Synergistic Ratio Research Articles

CPX-351 Exposure-Response Based on Cumulative Dose of Cytarabine and Daunorubicin in Patients with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

▪CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio. Intact CPX-351 liposomes containing the synergistic ratio are taken up by leukemia cells to a greater extent versus normal bone marrow cells, have a high retention of drug cargo, and have a long plasma half-life. In a phase 3 study in older adults with newly diagnosed, treatment-related AML or AML with myelodysplasia-related changes, CPX-351 demonstrated significantly improved overall survival and response rates compared with conventional 7+3 chemotherapy and a safety profile consistent with that of 7+3. Cumulative lifetime exposure to daunorubicin is associated with risks of cardiotoxicity. Therefore, it was of interest to determine if the superior efficacy observed with CPX-351 versus 7+3 was achieved with lower cumulative doses of cytarabine and daunorubicin relative to 7+3. An exposure-response analysis was conducted to document the relationships of cumulative doses of cytarabine and daunorubicin with efficacy outcomes for CPX-351 versus 7+3 therapy.Efficacy and cumulative exposure data were obtained from the phase 3 study CLTR0310-301 (NCT01696084), in which patients were randomized 1:1 to receive CPX-351 or 7+3 induction therapy. Cumulative dose corresponded to the total amount of drug (mg of cytarabine or daunorubicin) administered to an individual patient during the entire time that patient remained on the study. The clinical endpoints for efficacy were overall survival, complete remission (CR), and CR + CR with incomplete hematologic recovery (CR+CRi).A total of 309 patients were enrolled in the study; the exposure-response analysis for cumulative dose included 153 patients treated with CPX-351 and 149 patients treated with 7+3. Baseline characteristics were generally similar between the CPX-351 and 7+3 cohorts. In the overall study population, median duration of the treatment was 62 days in the CPX-351 arm and 41 days in the 7+3 arm. The most common reason for discontinuation among patients included in this analysis was lack of efficacy, but the incidence was lower for the CPX-351 cohort (34.6%) than for the 7+3 cohort (49.0%). In the exposure-response analysis for overall survival, patients treated with CPX-351 who were alive at the data cut-off time for the primary endpoint analysis (n = 47) tended to have received less cytarabine and daunorubicin than those treated with 7+3 (n = 23). The mean cumulative doses of cytarabine and daunorubicin for patients alive in the CPX-351 cohort were 61.9% and 76.8%, respectively, of cumulative doses for patients alive in the 7+3 cohort (Table). Among responders classified as achieving a CR or CR+CRi, those treated with CPX-351 tended to receive less cytarabine and daunorubicin than those treated with 7+3 chemotherapy. The mean cumulative doses of cytarabine and daunorubicin for patients who achieved a CR in the CPX-351 cohort were 26.5% and 63.2%, respectively, of cumulative doses for patient with CR in the 7+3 cohort, and the mean cumulative doses for patients who achieved a CR+CRi in the CPX-351 cohort were 36.2% and 65.1%, respectively, of those with CR+CRi in the 7+3 cohort (Table). For non-responders or deceased patients, the mean cumulative doses of cytarabine and daunorubicin similarly tended to be lower in patients who received CPX-351 than in those who received 7+3 therapy. The finding that a lower cumulative dose of cytarabine and daunorubicin in CPX-351 relative to standard 7+3 therapy led to improved efficacy and increased on-target myelosuppression supports the observation in animal models that CPX-351 is taken up in the bone marrow by leukemia cells to a greater extent than normal cells.Taken together, the results of this exposure-response analysis show that the mean cumulative doses of cytarabine and daunorubicin associated with an overall survival benefit were lower with CPX-351 than with 7+3, as were the mean cumulative doses associated with achieving a CR or CR+CRi. Thus, compared with 7+3, CPX-351 was associated with improved efficacy at a reduced total drug burden in this population of older adults with newly diagnosed, treatment-related AML or AML with myelodysplasia-related changes. [Display omitted] DisclosuresBanerjee:Celator/Jazz: Employment, Equity Ownership. Wang:Celator/Jazz: Employment, Equity Ownership. Wang:Celator/Jazz: Consultancy. Gibbons:Celator/Jazz: Employment, Equity Ownership.

Rates of Adverse Events per Patient-Year in a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

Rates of Adverse Events per Patient-Year in a Randomized, Phase 3 Study of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed, Treatment-Related Acute Myeloid Leukemia (AML) or AML with Myelodysplasia-Related Changes

