A promising choice in hypertension treatment:Fixed-dose combinations

Obtaining the target blood pressure level by monotherapy can be challenging currently,especially for the patients who are suffering from other diseases meanwhile.It is demonstrated that a majority of hypertensive patients need two or more antihypertensive drugs to lower their blood pressure effectively.Consequently,fixed-dose which can be defined as that several active agents were combined in single pharmaceutical formulations appears to be a novel and underlying power in overcoming the cardiovascular disease.Based on the analysis of some literature and relative data from FDA,the advantages of fixed-dose combination are elucidated and formulations of common dual,triple-combinations were summarized.Clinical practices proved that fixed-dose combinations had many benefits comparing with single drug and separate agents in terms of effects,convenience,compliance,and costs to a certain extent.From the patients’perspective,the fixed-dose combination therapy will be increasingly utilized in blood pressure control in the future.

A Bioequivalence Study of Empagliflozin/Metformin Fixed-Dose Combination in Healthy Subjects under Fasting Conditions

Background: This study evaluated the bioequivalence of empagliflozin 12.5 mg/metformin 1000 mg tablets compared to Synjardy® (Empagliflozin 12.5 mg/metformin 1000 mg) tablets in healthy male subjects under fasting conditions. Methods: This was a phase I, randomized, single-dose, two-period, two-sequence, crossover study to evaluate the bioequivalence (BE) profiles of two fixed-dose combinations (FDCs) of empagliflozin/metformin. Cmax, AUC0-t and AUC0-∞ from test and reference formulations were evaluated to access BE. The plasma concentrations were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) method. Of the 24 subjects enrolled, 23 completed both periods of the study. The two formulations test and reference were considered bioequivalent if 90% confidence interval (CI) fell within 80.00% - 125.00% for Cmax, AUC0-t and AUC0-∞. Tolerability and safety were assessed throughout the study. Results: The pharmacokinetic (PK) parameters were similar between the test product (T) and reference product (R) Synjardy®. The 90% CI of the test/reference ratios of log-transformed PK parameters point estimates was Cmax: 89.87% (85.68% - 94.27%), AUC0-t: 87.91% (83.65% - 92.39%) and AUC0-∞: 87.16% (82.80% - 91.75%) to empagliflozin and Cmax: 92.19% (87.95% - 96.65%), AUC0-t: 91.38% (84.42% - 98.91%) and AUC0-∞: 93.78% (83.82% - 104.93%) to metformin respectively (90% CI for all PK parameters fell within 80.00% - 125.00%). Conclusion: Our results demonstrated BE between the test and reference formulations of oral tablets of empagliflozin 12.5 mg/metformin 1000 mg (FDC) in healthy male subjects under fasting conditions.

Relative Bioavailability of Rifampicin in Four Chinese Fixed-dose Combinations Compared with Rifampicin in Free Combinations

Background：Decreases in the bioavailability of rifampicin （RFP） can lead to the development of drug resistance and treatment failure.Therefore,we investigated the relative bioavailability of RFP from one four-drug fixed-dose combination （FDC; formulation A） and three two-drug FDCs （formulations B,C,and D） used in China,compared with RFP in free combinations of these drugs （reference）,in healthy volunteers.Methods：Eighteen and twenty healthy Chinese male volunteers participated in two open-label,randomized two-period crossover （formulations A and C） or one three-period crossover （formulations B and D） study,respectively.The washout period between treatments was 7 days.Bioequivalence was assessed based on 90％ confidence intervals,according to two one-sided t-tests.All analyses were done with DAS 3.1.5 （Mathematical Pharmacology Professional Committee of China,Shanghai,China）.Results：Mean pharmacokinetic parameter values of RFP obtained for formulations A,B,C,and D products were 11.42 ± 3.41 μg/ml,7.86 ± 5.78 μg/ml,13.05 ± 6.80 μg/ml,and 16.18 ± 3.87 μg/ml,respectively,for peak plasma concentration （Cmax）,91.43± 30.82 μg·h-1 ·ml-1,55.49 ± 37.58 μg·h-1·ml-1,96.50 ± 47.24 μg·h-1·ml-1,101.47 ± 33.07 μg·h-1·ml-1,respectively,for area under the concentration-time curve （AUC0-2,4 h）.Conclusions：Although the concentrations of RFP for formulations A,C,and D were within the reported acceptable therapeutic range,only formulation A was bioequivalent to the reference product.The three two-drug FDCs （formulations B,C and D） displayed inferior RFP bioavailability compared with the reference （Chinese Clinical Trials registration number：ChiCTR-TTRCC-12002451）.

