre Singapore. Validity, reliability and responsiveness of MFSI-SF were evaluated in this study. Convergent validity was evaluated by correlating total and subscales of MFSI-SF to known related constructs in EORTC QLQ-C30. Known group validity was assessed based on patients' cancer stage, pain, insomnia and depression symptoms. Reliability was evaluated by Cronbach's α. Responsiveness analyses were performed with patients who have undergone at least one cycle of chemotherapy. Multiple regression was used to compare the total and subscale scores of MSFI-SF between the two language versions. RESULTS: Data from 246 (160 English and 86 Chinese version) breast cancer and lymphoma patients were included in the study. Moderate to high correlations were observed between correlated MFSI-SF subscales and EORTC QLQ-C30 domains (|r| = 0.524 to 0.774) except for a poor correlation (r = 0.394) observed between MFSI-SF vigour subscale and EORTC QLQ-C30 role functioning subscale. Total MFSI-SF scores could differentiate between patients with higher depression, pain and insomnia status. Internal consistency of MFSI-SF was also high (α = 0.749 to 0.944). Moderate correlation was observed between change in total MFSI-SF score and change in fatigue symptom scale score and global QoL score on EORTC QLQ-C30 (|r| = 0.478 and 0.404 respectively). Poor correlations were observed between change in scores of hypothesised subscales (|r| = 0.202 to 0.361) except for a moderate correlation between change in MFSI-SF emotional fatigue score and change in EORTC QLQ-C30 emotional functioning domain score. Measurement equivalence was established for all subscales and total MFSI-SF score except for the emotional and vigour subscales. CONCLUSIONS: This study supports the use of MFSI-SF as a reasonably valid scale with good internal consistency for measuring fatigue levels in the Singapore cancer population.

Minimal Clinically Important Difference of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF) for Fatigue Worsening in Asian Breast Cancer Patients.

CONTEXT: The minimal clinically important difference (MCID) of the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), a questionnaire that measures cancer-related fatigue, has not been established in patients with cancer. OBJECTIVES: This study aims to determine the MCID of the MFSI-SF. METHODS: Breast cancer patients completed the MFSI-SF and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC-QLQ-C30) before chemotherapy and at least three weeks later. The EORTC-QLQ-C30 fatigue scale (EORTC-FA) was used as an anchor, and a receiver operating characteristic (ROC) curve was also used to identify the optimal MCID cut-off for fatigue deterioration. A distribution-based approach used one-third of the SD, half of the SD, and one SEM of the total MFSI-SF score to determine the MCID. RESULTS: A total of 201 patients were analyzed. Change scores of the MFSI-SF and EORTC-FA were moderately correlated (r = 0.47, P < 0.001). The EORTC-FA-anchored MCID was 8.69 points (95% CI: 4.03-13.34). The MCID attained from the ROC curve method was 4.50 points (sensitivity: 68.8%; specificity: 64.1%). For the distribution-based approach, the MCIDs corresponding to one-third of the SD, half of the SD, and one SEM were 5.39, 8.99, and 10.79 points, respectively. CONCLUSION: The MCID of the MFSI-SF identified by all approaches ranged from 4.50 to 10.79 points. The MCID can be used to interpret the clinical significance of fatigue deterioration in patients with breast cancer and to determine sample sizes for future clinical trials.

Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study.

