Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a com...Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.展开更多
Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvatio...Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.展开更多
Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer.Herein,we have constru...Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer.Herein,we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib(Gefi),ferrocene(Fc)and dihydroartemisinin(DHA)for the combined therapy of both ferroptosis and apoptosis.In the tumor microenvironment,this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH.Interestingly,the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc,further executing tumor cell death with concomitant chemotherapy by Gefi.More importantly,this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis,as well as no noticeable side-effects during treatments.This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.展开更多
Immunotherapy targets the dysfunctional immune system to induce cancer cell killing by CD8-positive T cells.Immune checkpoint inhibitors(ICIs),specifically anti-PD-1 antibodies,anti-PD-L1 antibodies,and anti-CTLA4 ant...Immunotherapy targets the dysfunctional immune system to induce cancer cell killing by CD8-positive T cells.Immune checkpoint inhibitors(ICIs),specifically anti-PD-1 antibodies,anti-PD-L1 antibodies,and anti-CTLA4 antibodies,have revolutionized the management of many malignancies due to their significant role in generating a durable clinical response.However,clinical data suggest that response rates to ICI monotherapy are low due to the immunologically silent characteristics of breast cancer(BC).Chemotherapy,surgery,radiotherapy,and targeted therapy were recently reported to alter the tumor microenvironment and enhance the ICI response.Some clinical studies supported that ICIs,in combination with other treatment strategies,show superior efficacy in BC control,especially triple-negative breast cancer.Therefore,seeking a reasonable combination therapy is a promising way to improve ICI response.The present review highlights the clinical efficacy of ICIs treatment options in combination with standard-of-care therapies,such as chemotherapy and targeted therapy。展开更多
Background: Vaginal discharge is one of the most common troubles faced by childbearing age women. About 20% - 25% of women who visit service of gynecology complain of vaginal discharge and leucorrhoea. Management of v...Background: Vaginal discharge is one of the most common troubles faced by childbearing age women. About 20% - 25% of women who visit service of gynecology complain of vaginal discharge and leucorrhoea. Management of vaginal discharge in low-income countries generally depends on syndromic approach, which limits the understanding of specific responsible agents. Thus targeted management is based on the identification of causal organism and targeting of therapy against it, while syndromic management is based on presence of high risk factors. Thus the oral combination kit (Azimyn FS Kit®) offers convenience of a one-day treatment compared to other multidose treatments, which will also ensure high patient adherence to treatment, thus increasing chances of desired results. Due to its widespread use, it is proposed to evaluate the effectiveness of this oral association kit therapy in management of vaginal discharge in the population of our milieu in the Democratic Republic of Congo (DRC) particularly those received in outpatient consultation in some medical facilities in city of Kinshasa. Expensive laboratory tests and the associated waiting period for result mean that patient remains without treatment while waiting for test results. Therefore, by adopting a syndromic management approach, patient’s eligibility for treatment will be decided based on abnormal vaginal discharge, their characteristics, severity and other presentations symptomatic. This approach will also avoid losing sight of patients during follow-up and will help to reduce financial burden for patients. Objectives: To determine the efficacy and safety of oral combination kit therapy containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in syndromic treatment of abnormal vaginal discharge in patients received in outpatient consultation in some medical facilities in the city of Kinshasa;to measure rate of recurrence of abnormal vaginal discharge in these patients. And to identify the adverse effects observed in these patients who received treatment with the combined oral kit containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in outpatient consultation in some medical facilities in the city of Kinshasa. Methods: It will be a cross-sectional descriptive study. Sample size will be 319 women of childbearing age who consult the gynecology department with complaint of abnormal vaginal discharge and suspicion of vaginal infection, who agree to abstain from sex during treatment and who have given their written consent to use their personal and/or health data in the study. Conclusion: A study on clinical efficacy of oral combination therapy based on secnidazole, azithromycin and fluconazole is beneficial.展开更多
AIM: In the present study, the characteristics of PEI-RFA treatment were further elucidated by analyzing the relationship between the volume of coagulated necrosis and the energy requirement for ablation or the amount...AIM: In the present study, the characteristics of PEI-RFA treatment were further elucidated by analyzing the relationship between the volume of coagulated necrosis and the energy requirement for ablation or the amount of ethanol injected into HCC.METHODS: The volume of coagulated necrosis, total energy requirement and energy requirement for coagulation of per unit volume were examined in the groups of PEI-RFA and RFA alone using the Cool-tip RF system.RESULTS: The results showed that the volume of coagulated necrosis induced was significantly larger in PEI-RFA group than in routine RFA group, when the total energy administered was comparable in both groups.In PEI-RFA, enlargement of coagulated necrosis was admitted in 3 dimensions and the amount of energy requirement per unit volume of coagulated necrosis was negatively correlated with the amount of ethanol injected into HCC.CONCLUSION: These results suggest that, compared to RFA alone, PEI-RFA enables to induce comparable coagulated necrosis with smaller energy requirement, and that PEI-RFA is likely to be less invasive than RFA alone irrespective of inducing enhanced coagulated necrosis.Thus, simple prior injection of ethanol may make RFA treatment more effective and less invasive for the treatment of patients with HCC.展开更多