CPX-351 Population Pharmacokinetics in Patients with Hematologic Malignancies

CPX-351, a dual-drug liposomal encapsulation of cytarabine and daunorubicin at a synergistic ratio, demonstrated significant survival benefit versus the conventional 7+3 regimen of cytarabine/daunorubicin in patients with secondary acute myeloid leukemia. A population pharmacokinetic (PK) analysis of total (ie, encapsulated + unencapsulated drug) plasma concentrations of cytarabine and daunorubicin following IV administration of CPX-351 assessed sources of variability in PK and determined if covariate-based dose adjustments may be warranted, particularly in patients with renal or hepatic impairment.The PK population consisted of 195 patients with advanced hematologic malignancies. The median age was 67 years (range: 24-81) and body weight was 79.8 kg (range: 38.9-156.5). There were 119 (61.0%) male and 76 (39.0%) female patients, mainly of white race (84.6%). A total of 83 (42.6%) patients had normal renal function (creatinine clearance [CrCL] ≥90 mL/min), 83 (42.6%) had mild renal impairment (CrCL 60-89 mL/min), 28 (14.4%) had moderate renal impairment (CrCL 30-59 mL/min), and 1 (0.5%) had severe renal impairment (CrCL 15-29 mL/min). The majority (n = 179 [91.8%]) of patients had bilirubin <1.2 mg/dL; the rest (n = 16 [8.2%]) had bilirubin between 1.2-3 mg/dL. No patient had end-stage renal disease or bilirubin >3 mg/dL, as expected since these patients are not usually considered fit for intensive chemotherapy.Nonlinear mixed-effect modeling was performed using NONMEM. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and pertinent graphical representations of goodness-of-fit. Model validation/qualification was performed according to FDA and EMA guidelines for industry. Separate PK models were developed for cytarabine and daunorubicin, and intrinsic and extrinsic factors were evaluated as covariates. Intrinsic factors included body weight, body mass index, age, sex, race, white blood cell count, and markers of renal function (CrCL and serum creatinine) and hepatic function (bilirubin, aspartate and alanine aminotransferases, and alkaline phosphatase). The extrinsic factors were first dose amount, clinical study, and formulation.The base PK models for cytarabine and daunorubicin used 2-compartment structural models, with drug input into the central compartment, first-order distribution between the central and peripheral compartments, and first-order elimination from the central compartment. Two-compartment structural models with body surface area (BSA) as an allometric scalar provided minimum bias in estimates of systemic clearance (CL) and volume of distribution for the central compartment (Vc).Based on the final population PK model for cytarabine, a typical patient with BSA of 1.95 m2 receiving 100 units/m2 CPX-351 (100 mg/m2 cytarabine + 44 mg/m2 daunorubicin) is expected to have CL of 0.106 L/h with between-subject variability (BSV) of 70.5%, a Vc value of 5.12 L with BSV of 29.7%, and a peripheral volume of distribution (Vp) value of 0.214 L with BSV of 80.5%. Total volume of distribution (Vd = Vc + Vp) is predicted to be 5.33 L. The predicted half-lives associated with the distribution and elimination phases are 20.7 and 37.1 hours, respectively. The final population PK model for daunorubicin predicted a typical patient receiving the lyophilized formulation will have a CL value of 0.145 L/h with BSV of 49.4%, a Vc value of 4.34 L with BSV of 24.1%, and a Vp value of 0.523 L with BSV of 80.5%. Vd is predicted to be 4.86 L. The half-lives associated with the distribution and elimination phases are predicted to 11.1 and 26.2 hours, respectively.All covariates were eventually excluded from the population PK models, except dose and formulation, which had a small effect on PK and are not expected to result in detectable changes in clinical safety or efficacy. The PK of total cytarabine and daunorubicin were unaltered in patients with mild or moderate renal impairment (30 mL/min ≤ CrCL ≤ 89 mL/min). The potential effects of severe renal impairment could not be determined. Furthermore, the PK of total cytarabine and daunorubicin were unaltered in patients with serum bilirubin ≤3 mg/dL. In conclusion, the results of the population PK analysis indicated that dose adjustments of CPX-351 are not warranted for mild or moderate renal impairment or serum bilirubin up to 3 mg/dL. DisclosuresWang:Celator/Jazz: Employment, Equity Ownership. Banerjee:Celator/Jazz: Employment, Equity Ownership. Vasilinin:Celator/Jazz: Consultancy. Marier:Celator/Jazz: Consultancy. Gibbons:Celator/Jazz: Employment, Equity Ownership.

Cost-Effectiveness of CPX-351 Versus 7+3 Regimen in the Treatment of Treatment-Related Acute Myeloid Leukemia (tAML) or AML with Myelodysplasia-Related Changes (MRC)

CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic drug ratio. In a phase 3 trial (NCT01696084) in elderly patients with newly diagnosed tAML or AML-MRC, CPX-351 demonstrated superior overall survival (9.56 vs 5.95 months; HR = 0.69; P= 0.005) and significantly improved complete remission rate (38% vs 26%; P= 0.040) compared to the 7+3 regimen of cytarabine and daunorubicin, the current standard of care for remission induction. These clinical improvements may increase the cost of caring for patients with AML through higher drug costs, increased numbers of patients receiving hematopoietic cell transplant (HCT), and the costs of disease management during extended survival. In an era of increased scrutiny of drug costs and health care budgets, it is essential to understand the balance of clinical benefits and costs associated with treatment of AML using CPX-351.A health economic model with a lifetime time horizon was developed comparing the costs and outcomes of CPX-351 to those of 7+3 in the treatment of AML from the perspective of a US commercial payer. The model was developed in accordance with good modeling practice guidelines and recommendations of the US Second Panel on Cost-Effectiveness in Health and Medicine. The model considered a patient population stratified by age and AML subtype based on the CPX-351 phase 3 clinical trial design. Within each subpopulation, patients were distributed among potential treatment pathways in accordance with observed trial data. Treatment pathways in the model were defined in terms of whether or not patients responded following induction and whether or not patients received an HCT. The numbers of induction and consolidation cycles were also tracked. The model then projected overall and event-free survival over patients' lifetimes based on the patients' characteristics and treatment pathways using statistical extrapolation of observed data from the clinical trial. Specifically, for each treatment pathway, a parametric survival function was fit to the observed data with patient characteristics, treatment arm, cycles of induction, and cycles of consolidation included as risk factors. These survival functions were then applied in the model for each subpopulation and summed to estimate the overall clinical outcomes for the full population. Costs of drugs were assigned based on published sources for 7+3 and manufacturers' estimates for CPX-351. Costs of non-pharmaceutical management were estimated based on DRG coding and published literature. Quality of life at different disease stages was assessed using the time trade-off method in vignette-based interviews.We found that treatment with CPX-351 was projected to provide an additional 1.9 years of life compared to 7+3 (2.8 vs 0.9 years, respectively). These gains reflected shifts among the treatment pathways, particularly a larger fraction of patients receiving HCT with CPX-351 than with 7+3, and longer survival within pathways among patients who responded to induction therapy. While the CPX-351 treatment arm demonstrated increased numbers of responders, non-responders had no difference in outcomes between the arms in the model. When accounting for the quality of life of patients with different stages of AML, the additional life years were equivalent to an incremental increase of 1.02 quality-adjusted life years (QALYs) compared to 7+3. Patients in the CPX-351 arm incurred a total incremental cost of $113,658 compared to 7+3, primarily due to pharmacy costs and costs associated with the larger number of HCTs. Taken together, these costs and improved clinical outcomes yield an incremental cost-effectiveness ratio (ICER) of $111,385/QALY gained over 7+3.These results suggest a favorable balance between the clinical gains and incremental costs of treatment with CPX-351 versus the 7+3 standard of care and demonstrate that CPX-351 is a cost-effective option in the treatment of patients with tAML or AML-MRC. DisclosuresKansal:Celator/Jazz: Consultancy. Du:Celator/Jazz: Consultancy. Herrera-Restrepo:Celator/Jazz: Consultancy. Leipold:Celator/Jazz: Consultancy. Ryan:Celator/Jazz: Employment, Equity Ownership. Louie:Celator/Jazz Pharmaceuticals, Inc.: Employment, Equity Ownership, Patents & Royalties. Chung:Bayer: Equity Ownership; Amgen: Equity Ownership; Baxalta: Equity Ownership; Gilead: Employment; Shire: Equity Ownership; Baxter: Equity Ownership; Gilead: Equity Ownership; Jazz Pharmaceuticals: Employment, Equity Ownership.