Fabrication of Electrospun Levodopa-Carbidopa Fixed-Dose Combinations

Introduction Parkinson’s disease(PD)is a disabling disorder that signifi-cantly affects a patient’s quality of life[1].Treatments are available,but only 10%of PD patients fully adhere to their treatment regimens[2].Non-adherence is a serious problem linked to worsening symptoms and increased motor fluc-tuations[3-5].Levodopa(LD)remains the most effective treatment for PD[6].However,a single dosing treatment is only effective in the early phase of the disease.In the severe phase,4-5 years after diagnosis,the therapeutic window of dopamine becomes narrow,and due to its short half-life of between 0.7 and 1.4 h dosing of LD will be required every 2 h[7-9].One way to ameliorate this issue is to co-admin-ister LD with carbidopa(CD),which can increase LD’s oral bioavailability to 40-70%[10].

Clinical Utility of Amlodipine/Valsartan Fixed-Dose Combination in the Management of Hypertension in Chinese Patients

Amlodipine/valsartan(Aml/Val)single-pill combination(SPC)therapy has been widely used and studied in clinical practice in recent years.This article reviews the Chinese and English literature on the clinical use of Aml/Val SPC therapy in Chinese hypertensive patients.According to five studies concerning the efficacy and safety of this treatment,Aml/Val SPC therapy was more efficacious than monotherapy with valsartan,amlodipine,or the nifedipine gastrointestinal therapeutic system.This treatment showed greater blood pressure-lowering effects,a higher blood pressure control rate,and a higher response rate.Aml/Val SPC treatment was well tolerated,with adverse event rates similar to those of monotherapy with valsartan or amlodipine and significantly rarer adverse events compared with the nifedipine gastrointestinal therapeutic system.Aml/Val SPC is a highly efficacious and well-tolerated antihypertensive treatment in Chinese hypertensive patients.

LociScan,a tool for screening genetic marker combinations for plant variety discrimination

To reduce the cost and increase the efficiency of plant genetic marker fingerprinting for variety discrimination,it is desirable to identify the optimal marker combinations.We describe a marker combination screening model based on the genetic algorithm(GA)and implemented in a software tool,Loci Scan.Ratio-based variety discrimination power provided the largest optimization space among multiple fitness functions.Among GA parameters,an increase in population size and generation number enlarged optimization depth but also calculation workload.Exhaustive algorithm afforded the same optimization depth as GA but vastly increased calculation time.In comparison with two other software tools,Loci Scan accommodated missing data,reduced calculation time,and offered more fitness functions.In large datasets,the sample size of training data exerted the strongest influence on calculation time,whereas the marker size of training data showed no effect,and target marker number had limited effect on analysis speed.

Gaps and feasibility of fixed-dose combination strategy in the development of modern Chinese medicine

isTraditional Chinese medicine(TCM)is a highly complex chemical substance system,which not only reflected in the complexity of the chemical components and their interrelationships,but also in the intricacy of the prescription’s connection with the human body.Component compatibility strategy has been proposed for developing modern TCM since 2005 and established comprehensive relevant technologies and research approaches.Moreover,to meet the safety and efficacy of current pharmaceuticals,research on fixed-dose combination drugs is directed by modern scientific theories,conforms to TCM compatibility principles and clarifies material basis and pharmacological mechanisms and component-effect correlations.This review summarized gaps and feasibility of fixed-dose combination strategy in the development of modern TCM research and assessed their advantages and disadvantages in light of contemporary drug combination research practices.

A Study on the Effects of Different Interaction Combinations and Language Levels on Continuous Writing in Online Environments

This study was conducted with non-English sophomore students,aiming to explore the effects of different interaction combinations and language levels on continuous writing in an online environment,and compare the differences in lexical alignments and composition quality of learners with different interaction combinations and language levels in the same continuous writing task through experiments.The results show that the mean values of the word-phrase alignment of the paired group were higher than those of the individual group in different interaction combinations,and the two groups showed significant differences;in terms of composition quality,the individual group was better than the paired group,but there was no significant difference between the two groups in terms of task continuation.Secondly,the word-phrase alignment and composition scores of the different language-level groups were higher than those of the same language-level groups,and there was a significant difference between the two groups in terms of word-phrase alignments,but not in terms of composition scores.The results of this study can be useful and informative for second language teachers in future continuous teaching in online environments.