OBJECTIVE： To evaluate the efficacy of α-lipoic acid（ALA） plus epalrestat combination therapy in the treatment of diabetic peripheral neuropathy（DPN）. DATA SOURCES： The electronic databases of Pub Med, Medline,...OBJECTIVE： To evaluate the efficacy of α-lipoic acid（ALA） plus epalrestat combination therapy in the treatment of diabetic peripheral neuropathy（DPN）. DATA SOURCES： The electronic databases of Pub Med, Medline, Embase, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Wanfang Database and the Chinese Biomedical Database were used to retrieve relevant studies without language restrictions. The search was conducted from the inception of each database to 7 October 2016. The key terms were（diabetic peripheral neuropathy or diabetic neuropathy or DPN） AND（α-lipoic acid or lipoic acid or thioctic acid） AND epalrestat. DATA SELECTION： All of the eligible studies met the following inclusion criteria：（1） Randomized controlled trials that compared efficacy and safety of epalrestat plus ALA combination therapy versus epalrestat or ALA monotherapy in patients with DPN.（2） The minimum duration of treatment was 2 weeks.（3） The DPN patients were diagnosed using the World Health Organization standardized type 2 diabetes mellitus and DPN criteria.（4） Studies contained at least one measure that could reflect the efficacy of the drug and nerve conduction velocities. Studies in which the control group used epalrestat or ALA combined with other drugs were excluded. Statistical analyses were performed using STATA software for meta-analysis. OUTCOME MEASURES： The primary outcomes were the therapeutic efficacy, median motor nerve conduction velocity（MNCV）, median sensory nerve conduction velocity（SNCV）, peroneal MNCV and peroneal SNCV.RESULTS： Twenty studies with 1894 DPN patients were included, including 864 patients in the ALA plus epalrestat group, 473 in the ALA group and 557 in the epalrestat group. The efficacy of ALA plus epalrestat combination therapy was superior to ALA and epalrestat monotherapies（RR = 1.29, 95% CI： 1.21–1.38; RR = 1.43, 95% CI： 1.34–1.54, respectively）. ALA plus epalrestat combination therapy also significantly improved median MNCV（WMD = 5.41, 95% CI： 2.07–8.75）, median SNCV（WMD = 5.87, 95% CI： 1.52–10.22）, peroneal MNCV（WMD = 5.59, 95% CI： 2.70–8.47） and peroneal SNCV（WMD = 4.57, 95% CI： 2.46–6.68）.CONCLUSION： ALA plus epalrestat combination therapy was superior to ALA and epalrestat monotherapies for clinical efficacy and nerve conduction velocities in patients with DPN.展开更多
BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos (t)ide a...BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos (t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively],though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.展开更多
Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different phar...Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic(PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties(e.g.,those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus,a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy.展开更多
AIM: To summarize the effects of laparoscopic ethanol injection and radiofrequency ablation (L-EI-RFA), thora- coscopic (T-EI-RFA) and open-surgery assisted EI-RFA (O-EI-RFA) under general anesthesia for the treatment...AIM: To summarize the effects of laparoscopic ethanol injection and radiofrequency ablation (L-EI-RFA), thora- coscopic (T-EI-RFA) and open-surgery assisted EI-RFA (O-EI-RFA) under general anesthesia for the treatment of hepatocellular carcinoma (HCC). METHODS: Time-lag performance of RFA after ethanol injection (Time-lag PEI-RFA) was performed in all cases. The volume of coagulated necrosis and the applied en- ergy for total and per unit volume coagulated necrosis were examined in the groups treated under general (group G) or local anesthesia (group L). RESULTS: The results showed that the total applied energy and the applied energy per unit volume of whole and marginal, coagulated necrosis were significantly larger in group G than those in the group L, resulting in a larger volume of coagulated necrosis in the group G. The rate of local tumor recurrence within one year was extremely low in group G. CONCLUSION: These results suggest that EI-RFA, un- der general anesthesia, may be effective for the treat- ment of HCC because a larger quantity of ethanol and energy could be applied during treatment under pain- free condition for the patients.展开更多
Bevacizumab, an angiogenesis inhibitor, is a recombined humanized monoclonal antibody against vascular endothelial growth factor and a promising therapeutic option for angiosarcoma management. This is a ease report an...Bevacizumab, an angiogenesis inhibitor, is a recombined humanized monoclonal antibody against vascular endothelial growth factor and a promising therapeutic option for angiosarcoma management. This is a ease report and review of the literature using bevacizumab and combination chemotherapy for angiosarcoma. The understanding of the effectiveness of combined therapy of bevacizumab and chemotherapy agents is still limited. The benefits of bevacizumab treatment for angiosarcoma will need to be weighed against the risks of venous thromboembolism in this population.展开更多