Budget Impact Analysis of CPX-351 in the Treatment of Patients with Treatment-Related Acute Myeloid Leukemia (tAML) or AML with Myelodysplasia-Related Changes (MRC) from a US Payer Perspective

AML is a rapidly progressing and life-threatening blood cancer that disproportionately affects older adults. The treatment paradigm in AML has seen little change in the past 4 decades, with intensive chemotherapy with a 7-day continuous infusion of cytarabine plus an anthracycline such as daunorubicin on Days 1-3 (ie, “7+3” regimen) remaining the standard-of-care induction therapy for AML. CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that delivers a synergistic drug ratio into leukemia cells. In a phase 3 study (NCT01696084), CPX-351 demonstrated superior overall survival (9.56 vs 5.95 months; HR = 0.69; P= 0.005) and significantly improved complete remission rate (38% vs 26%; P= 0.040) compared with 7+3 in the treatment of elderly patients with newly diagnosed tAML or AML-MRC (Lancet JE, et al. ASCO 2016. Abstr 7000). Additionally, CPX-351 is administered as a 90-minute infusion on Days 1, 3, and 5 (induction cycle 1 only), and offers the potential for outpatient administration. The aim of this study was to estimate the budget impact associated with the introduction of CPX-351 for the treatment of patients with tAML or AML-MRC from a US payer perspective.A decision analytic model was developed to estimate the budget impact of using CPX-351 compared with 7+3 for induction and consolidation treatment of AML patients with tAML and AML-MRC. The decision algorithm was developed based on clinical practice guidelines from the National Comprehensive Cancer Network and validated by an oncologist. Epidemiology estimates were from SEER 2017. Clinical outcomes (response rate and incidence of adverse events [AE]) and site of care were from the CPX-351 phase 3 pivotal trial. In that study, CPX-351 was administered in the outpatient setting for 51% of patients in consolidation cycle 1 and 61% in cycle 2, compared with 6% and 0% of 7+3 patients in consolidation cycles 1 and 2 (Kolitz JE, et al. ASCO 2017. Abstr 7036). Administration costs were from CMS for Medicare and InGauge Healthcare Solutions for commercial costs. Hospital costs were from the CMS Limited Data Set. H-CUP National Inpatient Sample was used to estimate the AE costs by payer type. Drug costs were wholesale acquisition costs. The model did not include costs for hematopoietic cell transplant.For a hypothetical 1 million-member plan, it is estimated that there are approximately 12 patients with tAML and AML-MRC each year. Increasing the use of CPX-351 from year 1 to 3 (assumption of year 1 = 20%, year 2 = 50%, and year 3 = 80%) resulted in cost increases compared with 7+3 (year 1 = $7,471 to year 3 = $29,884, or <$0.01 per member per month increase in each year). Over the same time period, the estimated number of responders increased from 3.06 with 7+3 to 4.19 with CPX-351. The increased level of responses with CPX-351 reduced the cost/responder from $358,695 with 7+3 to $269,106 by year 3 following introduction of CPX-351. Of note, outcomes are derived from a phase 3 randomized, controlled trial of CPX-351 versus 7+3, the model did not account for potential regimen changes, and costs may not be generalizable across all settingsThis model predicted that the use of CPX-351 may be associated with improved patient outcomes and limited budget impact from the payer perspective. DisclosuresJensen:Celator/Jazz: Consultancy. Wu:Celator/Jazz: Consultancy. Sacks:Celator/Jazz: Consultancy. Cyr:Celator/Jazz: Consultancy. Chung:Baxter: Equity Ownership; Shire: Equity Ownership; Baxalta: Equity Ownership; Amgen: Equity Ownership; Gilead: Equity Ownership; Bayer: Equity Ownership; Gilead: Employment; Jazz Pharmaceuticals: Employment, Equity Ownership.