The Research on the Logic and Value of“Two Combinations”

Through the comprehensive analysis of the connotation and logic,inheritance and innovation and the value of social governance,and the dialectical relationship of“two combination”,the inheritance of the idea of Marxism,the inheritance of excellent traditional culture and the governance of contemporary society.

Advances in Breeding of High-amylose Indica Hybrid Rice Combinations in Sichuan Province

During 2000-2013, totally ten high-amylose specific hybrid rice combinations approved and five combinations for production test were bred in Sichuan Province. In the paper, rice yield, economic traits, quality indicators and rice blast-resistance identification results of these 15 hybrid combinations were described and analyzed. Results show that Chuanxiangyou37 and Tianlongyou540 have relatively high amylose content, good yielding ability, high resistance and appropriate growth period, which are new hybrid rice varieties with organic combination of high amylase content, high gel consistency, high yield, stable yield and wide adaptability. Therefore, Chuanxiangyou37 and Tianlongyou540 are recommended as the main combination for rice production.

Future of anti-PD-1/PD-L1 applications： Combinations with other therapeutic regimens

Programmed cell death 1（PD-1）/programmed cell death 1 ligand（PD-L1） blockade has shown promising effects in cancer immunotherapy. Removing the so-called ＂brakes＂ on T cell immune responses by blocking the PD-1/PDL1 check point should boost anti-tumor immunity and provide durable tumor regression for cancer patients.However, 30%–60% of patients show no response to PD-1/PD-L1 blockade. Thus, it is urgent to explore the underlying resistance mechanisms to improve sensitivity to anti-PD-1/PD-L1 therapy. We propose that the mechanisms promoting resistance mainly include T cell exclusion or exhaustion at the tumor site,immunosuppressive factors in the tumor microenvironment（TME）, and a range of tumor-intrinsic factors. This review highlights the power of studying the cellular and molecular mechanisms of resistance to improve the rational design of combination therapeutic strategies that can be translated to the clinic. Here, we briefly discuss the development of PD-1/PD-L1 blockade agents and focus on the current issues and future prospects for potential combinatorial therapeutic strategies that include anti-PD-1/PD-L1 therapy, based upon the available preclinical and clinical data.

Effects of water intrusion and loading rate on mechanical properties of and crack propagation in coal–rock combinations

Tackling the problems of underground water storage in collieries in arid regions requires knowledge of the effect of water intrusion and loading rate on the mechanical properties of and crack development in coal–rock combinations. Fifty-four coal–rock combinations were prepared and split equally into groups containing different moisture contents(dry, natural moisture and saturated) to conduct acoustic emission testing under uniaxial compression with loading rates ranging from 0.1 mm/min to 0.6 mm/min. The results show that the peak stress and strength-softening modulus, elastic modulus, strain-softening modulus, and post-peak modulus partly decrease with increasing moisture content and loading rate. In contrast, peak strain increases with increasing moisture content and fluctuates with rising loading rate. More significantly, the relationship between stiffness and stress, combined with accumulated counts of acoustic emission, can be used to precisely predict all phases of crack propagation. This is helpful in studying the impact of moisture content and loading rate on crack propagation and accurately calculating mechanical properties. We also determined that the stress thresholds of crack closure, crack initiation, and crack damage do not vary with changes of moisture content and loading rate, constituting 15.22%, 32.20%, and 80.98% of peak stress, respectively. These outcomes assist in developing approaches to water storage in coal mines, determining the necessary width of waterproof coal–rock pillars, and methods of supporting water-enriched roadways, while also advances understanding the mechanical properties of coal–rock combinations and laws of crack propagation.

EQUIVALENT THEOREMS ON SIMULTANEOUS APPROXIMATION BY COMBINATIONS OF BERNSTEIN OPERATORES

In this paper we give equivalent theorems on simultaneous approximation for the combinations of Bernstein operators by r-th Ditzian- Totik modulus of smoothness w^rφλ （f, t）（0 ≤ λ≤ 1）. We also investigate the relation between the derivatives of the combinations of Bernstein operators and the smoothness of derivatives of functions.