The introduction of oral phosphodiesterase-5 inhibitors （PDE51s） in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE51s are currently first-line monotherapy for erectile dysfunction...The introduction of oral phosphodiesterase-5 inhibitors （PDE51s） in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE51s are currently first-line monotherapy for erectile dysfunction （ED）. However, a significant proportion of patients with complex ED will be therapeutic non-responders to PDE51 monotherapy. Combination therapy has recently been adopted for more refractory cases of ED, but a critical evaluation of current combination therapies is lacking. A thorough PubMed and Cochrane Library search was conducted focusing on the effectiveness of combination therapies for ED in therapeutic non-responders to PDE51 therapy. Journal articles spanning the time period between January 1990 and December 2010 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Published combination therapies include PDE51 plus vacuum erectile device （VED）, intraurethral medication, intracavernosal injection （ICI）, androgen supplement, a-blocker or miscellaneous combinations. Based on this review, some of these combination treatments appeared to be quite effective in preliminary testing. Caution must be advised, however, as the majority of combination therapy articles in the last decade have numerous limitations including study biases and small subject size. Regardless of limitations, present combination therapy research provides a solid foundation for future studies in complex ED management.展开更多
AIM： The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C （CHC） and response of both viruses to combination therapy with high-dose interferon-alfa （IFN） plus ribavirin remai...AIM： The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C （CHC） and response of both viruses to combination therapy with high-dose interferon-alfa （IFN） plus ribavirin remain uncertain and are being investigated.METHODS： Total 164 （97 males and 67 females, the mean age 48.1＋11.4 years, range： 20-73 years, 128 histologically proved） naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method.Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay （COBAS AMPLICOR HCV Test, version 2.0）. HCV genotypes la,lb, 2a, 2b, and 3a were determined by using genotypespecific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay （Quantiplex HCV RNA 3.0）. There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined.RESULTS： Sixty-one （37.2%） patients were positive for SENV-D DNA and had higher mean age than those who were negative （50.7＋ 10.6 years vs 46.6＋ 11.6 years,P = 0.026）. The rate of sustained viral response （SVR） for HCV and SENV-D were 67.3% （105/156） and 56.3% （27/48）, respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b （P〈0.001）, younger ages （P = 0.014）, lower pretreatment levels of HCV RNA （P = 0.019） and higher histological activity index （HAI） score for intralobular regeneration and focal necrosis （P= 0.037）. By multivariate analyses, HCV genotype non-lb, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR （odds ratio （OR）/95% confidence interval （CI）： 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively）. The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy （P = 0.04）.CONCLUSION： Coexistent SENV-D infection, apparently associated with higher ages, is found in more than onethird Taiwan Residents CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.展开更多
Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrat...Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.展开更多
The present study evaluated the in vitro activity and in vivo efficacy of diminazene combined with chloroquine as a potential drug against Leishmania donovani. Amphotericin B was used as a positive control drug. In vi...The present study evaluated the in vitro activity and in vivo efficacy of diminazene combined with chloroquine as a potential drug against Leishmania donovani. Amphotericin B was used as a positive control drug. In vitro activity involved incubation of various drug concentrations with promastigotes or vero cells in culture before determination of parasite growth inhibition or cell death while in vivo evaluations involved infection of various mice groups with virulent L. donovani parasites and treatment with test drug compounds following disease establishment. Weight changes in experimental mice were also evaluated before infection and throughout the experiment. The results indicated that the diminazene-chloroquine combination was at least nine times more efficacious than individual drugs in killing promastigotes in culture. The diminazene-chloroquine combination was safer （Ld50=0.03±0.04） than Amphotericin B （Ld50=0.02±0.01）. Body weight in infected mice increased significantly （P=0.0007） from day 7 to day 37 following infection （P=0.026）. However, body weight remained comparable in all mice groups during treatment （P=0.16）. The diminazene-chloroquine combination significantly reduced splenic parasite numbers as compared to individual drug therapies （P=0.0001） although Amphotericin B was still more efficacious than any other treatment （P=0.0001）. Amongst the test compounds, the diminazene-chloroquine combination showed the lowest level of IgG antibody responses with results indicating significant negative correlation between antileishmanial antibody responses and protection against disease. These findings demonstrate the positive advantage and the potential use of a combined therapy of diminazene-chloroquine over the constituent drugs. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.展开更多
Sorafenib,a molecular targeted multi-kinase inhibitor,has received considerable interests in recent years due to its significant profiles of efficacy in cancer therapy.However,poor pharmacokinetic properties such as l...Sorafenib,a molecular targeted multi-kinase inhibitor,has received considerable interests in recent years due to its significant profiles of efficacy in cancer therapy.However,poor pharmacokinetic properties such as limited water solubility,rapid elimination and metabolism lead to low bioavailability,restricting its further clinical application.Over the past decade,with substantial progress achieved in the development of nanotechnology,various types of smart sorafenib nanoformulations have been developed to improve the targetability as well as the bioavailability of sorafenib.In this review,we summarize various aspects from the preparation and characterization to the evaluation of antitumor efficacy of numerous stimuli-responsive sorafenib nanodelivery systems,particularly with emphasis on their mechanism of drug release and tumor microenvironment response.In addition,this review makes great effort to summarize the nanosystem-based combination therapy of sorafenib with other antitumor agents,which can provide detailed information for further synergistic cancer therapy.In the final section of this review,we also provide a detailed discussion of future challenges and prospects of designing and developing ideal sorafenib nanoformulations for clinical cancer therapy.展开更多
Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination th...Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c,body weight,and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects.Since several agents from each class of these drugs have shown an improvement in cardiovascular(CV)and renal outcomes in their respective cardiovascular outcome trials(CVOT),combination therapy is theoretically expected to have additional CV and renal benefits.In this comprehensive opinion review,we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone,although body weight lowering was nearly additive and the SBP lowering was more than additive.Our additional meta-analysis of CV outcomes with GLP1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone,against placebo.Interestingly,a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials.Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.展开更多
The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties.As rep...The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties.As reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications,we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs;we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in mice.An increase in the expression of the tumor suppressor P21^(WAF1/CIP1) contributed to the synergistic mechanism of the combination therapy.These findings open a novel avenue for the treatment of KRAS-mutant lung cancer.展开更多
Diabetic wounds(DWs)are a common complication of diabetes mellitus;DWs have a low cure rate and likely recurrence,thus affecting the quality of patients’lives.As traditional therapy cannot effectively improve DW clos...Diabetic wounds(DWs)are a common complication of diabetes mellitus;DWs have a low cure rate and likely recurrence,thus affecting the quality of patients’lives.As traditional therapy cannot effectively improve DW closure,DW has become a severe clinical medical problem worldwide.Unlike routine wound healing,DW is difficult to heal because of its chronically arrested inflammatory phase.Although mesenchymal stem cells and their secreted cytokines can alleviate oxidative stress and stimulate angiogenesis in wounds,thereby promoting wound healing,the biological activity of mesenchymal stem cells is compromised by direct injection,which hinders their therapeutic effect.Hydrogels form a three-dimensional network that mimics the extracellular matrix,which can provide shelter for stem cells in the inflammatory microenvironment with reactive oxygen species in DW,and maintains the survival and viability of stem cells.This review summarizes the mechanisms and applications of stem cells and hydrogels in treating DW;additionally,it focuses on the different applications of therapy combining hydrogel and stem cells for DW treatment.展开更多
The long-term success of standard anticancer monotherapeutic strategies has been hampered by intolerable side effects,resistance to treatment and cancer relapse.These monotherapeutic strategies shrink the tumor bulk b...The long-term success of standard anticancer monotherapeutic strategies has been hampered by intolerable side effects,resistance to treatment and cancer relapse.These monotherapeutic strategies shrink the tumor bulk but do not effectively eliminate the population of self-renewing cancer stem cells(CSCs)that are normally present within the tumor.These surviving CSCs develop mechanisms of resistance to treatment and refuel the tumor,thus causing cancer relapse.To ensure durable tumor control,research has moved away from adopting the monotreatment paradigm towards developing and using combination therapy.Combining different therapeutic modalities has demonstrated significant therapeutic outcomes by strengthening the anti-tumor potential of monotreatment against cancer and cancer stem cells,mitigating their toxic adverse effects,and ultimately overcoming resistance.Recently,there has been growing interest in combining natural products from different sources or with clinically used chemotherapeutics to further improve treatment efficacy and tolerability.Thymoquinone(TQ),the main bioactive constituent of Nigella sativa,has gained great attention in combination therapy research after demonstrating its low toxicity to normal cells and remarkable anticancer efficacy in extensive preclinical studies in addition to its ability to target chemoresistant CSCs.Here,we provide an overview of the therapeutic responses resulting from combining TQ with conventional therapeutic agents such as alkylating agents,antimetabolites and antimicrotubules as well as with topoisomerase inhibitors and non-coding RNA.We also review data on anticancer effects of TQ when combined with ionizing radiation and several natural products such as vitamin D3,melatonin and other compounds derived from Chinese medicinal plants.The focus of this review is on two outcomes of TQ combination therapy,namely eradicating CSCs and treating various types of cancers.In conclusion,the ability of TQ to potentiate the anticancer activity of many chemotherapeutic agents and sensitize cancer cells to radiotherapy makes it a promising molecule that could be used in combination therapy to overcome resistance to standard chemotherapeutic agents and reduce their associated toxicities.展开更多
文摘Inflammatory bowel disease(IBD)is entering a potentially new era of combined therapeutics.Triantafillidis et al provide an insightful review of the current state of combination therapy,with a focus on the use of a combined biologic and immunomodulator,as well as emerging data on the future potential of dual-biologic therapy(DBT).While current evidence for DBT is limited,encouraging safety profiles and ongoing trials suggest a brighter future for this approach.The importance of controlled trials should be stressed in establishing new treatment paradigms.Ongoing prospective randomized trials of DBT and perhaps future combinations of biologics and small molecule therapies will hopefully guide the next generation of IBD care.