Evaluation of photodynamic effect of Indocyanine green (ICG) on the colon and glioblastoma cancer cell lines pretreated by cold atmospheric plasma

BackgroundCold Atmospheric Plasma (CAP) has been proposed as a new approach based on its anticancer potential. However, its biological effects in combination with other physical modalities may also enhance efficiency and expand the applicability of the CAP method Photodynamic Therapy (PDT) may be improved by the use of indocyanine green (ICG) photosensitizer with absorption wavelength in the near infrared region to allow for deeper treatment depth.. In this study, the effectiveness of cold atmospheric helium plasma (He-CAP) as a pretreatment on the efficiency of ICG mediated PDT was investigated. Methods and materialFirst, toxicity of different concentrations of ICG on HT-29 and U-87MG cell lines was examined for 24 h. IC10 and IC30 of ICG were determined and then cells were treated with this ICG concentrations with different plasma radiation doses and light exposures for 48 h. Finally, MTT assay was performed for all treatment groups. The experiments were repeated at least 4 times at each group for two cell lines, separately. In order to compare the results, several indicators such as treatment efficiency, synergistic ratio, and the amount of optical exposure required for 50% cell death (ED50) were also defined. Finally, SPSS 20 software is used for statistical analysis of data. ResultsPretreatment with CAP could significantly reduce cell survival in both cell lines (P<0.05). Also concentrations, irradiation time with CAP, and appropriate light exposure in both cell lines increased therapeutic efficiency compared to either treatment alone (P<0.05). While increasing the efficiency of photodynamic therapy varied between the two cell lines, the improvement in the PDT process was demonstrated by pretreatment with CAP. ConclusionSynergistic effect in the cell death with PDT were observed following He-CAP treatment and the results indicated that pretreatment with He-CAP improves the efficiency of photodynamic therapy.

Low dose shikonin and anthracyclines coloaded liposomes induce robust immunogenetic cell death for synergistic chemo-immunotherapy

Chemo-immunotherapy based on immunogenic cell death (ICD) is a promising strategy for cancer therapy. However, the effective ICD requires a high dosage of ICD stimulus, which could be associated to a dose-dependent toxicity. Therefore, in this study, a liposome remote-loaded with shikonin (a potent ICD stimulus) was developed, with the ability to effectively induce ICD at high dosage in vivo. However, a hepatotoxic effect was observed. To circumvent this problem, shikonin was combined with the anthracycline mitoxantrone or doxorubicin to develop co-loaded liposomes inducing a synergistic ICD effect and cytotoxicity to tumor cells. Cytotoxicity and uptake experiment in vitro were performed to analyze the optimal synergistic ratio of shikonin and anthracyclines based on a “formulated strategy”. Interestingly, copper mediated co-loaded liposomes resulted in a pH and GSH dual-responsive release property. More importantly, pharmacokinetics and tumor biodistribution studies revealed an outstanding capacity of ratiometric delivery of dual drugs. Thus, the dual-loaded liposome enhanced the antitumor effect by the stimulation of a robust immune response at lower doses of the drugs with a higher safety compared to single-loaded liposomes. Summarized, the current work provided a reference for a rational design and development of liposomal co-delivery system of drugs and ICD-induced chemo-immunotherapy, and established a potential clinical application of shikonin-based drug combinations as a new chemo-immunotherapeutic strategy for cancer treatment.

Overexpression of ATP‐binding cassette transporters associated with sulfoxaflor resistance in Aphis gossypii glover

Sulfoxaflor is a new insecticide for controlling against Aphis gossypii in the field. ATP-binding cassette (ABC) transporters belong to a large superfamily of proteins and play an important role in the detoxification process. However, the potential role of ABC transporters in sulfoxaflor resistance in A. gossypii is unknown. In this study, an ABC transporter inhibitor, verapamil, dramatically increased the toxicity of sulfoxaflor in the resistant population with a synergistic ratio of 8.55. However, verapamil did not synergize sulfoxaflor toxicity in the susceptible population. The contents of ABC transporters were significantly increased in the Sul-R population. Based on RT-qPCR analysis, 10 of 23 ABC transcripts, ABCA1, ABCA2, ABCB1, ABCB5, ABCD1, ABCG7, ABCG16, ABCG26, ABCG27, and MRP7, were up-regulated in the Sul-R population compared to the Sus population. Meanwhile, inductive effects of ABCA1, ABCD1, ABCG7 and ABCG26 by sulfoxaflor were found in A. gossypii. Furthermore, knockdown of ABCA1 and ABCD1 using RNAi significantly increased the sulfoxaflor sensitivity in Sul-R aphids. These results suggested that ABC transporters, especially the ABCA1 and ABCD1 genes, might be related with sulfoxaflor resistance in A. gossypii. This study will promote further work to validate the functional roles of these ABCs in sulfoxaflor resistance and might be helpful for the management of sulfoxaflor-resistant A. gossypii.

Mechanism of metabolic resistance to pymetrozine in Nilaparvata lugens: over-expression of cytochrome P450 CYP6CS1 confers pymetrozine resistance.

Pymetrozine is commonly used for the control of Nilaparvata lugens, and resistance to pymetrozine has been frequently reported in the field populations in recent years. However, the mechanism of brown planthopper resistance to pymetrozine is still unknown. In this study, a pymetrozine-resistant strain (PMR) was established, and the potential biochemical resistance mechanism of N. lugens to pymetrozine was investigated. Pymetrozine was synergized by the inhibitor piperonyl butoxide (PBO) in the PMR with 2.83-fold relative synergistic ratios compared with the susceptible strain (Sus). Compared with the Sus, the cytochrome P450 monooxygenase activity of PMR was increased by 1.7 times, and two P450 genes (NlCYP6CS1 and NlCYP301B1) were found to be significantly overexpressed more than 6.0-fold in the PMR. Pymetrozine exposure induced upregulation of NlCYP6CS1 expression in the Sus, but the expression of NlCYP301B1 did not change significantly. In addition, RNA interference (RNAi)-mediated suppression of NlCYP6CS1 gene expression dramatically increased the toxicity of pymetrozine against N. lugens. Moreover, transgenic lines of Drosophila melanogaster expressing NlCYP6CS1 were less susceptible to pymetrozine, and had a stronger ability to metabolize pymetrozine. Taken together, our findings indicate that the overexpression of NlCYP6CS1 is one of the key factors contributing to pymetrozine resistance in N. lugens. And this result is helpful in proposing a management strategy for pymetrozine resistance.

Combination of Modified Atmosphere and Irradiation for the Phytosanitary Disinfestation of Trogoderma granarium Everts (Coleoptera: Dermestidae).