BACKGROUND: Preliminary evidence suggests that changes in plasma brain-derived neurotrophic factor (BDNF) levels may contribute to the occurrence of chemotherapy-associated cognitive impairment (CACI), and a previous study suggested that carriers of the BDNF Met homozygous genotype are protected from CACI. METHODS: This multicenter, prospective cohort study involved chemotherapy-receiving early-stage breast cancer (ESBC) patients. Self-perceived cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) across three time points: Prior to chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). Plasma BDNF levels were quantified using enzyme-linked immunosorbent assay. Genotyping was performed using Sanger Sequencing. RESULTS: A total of 51 chemotherapy-receiving ESBC patients (mean age: 52.6 ± 9.5 years) were recruited, and 11 patients (21.6%) reported subjective cognitive impairment post-chemotherapy. Overall, there was a reduction in median plasma BDNF levels over time (T1: 5423.0 pg/ml; T2: 5313.6 pg/ml; T3: 4050.3 pg/ml; p < 0.01). After adjusting for confounding factors, longitudinal analysis revealed that BDNF levels were associated with self-reported concentration deficit (p = 0.032). Carriers of Val/Val (p = 0.011) and Val/Met (p = 0.003) BDNF genotypes demonstrated a significant reduction in plasma BDNF levels over time; however, plasma BDNF levels were similar across all time points among Met homozygous carriers (p = 0.107). CONCLUSION: There was a statistically significant change in BDNF levels post-chemotherapy in ESBC patients, and plasma BDNF levels were associated with self-perceived concentration deficit in patients receiving chemotherapy.

Perceptions and Barriers of Survivorship Care in Asia: Perceptions From Asian Breast Cancer Survivors.

PURPOSE: With the long-term goal to optimize post-treatment cancer care in Asia, we conducted a qualitative study to gather in-depth descriptions from multiethnic Asian breast cancer survivors on their perceptions and experiences of cancer survivorship and their perceived barriers to post-treatment follow-up. METHODS: Twenty-four breast cancer survivors in Singapore participated in six structured focus group discussions. The focus group discussions were voice recorded, transcribed verbatim, and analyzed by thematic analysis. RESULTS: Breast cancer survivors were unfamiliar with and disliked the term "survivorship," because it implies that survivors had undergone hardship during their treatment. Cognitive impairment and peripheral neuropathy were physical symptoms that bothered survivors the most, and many indicated that they experienced emotional distress during survivorship, for which they turned to religion and peers as coping strategies. Survivors indicated lack of consultation time and fear of unplanned hospitalization as main barriers to optimal survivorship care. Furthermore, survivors indicated that they preferred receipt of survivorship care at the specialty cancer center. CONCLUSION: Budding survivorship programs in Asia must take survivor perspectives into consideration to ensure that survivorship care is fully optimized within the community.

Impact of TNF-α (rs1800629) and IL-6 (rs1800795) Polymorphisms on Cognitive Impairment in Asian Breast Cancer Patients.

OBJECTIVE: Expression of pro-inflammatory cytokines is influenced by single nucleotide polymorphisms (SNPs) in the promoter regions of the pro-inflammatory cytokine genes, and cytokines are associated with the occurrence of post-chemotherapy cognitive impairment. Hence, the aim of this study was to evaluate the associations between two common pro-inflammatory cytokine gene polymorphisms namely, IL6-174 (rs1800795 G>C) and TNF-308 (rs1800629 G>A), and chemotherapy-associated cognitive impairment (CACI) among Asian early-stage breast cancer patients. In addition, the differential effect of these SNPs on plasma IL-6 and TNF-α levels, and the associations of plasma IL-6 and TNF-α levels with CACI were also assessed. METHODS: Asian early-stage breast cancer patients (Stage I to III) receiving chemotherapy were prospectively recruited from two cancer centers in Singapore. Patients' cognitive function was longitudinally assessed using the validated FACT-Cog (ver. 3) and an objective computerized battery, Headminder™ at three-time points. Plasma IL-6 and TNF-α levels were analyzed using the multiplex immunoassay, and genotyping was performed using Sanger sequencing. Regression analyses and generalized estimating equation were utilized for statistical analysis. RESULTS: A total of 125 patients were included (mean age: 50.3; Chinese: 80.8%; post-menopausal: 48.0%; 68.0% received anthracycline-based chemotherapy). 36.8% patients experienced self-perceived cognitive impairment, detected in memory (32.8%) and attention (34.2%) domains. Patients with higher levels of anxiety (p<0.001) and insomnia (p = 0.003) also reported more self-perceived cognitive impairment. Higher plasma concentrations of IL-6 were associated with greater severity of self-perceived cognitive impairment (p = 0.001). Polymorphisms of cytokine genes were not associated with expression of plasma cytokines. CONCLUSION: Present findings further contribute to the growing evidence that supports the role of the pro-inflammatory cytokine IL-6 in the occurrence of cognitive impairment post-chemotherapy. However, genetic polymorphism of these cytokines did not play a major role to the cytokine fluctuations as well as cognitive impairment in this cohort. With an increasing evidence to support the cytokine hypothesis, future studies should investigate the role of anti-inflammatory agents in mitigating the cognitive impairment associated with chemotherapy.