基金the National Natural Science Foundation of China(Grant Nos.:82102767 and 82002655)the 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project,West China Hospital,Sichuan University,China(Grant No.:2020HXFH036)+2 种基金the Knowledge Innovation Program of the Chinese Academy of Sciences,China(Grant No.:JH2022007)the Cultivation Project of Basic Medical College of Xinxiang Medical University,China(Grant No.:JCYXYKY202112)the Key Project of Science and Technology of Henan Province,China(Grant No.:222102310260).
文摘Despite decades of laboratory and clinical trials,breast cancer remains the main cause of cancer-related disease burden in women.Considering the metabolism destruction effect of metformin(Met)and cancer cell starvation induced by glucose oxidase(GOx),after their efficient delivery to tumor sites,GOx and Met may consume a large amount of glucose and produce sufficient hydrogen peroxide in situ.Herein,a pH-responsive epigallocatechin gallate(EGCG)-conjugated low-molecular-weight chitosan(LC-EGCG,LE)nanoparticle(Met–GOx/Fe@LE NPs)was constructed.The coordination between iron ions(Fe3+)and EGCG in this nanoplatform can enhance the efficacy of chemodynamic therapy via the Fenton reaction.Met–GOx/Fe@LE NPs allow GOx to retain its enzymatic activity while simultaneously improving its stability.Moreover,this pH-responsive nanoplatform presents controllable drug release behavior.An in vivo biodistribution study showed that the intracranial accumulation of GOx delivered by this nanoplatform was 3.6-fold higher than that of the free drug.The in vivo anticancer results indicated that this metabolism destruction/starvation/chemodynamic triple-combination therapy could induce increased apoptosis/death of tumor cells and reduce their proliferation.This triple-combination therapy approach is promising for efficient and targeted cancer treatment.
基金financial supports from National Natural Science Foundation of China(32000992,21977081,32101124)the Zhejiang Provincial Natural Science Foundation for Distinguished Young Scholar(LR23C100001)+1 种基金Wenzhou Medical University(KYYW201901)Zhejiang Qianjiang Talent Plan(QJD20020224)
文摘Ferroptosis has emerged as a potent form of no-apoptotic cell death that offers a promising alternative to avoid the chemoresistance of apoptotic pathways and serves as a vulnerability of cancer.Herein,we have constructed a biomimetic self-assembly nano-prodrug system that enables the co-delivery of gefitinib(Gefi),ferrocene(Fc)and dihydroartemisinin(DHA)for the combined therapy of both ferroptosis and apoptosis.In the tumor microenvironment,this nano-prodrug is able to disassemble and trigger drug release under high levels of GSH.Interestingly,the released DHA can downregulate GPX4 level for the enhancement of intracellular ferroptosis from Fc,further executing tumor cell death with concomitant chemotherapy by Gefi.More importantly,this nano-prodrug provides highly homologous targeting ability by coating related cell membranes and exhibits outstanding inhibition of tumor growth and metastasis,as well as no noticeable side-effects during treatments.This simple small molecular self-assembled nano-prodrug provides a new reasonably designed modality for ferroptosis-combined chemotherapy.