Simple SummaryThe khapra beetle is defined as one of the most important quarantine pests globally, and fumigating by methyl bromide, one of the ozone-depleting substances under the Montreal Protocol, is a routine measure used for phytosanitary treatment. To protect the Ozone layer, an environmentally friendly measure is needed to be developed. The middle- to late-stage larvae and adults were treated with irradiation, modified atmosphere (MA) alone, and their combinations at room temperature of 24–26 ℃. As a result, late-stage larvae are determined as the most tolerant stage. Ionizing radiation was used to enhance the effects of 1% and 2% O2 MA treatments that the obvious synergistic effects are presented in all combinations, resulted in saving as high as 60% of the estimated exposure times comparing with MA treatment alone. A total of 111,366 late-stage larvae were exposed to a 1% O2 atmosphere for 14 or 15 days after a 200 Gy irradiation, resulted in no survivor in the validating tests. Therefore, the MA-irradiation combination treatment can provide quarantine security at a very high level, it may be combined with international transportation (train or sea container) to disinfest the commodities infested by khapra beetle and other stored products insect pests.The khapra beetle, Trogoderma granarium Everts, is defined as one of the most important quarantine pests globally, and fumigation with methyl bromide, an ozone-depleting substance, is a common phytosanitary measure currently used. The modified atmosphere (MA), irradiation, and their combination treatments of T. granarium larvae and adults were performed at room temperature (24–26 ℃) to develop an ecofriendly phytosanitary disinfestation measure and to shorten the exposure time and overcome treatment disadvantages of irradiation. Late-stage larvae are determined as the most tolerant stage resulted in large LT99.9968 values of 32.6 (29.2–37.5) and 38.0 (35.1–41.7) days treated under 1% and 2% O2 (with N2 balance) atmosphere, respectively. Ionizing radiation was used to enhance the effect of MA and the mortality was highly significantly affected by all the interaction effects, indicating that the synergistic effects present in all the combined treatments. The synergistic ratios, which is defined as the estimated lethal time for MA treatment (LD90, LD99, and LD99.9968), divided by that of combined treatment, were between 1.47 and 2.47. In the confirmatory tests, no individuals recovered from a sum of 111,366 late-stage larvae treated under 1% O2 atmosphere for 14- or 15-d after 200 Gy irradiation, which resulted in validating the probit estimations and achieving an efficacy of 99.9973% mortality at 95% confidence level. Therefore, these treatment schedules are recommended to disinfest T. granarium infecting commodities for phytosanitary purposes under the warehouse, MA packaging, or in combination with international transportation by train or sea container.

Targeting Signaling Pathways of Hyaluronic Acid and Integrin Receptors by Synergistic Combination Nanocomposites Inhibits Systemic Metastases and Primary Triple Negative Breast Cancer

AbstractTriple negative breast cancer (TNBC) has a poor prognosis due to its aggressive nature, high incidence of distant metastasis, and lack of targets for effective therapy. Therefore, a novel multifunctional biopolymer‐anticancer drug combination nanomedicine is designed for the prevention of spontaneous metastasis while treating primary TNBC. Oligomeric hyaluronic acid (oHA) and doxorubicin (DOX) at a synergistic ratio against TNBC cells are co‐loaded in a polymer‐lipid hybrid nanoparticle (PLN) which is then functionalized with an internalizing cyclic peptide iRGD (iRGD‐DOX‐oHA‐PLN). iRGD conjugation enhances cellular uptake and cytotoxicity in vitro and nanoparticle (NP) accumulation in human TNBC tumors that overexpress integrins. NP‐delivered oHA inhibits cell migration and invasion in vitro via the intracellular release of oHA that interacts with the receptor for hyaluronan mediated motility and downregulates the phospho‐extracellular signal‐regulated kinase (p‐ERK) signaling pathway. Intravenously injected iRGD‐DOX‐oHA‐PLN significantly inhibits the growth of primary TNBC tumors in a mouse model and prevents spontaneous metastasis to the lungs and lymph nodes, superior to free solutions of DOX, oHA, or both and NP formulations loaded with DOX or oHA. These results suggest that iRGD‐DOX‐oHA‐PLN can be a promising bioactive polymer‐drug combination nanomedicine for the treatment of TNBC and prevention of its spontaneous metastasis.

Effects of Combining Antioxidants on the Oxidative Stability of Refined, Bleached and Deodorized Palm Olein during Continuous Deep Frying of Potato Chips

In this study, the effect of a novel antioxidants composite system based on a synergetic composite between Tertiary butyl hydroquinone (TBHQ), Ascorbyl palmitate, citric acid, and Dimethicone have been evaluated against the classical common antioxidant system based on TBHQ at the highest permitted dose of 200 ppm during successive deep-frying cycles. Also, the shelf life of fried food and its sensory performance and oil absorption content o fried food were comparatively studied. The Novel antioxidant composite system is a synergetic blend of an artificial antioxidant, TBHQ and vitamin C palmitate( Ascorbyl palmitate) as natural identical antioxidants, an effective sequestrant which is Citric acid and poly dimethyl siloxane as an anti-foaming system to obtain the highest oxidative stability impact during deep frying. The frying processes were carried at 180 ᴼC for sliced potato chips for 8 successive frying cycles.Sensory evaluation of the fried potato has been conducted under accelerated storage conditions to determine the effect of the oil oxidative stability on the shelf life of fried food. The oxidative degradation of the oil was evaluated by measuring different oxidation and degradation parameters for their respective peroxide value ( PV), free fatty acid( FFA %), the content of conjugated dienes, P-anisidine value,( p-A.V), induction period (IP), and Lovibond color. The (%) of oil absorption in the potato chips was also measured. The sensory evaluation has been done for fried foods to evaluate the crunchiness and likability of obtained french fries. Results revealed that the jump in primary &amp; secondary oxidation parameters as PV and p- A.V.of palm olein after 8 successive frying cycles was very limited for the antioxidant composite system I by only 1.842± 0.1 meq O2/ kg in PV and by 6.2315±0.45 for p-A.V. Same for FFA, the jump was limited for the antioxidant composite system I for only 0.084+/-0.005 as well. However, the final PV, FFA after the 8 frying cycles are still within the Codex and local Egyptian regulation limits the edible oil human usage. Same for other quality parameters like color jump was limited to 3.4 Red jumps on Lovi bond scale for composite I. Study proofed that palm olein fortified with 650 ppm of the antioxidant composite (I) consists of TBHQ, Ascorbyl palmitate, citric acid, and polydimethylsiloxane at the specified synergistic ratios gives outstanding stability to refined Palm olein during the successive deep frying up to 8 successive frying cycles. It also achieved less oil absorption for french fries by about 3.5% less than the same oil fortified with 200 ppm TBHQ, which is the highest permitted dose of this strong antioxidant. (P≤0.05). Furthermore, sensory evaluation of the fried potatoes has been improved with the novel antioxidant system compared to theclassical TBHQ system.