Immuno-oncology combinations： raising the tail of the survival curve

There have been exponential gains in immuno-oncology in recent times through the development of immune checkpoint inhibitors. Already approved by the U.S. Food and Drug Administration for advanced melanoma and non-small cell lung cancer,immune checkpoint inhibitors also appears to have significant antitumor activity in multiple other tumor types. An exciting component of immunotherapy is the durability of antitumor responses observed, with some patients achieving disease control for many years. Nevertheless, not all patients benefit, and efforts should thus now focus on improving the efficacy of immunotherapy through the use of combination approaches and predictive biomarkers of response and resistance. There are multiple potential rational combinations using an immunotherapy backbone, including existing treatments such as radiotherapy, chemotherapy or molecularly targeted agents, as well as other immunotherapeutics. The aim of such antitumor strategies will be to raise the tail on the survival curve by increasing the number of long term survivors, while managing any additive or synergistic toxicities that may arise with immunotherapy combinations. Rational trial designs based on a clear understanding of tumor biology and drug pharmacology remain paramount. This article reviews the biology underpinning immuno-oncology, discusses existing and novel immunotherapeutic combinations currently in development, the challenges of predictive biomarkers of response and resistance and the impact of immuno-oncology on early phase clinical trial design.

Pointwise characterization for combinations of Szász-Mirakjan operators

The purpose of this paper is to characterize the pointwise rate of convergence for the combinations of Szász-Mirakjan operators using Ditzian-Totik modulus of smoothness.

Key factors and potential drug combinations of nonalcoholic steatohepatitis:Bioinformatic analysis and experimental validation-based study

Background:Nonalcoholic fatty liver disease and its advanced stage,nonalcoholic steatohepatitis(NASH),are the major cause of hepatocellular carcinoma(HCC)and other end-stage liver disease.However,the potential mechanism and therapeutic strategies have not been clarified.This study aimed to identify potential roles of mi RNA/m RNA axis in the pathogenesis and drug combinations in the treatment of NASH.Methods:Microarray GSE59045 and GSE48452 were downloaded from the Gene Expression Omnibus and analyzed using R.Then we obtained differentially expressed genes(DE-genes).DAVID database was used for Gene Ontology(GO)analysis and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment pathway analysis.Protein-protein interaction(PPI)networks were used for the identification of hub genes.We found upstream regulators of hub genes using mi RTar Base.The expression and correlation of key mi RNA and its targets were detected by q PCR.Drug Pair Seeker was employed to predict drug combinations against NASH.The expression of mi RNA and hub genes in HCC was identified in the Cancer Genome Atlas database and Human Protein Atlas database.Results:Ninety-four DE-genes were accessed.GO and KEGG analysis showed that these predicted genes were linked to lipid metabolism.Eleven genes were identified as hub genes in PPI networks,and they were highly expressed in cells with vigorous lipid metabolism.hsa-mi R-335-5 p was the upstream regulator of 9 genes in the 11 hub genes,and it was identified as a key mi RNA.The hub genes were highly expressed in NASH models,while hsa-mi R-335-5 p was lowly expressed.The correlation of mi RNA-m RNA was established by q PCR.Functional verification indicated that hsa-mi R-335-5 p had inhibitory effect on the development of NASH.Finally,drug combinations were predicted and the expression of mi RNA and hub genes in HCC was identified.Conclusions:In the study,potential mi RNA-m RNA pathways related to NASH were identified.Targeting these pathways may be novel strategies against NASH.

Comparative Study on Growing-finishing Performance and Meat Quality of Different Hybrid Combinations in Pigs