文摘Immunotherapy targets the dysfunctional immune system to induce cancer cell killing by CD8-positive T cells.Immune checkpoint inhibitors(ICIs),specifically anti-PD-1 antibodies,anti-PD-L1 antibodies,and anti-CTLA4 antibodies,have revolutionized the management of many malignancies due to their significant role in generating a durable clinical response.However,clinical data suggest that response rates to ICI monotherapy are low due to the immunologically silent characteristics of breast cancer(BC).Chemotherapy,surgery,radiotherapy,and targeted therapy were recently reported to alter the tumor microenvironment and enhance the ICI response.Some clinical studies supported that ICIs,in combination with other treatment strategies,show superior efficacy in BC control,especially triple-negative breast cancer.Therefore,seeking a reasonable combination therapy is a promising way to improve ICI response.The present review highlights the clinical efficacy of ICIs treatment options in combination with standard-of-care therapies,such as chemotherapy and targeted therapy。
文摘Background: Vaginal discharge is one of the most common troubles faced by childbearing age women. About 20% - 25% of women who visit service of gynecology complain of vaginal discharge and leucorrhoea. Management of vaginal discharge in low-income countries generally depends on syndromic approach, which limits the understanding of specific responsible agents. Thus targeted management is based on the identification of causal organism and targeting of therapy against it, while syndromic management is based on presence of high risk factors. Thus the oral combination kit (Azimyn FS Kit®) offers convenience of a one-day treatment compared to other multidose treatments, which will also ensure high patient adherence to treatment, thus increasing chances of desired results. Due to its widespread use, it is proposed to evaluate the effectiveness of this oral association kit therapy in management of vaginal discharge in the population of our milieu in the Democratic Republic of Congo (DRC) particularly those received in outpatient consultation in some medical facilities in city of Kinshasa. Expensive laboratory tests and the associated waiting period for result mean that patient remains without treatment while waiting for test results. Therefore, by adopting a syndromic management approach, patient’s eligibility for treatment will be decided based on abnormal vaginal discharge, their characteristics, severity and other presentations symptomatic. This approach will also avoid losing sight of patients during follow-up and will help to reduce financial burden for patients. Objectives: To determine the efficacy and safety of oral combination kit therapy containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in syndromic treatment of abnormal vaginal discharge in patients received in outpatient consultation in some medical facilities in the city of Kinshasa;to measure rate of recurrence of abnormal vaginal discharge in these patients. And to identify the adverse effects observed in these patients who received treatment with the combined oral kit containing secnidazole, azithromycin and fluconazole (Azimyn FS Kit®) in outpatient consultation in some medical facilities in the city of Kinshasa. Methods: It will be a cross-sectional descriptive study. Sample size will be 319 women of childbearing age who consult the gynecology department with complaint of abnormal vaginal discharge and suspicion of vaginal infection, who agree to abstain from sex during treatment and who have given their written consent to use their personal and/or health data in the study. Conclusion: A study on clinical efficacy of oral combination therapy based on secnidazole, azithromycin and fluconazole is beneficial.
文摘AIM: In the present study, the characteristics of PEI-RFA treatment were further elucidated by analyzing the relationship between the volume of coagulated necrosis and the energy requirement for ablation or the amount of ethanol injected into HCC.METHODS: The volume of coagulated necrosis, total energy requirement and energy requirement for coagulation of per unit volume were examined in the groups of PEI-RFA and RFA alone using the Cool-tip RF system.RESULTS: The results showed that the volume of coagulated necrosis induced was significantly larger in PEI-RFA group than in routine RFA group, when the total energy administered was comparable in both groups.In PEI-RFA, enlargement of coagulated necrosis was admitted in 3 dimensions and the amount of energy requirement per unit volume of coagulated necrosis was negatively correlated with the amount of ethanol injected into HCC.CONCLUSION: These results suggest that, compared to RFA alone, PEI-RFA enables to induce comparable coagulated necrosis with smaller energy requirement, and that PEI-RFA is likely to be less invasive than RFA alone irrespective of inducing enhanced coagulated necrosis.Thus, simple prior injection of ethanol may make RFA treatment more effective and less invasive for the treatment of patients with HCC.