Dual-Drug Backboned Polyprodrug with a Predefined Drug Combination for Synergistic Chemotherapy.

The codelivery of drugs at specific optimal ratios to cancer cells is vital for combination chemotherapy. However, most of the current strategies are unable to coordinate the loading and release of drug combinations to acquire precise and controllable synergistic ratios. In this work, we designed an innovative dual-drug backboned and reduction-sensitive polyprodrug PEG-P(MTO-ss-CUR) containing the anticancer drugs mitoxantrone (MTO) and curcumin (CUR) at an optimal synergistic ratio to reverse drug resistance. Due to synchronous drug activation and polymer backbone degradation, drug release at the predefined ratio with a synergistic anticancer effect was demonstrated by in vitro and in vivo experiments. Therefore, the dual-drug delivery system developed in this work provides a novel and efficient strategy for combination chemotherapy.

Irinotecan and berberine co-delivery liposomes showed improved efficacy and reduced intestinal toxicity compared with Onivyde for pancreatic cancer.

Onivyde is the first irinotecan (IRI) nanoliposome that could improve pharmacokinetics and tumor biodistribution of irinotecan. Although FDA approves Onivyde for the treatment of pancreatic cancer patients who are not effective for GEM, the gastrointestinal toxicity caused by Onivyde is still a problem to be solved in clinical application. Berberine (BER), an isoquinolone alkaloid extracted from several different plants, has been reported to exhibit beneficial effect in alleviating intestinal mucositis and generating synergistic anticancer effect in combination with cytotoxic drugs. However, its therapeutic effect is affected by the different pharmacokinetic behavior of two drugs. Therefore, we utilized triethylamine-sucrose octasulfate gradient to construct nanoliposomes for co-delivery of irinotecan and berberine, termed as lipBI. This co-delivery nanoliposomes remained the synergistic ratio in the body and improved tumor distribution of IRI and BER. The lipBI significantly inhibited tumor growth in the BXPC-3 pancreatic cancer model compared with Onivyde (p<0.05) and reduced the gastrointestinal toxicity in mice caused by IRI. Overall, IRI/BER co-loaded liposomes possessed great potential in the treatment of pancreatic cancer.

Barium Titanate-reinforced Acrylonitrile-Butadiene Rubber: Synergy Effect of Carbon-based Secondary Filler

Acrylonitrile rubber (NBR) composites filled with barium titanate (BT) were prepared using an internal mixer and a two-roll mill. Also, a secondary filler, namely carbon nanotubes (CNT), was added in order to find a potential synergistic blend ratio of BT and CNT. The cure characteristics, tensile and dielectric properties (dielectric constant and dielectric loss) of the composites were determined. It was found that NBR/BT composites with CNT secondary filler, at a proper BT:CNT ratio, exhibited shorter scorch time (ts1) and cure time (tc90) together with superior tensile properties and reinforcement efficiency, relative to the one with only the primary filler. In addition, the NBR/BT-CNT composite with 80 phr BT and 1–2 phr CNT had dielectric constant of 100–500, dielectric loss of 12–100 and electrical conductivity below 10−4 S/m together with high thermal stability. Thus, with a proper BT:CNT mix and filler loading, we can produce mechanically superior rubber composites that are easy to process and low-cost, for flexible dielectric materials application.

Synergistic Treatment of Obesity via Locally Promoting Beige Adipogenesis and Antioxidative Defense in Adipose Tissues.

Obesity is a primary risk factor for type 2 diabetes, cardiovascular diseases, cancer, and other chronic diseases. Current antiobesity medications need frequent administration and show limited efficacy with severe side effects. Herein, browning agent rosiglitazone (Rsg) and antioxidant manganese tetroxide nanoparticles (MnNPs, around 250 nm) are integrated into electrospun short fibers (SF@Rsg-Mn) with a 1.5 μm width and a 20 μm length. Upon injection into inguinal adipose tissues, SF@Rsg-Mn are well retained in the local depots to sustainably release Rsg in 30 days for adipose tissue browning, while MnNPs on the fiber surface continuously scavenge adipose reactive oxygen species (ROS) for an extended period of time. Synergistic inhibition of fat accumulation through ROS scavenging and white adipocyte browning has been demonstrated for the first time, and the optimal synergistic ratio of Rsg and MnNPs is determined to be 1/14 via combination index examination. SF@Rsg-Mn inhibit lipid accumulation through downregulation of adipogenic gene PPARγ while promoting energy expenditure through upregulation of brown-specific gene UCP1 and mitochondrial function gene COX7A1. In a diet-induced obesity mouse model, a single injection of SF@Rsg-Mn into inguinal adipose tissues has accomplished a synergistic effect on body weight loss, fat reduction, glucose, and lipid metabolic improvement while minimizing adverse effects on other tissues, thereby paving the way to efficacious, safe, and practical treatment of obesity.