[Objective] The aim of this study was to investigate the production performance of three pig cultivars through their fattening performance, carcass traits and meat quality for facilitating its application in practical production. [ Method] Three pig cultivars were selected including Yesong （ F1 hybrid of pure-bred wild boar cross with songliao black sow as female parent） hybrid pigs, D × L × Y pigs from three-way cross and L x Y pigs from two-way cross. The test pigs in early period （before 60 kg） and late period （after 60 kg） were all fed with diets of the same nutritional level by free feeding and drinking water. The pre-test period was 3 d, while the test period was 120 d. Every 30 days, pigs with an empty stomach were weighed on morning, and when fattening to 120 d, five pigs with good growth and development in each cultivar were selected for slaughter to determine carcass traits and meat quality. [ Result] Under the same diets and feeding conditions, average daily gain and weight gain in the whole period of pigs from three-way cross were all significantly higher than those of pigs from two-way cross, and also extremely higher than those of Yesong pigs. There was no difference in dressed carcass percentage, backfat thickness and proportion of hind leg among three hybrid combinations. Lean meat percentage and eye muscle area of pigs from three-way cross and pigs from two-way cross were all significantly higher than those of Yesong pigs. Yesong pigs had relatively darker carnation, but marble vein （P〈0.05） and water loss rate （P〈0. 01 ） of Yesong pigs were relatively fewer than those of pigs from two-way cross and pigs from three-way cross. Shear force of Yesong pigs was significantly higher than that of pigs from two-way cross and pigs from three-way cross, [ Conclusion] Yesong hybrid pigs make full use of heterosis between wild pigs and Songliao black pigs for improvement of its meat quality, but some values of major economic traits in Yesong hybrid pigs is still lower than those in pigs from thrae-way cross and pigs from two-way cress.

Growth Performance, Undergrowth Diversity and Carbon Sequestration Potentials of Tree Species Stand Combinations, Ghana

The limited number of studies on mixed plantations makes it difficult to accurately predict success of mixed-species combination especially with regards to growth, undergrowth diversity and carbon sequestration potentials. This study therefore provides information on the effects of Ceiba pentandra, Terminalia superba, Cedrela odorata and Khaya anthotheca in three different stand combinations on growth, undergrowth diversity and carbon sequestration potential. A 15-year-old coupe of 32 ha of mixed tree species stand combinations was selected for the study. The coupe was stratified based on the species combinations. Nested sub-plots (25 m × 25 m) were randomly laid in different species stand combinations for growth data collection. In each nested sub-plot, 1 m × 1 m plots were also randomly laid for undergrowth diversity study. The results revealed that two species stand combination of Ceiba pentandra and Terminalia superba performed better in terms of growth, carbon sequestration and carbon content as compared to the other species stand combinations. The saplings on the other hand, were more diverse under the three species stand combination plots. Also, the effective number of species, species richness, evenness, and dominance were higher in the four species stand combination plots. Generally, Ceiba pentandra and Terminalia superba are compatible as it produced the highest growth and carbon sequestration potential.

Positioning Precision Analysis of GNSS Multi-frequency Carrier Phase Combinations

GPS positioning precision is affected by various error sources, and traditional combinations of GPS carrier phase observations have their own limitations such as the wide-lane, the narrow-lane and the ionospheric-free combinations. To obtain the optimal positioning precision, a new linear combination method is addressed through the variance-covariance （VCV） of the GPS multi-frequency carrier phase combination equations, and the impact of the positioning precision is analyzed with the changing of the observation errors deduced by the law of error propagation. For the high precision positioning with only one carrier phase combination, the optimal combination method is deduced and further validated by an example of a baseline resolution with 60 km length. The result indicates that this method is the simplest, and the positioning precision is the best. Therefore, it is useful for long baseline quick positioning for different precision requirements in various distances.

Immunotherapy in pancreatic cancer:Unleash its potential through novel combinations

Pancreatic cancer is the third leading cause of cancer mortality in both men and women in the United States,with poor response to current standard of care,short progression-free and overall survival.Immunotherapies that target cytotoxic T lymphocyte antigen-4,programmed cell death protein-1,and programmed death-ligand 1 checkpoints have shown remarkable activities in several cancers such as melanoma,renal cell carcinoma,and nonsmall cell lung cancer due to high numbers of somatic mutations,combined with cytotoxic T-cell responses.However,single checkpoint blockade was ineffective in pancreatic cancer,highlighting the challenges including the poor antigenicity,a dense desmoplastic stroma,and a largely immunosuppressive microenvironment.In this review,we will summarize available clinical results and ongoing efforts of combining immune checkpoint therapies with other treatment modalities such as chemotherapy,radiotherapy,and targeted therapy.These combination therapies hold promise in unleashing the potential of immunotherapy in pancreatic cancer to achieve better and more durable clinical responses by enhancing cytotoxic T-cell responses.