BSA and ABCB1 polymorphism affect the pharmacokinetics of sunitinib and its active metabolite in Asian mRCC patients receiving an attenuated sunitinib dosing regimen.

PURPOSE: An attenuated dosing (AD) sunitinib regimen of 37.5 mg daily has been suggested to reduce the toxicity reported with the standard dosing regimen to metastatic renal cell carcinoma (mRCC) patients. The aim of this study was to characterize the population pharmacokinetic (PK) properties of sunitinib and SU12662, the active metabolite, in patients receiving the AD regimen and to ascertain significant covariates influencing PK parameters. METHODS: Thirty-one mRCC patients receiving AD sunitinib regimen were included. Plasma samples were collected on day 29 of each treatment cycle after the start of the therapy. Nonlinear mixed-effects modeling was applied to estimate the population PK properties of sunitinib and SU12662 as well as the effect of covariates on PK parameters. Monte Carlo simulation was also performed to predict the total trough level (TTL) of sunitinib and SU12662. RESULTS: Sunitinib population means for CL/F and V d /F central were 13.8 L/h and 1720 L, respectively. SU12662 population means for CL/F and V d /F were 42.1 L/h and 1410 L, respectively. Body surface area (BSA) and ABCB1 polymorphism significantly influenced the CL/F variability of sunitinib: CL/F parent = 13.8 × exp((BSA - 1.75) × 2.08 + (ABCB1 genotype - 0.67) × 0.61), ABCB1-0: wild genotype, 1: mutant genotype. The effect size of ABCB1 mutant genotype and BSA greater than 1.75 m(2) in relation to sunitinib clearance was 31.14 % (p = 0.006) and 22.11 % (p = 0.011), respectively, relative to the reference group. CONCLUSIONS: Adjusting doses of sunitinib according to BSA and ABCB1 polymorphism in Asian mRCC patients may be recommended for sufficient attainment of a target TTL of sunitinib and its metabolite.

A novel HPLC-MS/MS method for the simultaneous determination of astemizole and its major metabolite in dog or monkey plasma and application to pharmacokinetics.

Astemizole (AST), a second-generation antihistamine, is metabolized to desmethyl astemizole (DEA), and although it has been removed from the market for inducing QT interval prolongation, it has reemerged as a potential anticancer and antimalarial agent. This report describes a novel high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method for simultaneously determining the concentrations of AST and DEA in beagle dog and cynomolgus monkey plasma with simple preparation method and short retention time. Prior to HPLC analyses, the plasma samples were extracted with simple liquid-liquid extraction method. The isocratic mobile phase was 0.025% trifluoroacetic acid (TFA dissolved in acetonitrile) and 20 mM ammonium acetate (94:6) at a flow rate of 0.25 mL/min and diphenhydramine used as internal standard. In MS/MS analyses, precursor ions of the analytes were optimized as protonated molecular ions: [M+H](+). The lower limit of quantification of astemizole was 2.5 ng/mL in both species and desmethyl astemizole were 7.5 ng/mL and 10 ng/mL in dog and monkey plasma, respectively. The accuracy, precision, and stability of the method were in accordance with FDA guidelines for the validation of bioanalytical methods. Finally this validated method was successfully applied to a pharmacokinetic study in dogs and monkeys after oral administration of 10 mg/kg AST.