Estimating the synergistic and antagonistic effects of dual antibiotics on plants through root elongation test.

Antibiotics are recently recognized as a group of emerging environmental contaminants that are frequently detected in various environmental matrixes. Relative root elongation (RRE) test is a rapid and effective strategy to evaluate the water/soil quality and the toxic effects of environmental contaminants on plants. In the present study, we examine the toxicity effect of ciprofloxacin (CIP), norfloxacin (NOR), and tetracycline (TET) to pakchoi individually and in combinations. Both independent action (IA) and concentration addition (CA) models are used for toxicity assessment. Results showed that the EC50 values of CIP, NOR, and TET are 193.59, 60.81, and 40.37 μM, respectively. Combinations of TET + CIP and TET + NOR caused more inhibitory effects on root elongation than those of CIP + NOR. Toxic Unit (TU) and Synergistic Ratio (SR) analysis showed that the relatively lower (higher) EC values are observed in the combinations with lower (higher) antibiotic concentrations, suggesting an effect of low-dose synergism and high-dose antagonism. The reliability of the simulation results from IA and CA models to predict that combined toxicity is highly dependent upon the results from the analysis of TU or SR.

CPX-351 Population Pharmacokinetics in Pediatric and Adult Patients with Acute Myeloid Leukemia (AML)

CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine at a 1:5 synergistic ratio, is approved by the US FDA and EMA for the treatment of adults with newly diagnosed therapy-related AML or AML with myelodysplasia-related changes. Recently, CPX-351 was used in pediatric patients (pts) with relapsed AML (JCO 2020, ASH 2019, ASH 2018). A population pharmacokinetic (PK) analysis of plasma concentrations of cytarabine and daunorubicin following IV administration of CPX-351 was performed to assess sources of variability in PK and to determine if age-based dose adjustments may be warranted, particularly in pediatric pts. The PK population consisted of 250 pts with advanced hematologic malignancies from 7 studies and included 46 (18%) pediatric pts (1-17 y) and 204 (82%) adults (≥18 y). The population included 148 (59%) males, mainly of white origin (82%). Nonlinear mixed-effect modeling was performed using NONMEM®. Model evaluation and selection were assessed using a standard model discrimination process that included statistical criteria (eg, objective function value) and pertinent graphical representations of goodness-of-fit. Separate PK models were developed for cytarabine and daunorubicin; intrinsic and extrinsic factors were evaluated as covariates. The intrinsic factors included body weight, body mass index, age, sex, race, white blood cell count, and markers of renal function (creatinine clearance, serum creatinine) and hepatic function (bilirubin, aspartate and alanine aminotransferases, alkaline phosphatase). The extrinsic factors included study type (adult vs pediatric/young adult) and formulation (frozen vs lyophilized). Based on previous population PK models developed for adults, the PK models for cytarabine and daunorubicin used 2-compartment structural models, with drug input into the central compartment, first-order distribution between the central and peripheral compartments, and first-order elimination from the central compartment. Two-compartment structural models with body surface area (BSA) as an allometric scalar provided minimum bias in estimates of systemic clearance (CL) and volume of distribution for the central compartment (Vc). Based on the final population PK models, the estimates of CL and Vc in adults were 0.101 L/h and 4.76 L, respectively, for cytarabine and 0.140 L/h and 4.04 L for daunorubicin. The population estimates of CL and Vc for cytarabine in children, adolescents, and young adults (&amp;lt;22 y) were 0.073 L/h and 3.91 L, respectively, for cytarabine and 0.093 L/h and 3.28 L for daunorubicin. The population PK models included an allometric component that accounted for differences in BSA. The exponent for the effect of BSA on CL was 0.948 and 0.876 for cytarabine and daunorubicin, respectively, suggesting a faster clearance in pts with higher BSA. These differences in CL are expected to be offset by BSA-based dosing of CPX-351. Bilirubin and formulation (frozen) remained statistically significant covariates on the CL of daunorubicin. All tested covariates were eventually excluded from the population PK models, except BSA, bilirubin, study type, and formulation, which have a small effect on PK and are not expected to result in detectable changes in clinical safety or efficacy. Age was evaluated both as a continuous and categorical variable (1-5, 6-11, and 12-17 y) and was not a significant covariate for cytarabine and daunorubicin CL and Vc. Study type was identified as a significant covariate for CL and Vc for cytarabine and daunorubicin, which was possibly due to a change in analytical site for pediatric studies. Mean AUC0-48 values of cytarabine in pts aged 1-5, 6-11, and 12-17 y (135 U/m2) were similar (2767, 2783, and 2806 μg·h/mL, respectively) and approximately 40% higher than that observed in pts ≥18 y (100 U/m2, 1928 μg·h/mL), proportional to the 35% higher dose in pediatric pts. Mean AUC0-48 values of daunorubicin in pts aged 1-5, 6-11, and 12-17 y (135 U/m2) were similar (967, 896, and 982 μg·h/mL, respectively) and approximately 40% higher than that observed in pts ≥18 y (100 U/m2, 615 μg·h/mL), proportional to the 35% higher dose in pediatric pts. The results of this population PK analysis indicated exposures to CPX-351 in pediatric pts were not affected by age and were similar to those in adults when administered at the same BSA-normalized dose. Disclosures Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019). Absalon:Jazz Pharmaceuticals: Research Funding. OffLabel Disclosure: Yes, in this study, CPX-351 was also evaluated in pediatric AML

CPX351 Has Short Remission Duration but Is an Effective Bridge to Allogeneic Transplant in High Risk AML: Results from Canadian Real-World Multi-Centre Study