基金supported by the National Natural Science Foundation of China,No.81370165a grant from the Public Benefit Technology and Society Development Program of Zhejiang Province of China,No.2015C33309+2 种基金a grant from the Ningbo Science and Technology Innovation Team Program in China,No.2014B82002,2015B11050a grant from the Ningbo Science and Technology Project in China,No.2015A610217the Fang Runhua Fund of Hong Kong,K.C.Wong Magna Fund in Ningbo University
文摘OBJECTIVE： To evaluate the efficacy of α-lipoic acid（ALA） plus epalrestat combination therapy in the treatment of diabetic peripheral neuropathy（DPN）. DATA SOURCES： The electronic databases of Pub Med, Medline, Embase, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Wanfang Database and the Chinese Biomedical Database were used to retrieve relevant studies without language restrictions. The search was conducted from the inception of each database to 7 October 2016. The key terms were（diabetic peripheral neuropathy or diabetic neuropathy or DPN） AND（α-lipoic acid or lipoic acid or thioctic acid） AND epalrestat. DATA SELECTION： All of the eligible studies met the following inclusion criteria：（1） Randomized controlled trials that compared efficacy and safety of epalrestat plus ALA combination therapy versus epalrestat or ALA monotherapy in patients with DPN.（2） The minimum duration of treatment was 2 weeks.（3） The DPN patients were diagnosed using the World Health Organization standardized type 2 diabetes mellitus and DPN criteria.（4） Studies contained at least one measure that could reflect the efficacy of the drug and nerve conduction velocities. Studies in which the control group used epalrestat or ALA combined with other drugs were excluded. Statistical analyses were performed using STATA software for meta-analysis. OUTCOME MEASURES： The primary outcomes were the therapeutic efficacy, median motor nerve conduction velocity（MNCV）, median sensory nerve conduction velocity（SNCV）, peroneal MNCV and peroneal SNCV.RESULTS： Twenty studies with 1894 DPN patients were included, including 864 patients in the ALA plus epalrestat group, 473 in the ALA group and 557 in the epalrestat group. The efficacy of ALA plus epalrestat combination therapy was superior to ALA and epalrestat monotherapies（RR = 1.29, 95% CI： 1.21–1.38; RR = 1.43, 95% CI： 1.34–1.54, respectively）. ALA plus epalrestat combination therapy also significantly improved median MNCV（WMD = 5.41, 95% CI： 2.07–8.75）, median SNCV（WMD = 5.87, 95% CI： 1.52–10.22）, peroneal MNCV（WMD = 5.59, 95% CI： 2.70–8.47） and peroneal SNCV（WMD = 4.57, 95% CI： 2.46–6.68）.CONCLUSION： ALA plus epalrestat combination therapy was superior to ALA and epalrestat monotherapies for clinical efficacy and nerve conduction velocities in patients with DPN.
基金supported by grants from the Major State Basic Research Development Program (973) (No. 2007CB512905)the National Natural Science Foundation of China (No. 30771918)the Major State S&T Projects of China (11th Five-Year) (2008ZX10002-007)
文摘BACKGROUND: It has been demonstrated that only a minority of patients with hepatitis B e antigen (HBeAg) negative chronic hepatitis B (CHB) obtain a sustained response after either interferon (IFN) or nucleos (t)ide analogue monotherapy. Therefore, combination therapy of drugs with synergistic antiviral effects was proposed to have a sustained response in these patients. We compared the effect and safety of lamivudine monotherapy and its combination with IFN including conventional interferon (CON-IFN) and pegylated interferon (PEG-IFN) for HBeAg-negative CHB patients. DATA SOURCES: A group of three independent reviewers identified 9 eligible randomized controlled trials through electronic searches (MEDLINE, OVID, EMBASE, the Cochrane Library Clinical Trials Registry, and the Chinese Medical Database), manual searches, and contact with experts. Sustained virological and biochemical responses were defined as primary efficacy measures. We performed quantitative meta-analyses to assess differences between CON-IFN plus lamivudine combination and lamivudine monotherapy groups. RESULTS: No greater sustained virological and biochemical rates were found in patients receiving CON-IFN/lamivudine combination therapy [29.1% vs. 26.7%, odds ratio (OR)=0.98, 95% confidence interval (CI) 0.65-1.50, P=0.94, and 41.8% vs. 40.3%, OR=1.13, 95% CI 0.78-1.65, P=0.51, respectively],though a reduced YMDD mutation rate was achieved in the combination group [8.39% vs. 30.0%, OR=0.16, 95% CI 0.076-0.33, P<0.001]. However, data from one PEG-IFN trial showed greater sustained virological and biochemical rates in patients receiving combination therapy [response rate 19.5% vs. 6.6%, OR=3.42, 95% CI 1.71-6.84, P<0.001 and 60.0% vs. 44.2%, OR=1.88, 95% CI 1.23-2.85, P=0.003, respectively]. CONCLUSIONS: Addition of CON-IFN to lamivudine did not improve treatment efficacy but suppressed YMDD mutation by lamivudine. Combination of PEG-IFN and lamivudine might increase the sustained response, and further clinical trials are needed for confirmation.