Background and objectives: CPX-351 is a liposomal formulation of daunorubicin and cytarabine in a fixed synergistic ratio of 5:1. It has been approved by both the FDA and EMA for use in high risk AML including therapy related AML (t-AML) and AML with myelodysplastic related change (AML-MRC). When compared with '3+7', CPX-351 resulted in superior OS (9.56 vs 5.96 months) and overall response rate (47.7% v 33.3%; P = .016; Lancet JCO 2018). However, this is little data of CPX-351 in a real world setting. The primary objective of our multi-centre study was to assess outcomes and associated toxicities of CPX-351 in these high risk AML patients. Methods: Patients aged 18 and over who were treated with CPX-351 and who met the WHO criteria for t-AML and AML-MRC were included in the study. Retrospective data was collected from 6 centres throughout Canada. Targeted sequencing was performed on DNA samples using the TruSight Myeloid Sequencing Panel isolated from peripheral blood or bone marrow samples at diagnosis. Overall survival (OS) and progression free survival (PFS) rates were calculated using the Kaplan-Meier method. Results: Fifty patients treated with CPX-351 were identified from six centres. Baseline characteristics are seen in Table 1. Cytogenetics was available in 45 (90%) patients and an abnormal karyotype was seen in 30 (60%) patients. Monosomal (33%) and complex (28%) karyotype were the most common chromosomal abnormalities seen. Targeted sequencing was performed on 64% patients (32/50) and the average number of mutations was 2(0-7). RUNX1 was the most commonly mutated gene found in 22% (7/32), followed by SRSF2 in 19% (6/32) with ASXL1 and NRAS both at 16% (5/32). Other commonly mutated genes were NPM1, IDH2, DNMT3a and TP53 all occurred at a frequency of 12% (4/32). Of the 10 patients (20%) that were FLT3 mutated (80% ITD and 20% TKD), 5 patients received the FLT3 inhibitor midostaurin in combination with CPX-351. Assessing treatment responses, 50% (25/50) of patients achieved a complete remission (CR) or a complete remission with incomplete recovery (CRi). Median neutrophil recovery (≥500/μl) was 32 days (range 18-68) and median platelet recovery (≥50 000/μl) was 34 days (range 19-70). Proven or probable fungal infection was seen in 10 (20%) patients. 30 day mortality was 4% (2/50) and 60-day mortality was 10% (5/50). The median CR duration was short at 7.17 months. Of the 25 patients who did not achieve a CR, 6 (24%) had prior azacitidine use for MDS suggesting CPX-351 may not have activity in this group of patients. Median follow up was 7.43 months (range 0.2 to 18 months). OS was 44% at 12 months (0.28-0.58 95% CI) and 29% at 18 months (Fig 1; 0.13-0.46 95% CI). PFS was 28% at 12 months (0.15-0.43 95% CI) and 18% at 18 months (0.06-0.39 95% CI). There were no differences in OS when stratified by ELN risk (p=0.25), adverse risk cytogenetics (p=0.1485), or poor risk mutations such as FLT3-ITD (p=0.29), RUNX1 (p=0.123) or ASXL1 (p=0.06). This is consistent with previous studies, which suggest that CPX-351 overcomes the poor prognosis associated with these mutations. 18 (36%) patients received an allogeneic stem cell transplant (ASCT) in CR1. Patients who received a allogeneic transplant had significant improvement of OS of 62% at 18 months compared to those who did not receive a transplant of 14.5% at 18 months (Fig 2; p=0.0008). Conclusion Our study reveals that CPX-351 produces high remission rates in patients with AML with a similar efficacy and toxicity profile seen in the Phase 3 trial data (Lancet JCO 2018). However, response rates are short and therefore CPX-351 is most effective when used as a bridge for allogeneic stem cell transplantation in this high risk population. Disclosures Assouline: AbbVie: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria, Speakers Bureau; Takeda: Research Funding; BeiGene: Consultancy, Honoraria, Research Funding. Brandwein:Celgene: Honoraria; Astellas: Honoraria; Taiho: Honoraria; Roche: Honoraria; Jazz Pharmaceuticals: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Gupta:Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Maze:Pfizer: Consultancy; Takeda: Research Funding; Novartis: Honoraria. McNamara:Novartis: Honoraria. Sanford:Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Schimmer:Medivir AB: Research Funding; AbbVie Pharmaceuticals: Other: owns stock ; Takeda: Honoraria, Research Funding; Novartis: Honoraria; Jazz: Honoraria; Otsuka: Honoraria.

Transcriptome profiling and functional analysis suggest that the constitutive overexpression of four cytochrome P450s confers resistance to abamectin in Tetranychus urticae from China.

The two-spotted spider mite Tetranychus urticae is a polyphagous and cosmopolitan pest that has developed high resistance to abamectin, making it difficult to control. Although 'target resistance' related to glutamate-gated chloride channel mutations was found in T. urticae field populations in China, other resistance mechanisms appear to be involved. Here, we conducted genome-wide transcriptome profiling using RNA-sequencing of two abamectin-resistant populations (NB-ZJ and SY-BJ) and one susceptible strain (Lab-SS) to identify differentially expressed genes that might contribute to the resistance of T. urticae to abamectin in China. Our experiments showed that abamectin resistance was synergized by piperonyl butoxide (PBO) and triphenyl phosphate (TPP), with synergistic ratios (SR) of 2.95-fold and 2.21-fold for PBO and 3.55-fold and 2.84-fold for TPP in NB-ZJ and SY-BJ populations, respectively. Transcriptome data and quantitative real-time PCR (qRT-PCR) revealed that seven detoxification enzyme genes were overexpressed in the two resistant populations. Furthermore, functional analysis by RNA interference (RNAi) indicated that the mortality caused by abamectin was significantly increased by the separate silencing of the P450 genes CYP389C10, CYP392D8, CYP392A11, and CYP392A12. qRT-PCR expression and RNAi data suggest that the overexpression of P450 genes CYP389C10, CYP392D8, CYP392A11, and CYP392A12 may be involved in the abamectin-resistance of field populations of T. urticae in China. This knowledge could facilitate the elucidation of resistance mechanisms and the development of resistance management of T. urticae field populations. © 2020 Society of Chemical Industry.