基金supported by the grants from the National Basic Research Program of China(Grant No.973 Program 2014CB931900,2013CB932503)National Natural Science Foundation of China(Grant No.81373357,81422048,81673382,81521005)
文摘Multidrug resistance(MDR) is a major obstacle to successful cancer treatment and is crucial to cancer metastasis and relapse.Combination therapy is an effective strategy for overcoming MDR. However, the different pharmacokinetic(PK) profiles of combined drugs often undermine the combination effect in vivo, especially when greatly different physicochemical properties(e.g.,those of macromolecules and small drugs) combine. To address this issue, nanotechnology-based codelivery techniques have been actively explored. They possess great advantages for tumor targeting, controlled drug release, and identical drug PK profiles. Thus,a powerful tool for combination therapy is provided, and the translation from in vitro to in vivo is facilitated. In this review, we present a summary of various combination strategies for overcoming MDR and the nanotechnology-based combination therapy.
文摘AIM: To summarize the effects of laparoscopic ethanol injection and radiofrequency ablation (L-EI-RFA), thora- coscopic (T-EI-RFA) and open-surgery assisted EI-RFA (O-EI-RFA) under general anesthesia for the treatment of hepatocellular carcinoma (HCC). METHODS: Time-lag performance of RFA after ethanol injection (Time-lag PEI-RFA) was performed in all cases. The volume of coagulated necrosis and the applied en- ergy for total and per unit volume coagulated necrosis were examined in the groups treated under general (group G) or local anesthesia (group L). RESULTS: The results showed that the total applied energy and the applied energy per unit volume of whole and marginal, coagulated necrosis were significantly larger in group G than those in the group L, resulting in a larger volume of coagulated necrosis in the group G. The rate of local tumor recurrence within one year was extremely low in group G. CONCLUSION: These results suggest that EI-RFA, un- der general anesthesia, may be effective for the treat- ment of HCC because a larger quantity of ethanol and energy could be applied during treatment under pain- free condition for the patients.
基金supported by the Wu Jieping Medical Foundation Grant (No. 320.6750.11074)
文摘Bevacizumab, an angiogenesis inhibitor, is a recombined humanized monoclonal antibody against vascular endothelial growth factor and a promising therapeutic option for angiosarcoma management. This is a ease report and review of the literature using bevacizumab and combination chemotherapy for angiosarcoma. The understanding of the effectiveness of combined therapy of bevacizumab and chemotherapy agents is still limited. The benefits of bevacizumab treatment for angiosarcoma will need to be weighed against the risks of venous thromboembolism in this population.
文摘The introduction of oral phosphodiesterase-5 inhibitors （PDE51s） in the late 1990s and early 2000s revolutionized the field of sexual medicine and PDE51s are currently first-line monotherapy for erectile dysfunction （ED）. However, a significant proportion of patients with complex ED will be therapeutic non-responders to PDE51 monotherapy. Combination therapy has recently been adopted for more refractory cases of ED, but a critical evaluation of current combination therapies is lacking. A thorough PubMed and Cochrane Library search was conducted focusing on the effectiveness of combination therapies for ED in therapeutic non-responders to PDE51 therapy. Journal articles spanning the time period between January 1990 and December 2010 were reviewed. Criteria included all pertinent review articles, randomized controlled trials, cohort studies and retrospective analyses. References from retrieved articles were also manually scanned for additional relevant publications. Published combination therapies include PDE51 plus vacuum erectile device （VED）, intraurethral medication, intracavernosal injection （ICI）, androgen supplement, a-blocker or miscellaneous combinations. Based on this review, some of these combination treatments appeared to be quite effective in preliminary testing. Caution must be advised, however, as the majority of combination therapy articles in the last decade have numerous limitations including study biases and small subject size. Regardless of limitations, present combination therapy research provides a solid foundation for future studies in complex ED management.
基金Supported by the National Science Council Grant, No. NSC-91-2314-B037-344
文摘AIM： The clinical significance of co-infection of SENV-D among patients with chronic hepatitis C （CHC） and response of both viruses to combination therapy with high-dose interferon-alfa （IFN） plus ribavirin remain uncertain and are being investigated.METHODS： Total 164 （97 males and 67 females, the mean age 48.1＋11.4 years, range： 20-73 years, 128 histologically proved） naive CHC patients were enrolled in this study. SENV-D DNA was tested by PCR method.Detection of serum HCV RNA was performed using a standardized automated qualitative RT-PCR assay （COBAS AMPLICOR HCV Test, version 2.0）. HCV genotypes la,lb, 2a, 2b, and 3a were determined by using genotypespecific primers. Pretreatment HCV RNA levels were determined by using the branched DNA assay （Quantiplex HCV RNA 3.0）. There are 156 patients receiving combination therapy with IFN 6 MU plus ribavirin for 24 wk and the response to therapy is determined.RESULTS： Sixty-one （37.2%） patients were positive for SENV-D DNA and had higher mean age than those who were negative （50.7＋ 10.6 years vs 46.6＋ 11.6 years,P = 0.026）. The rate of sustained viral response （SVR） for HCV and SENV-D were 67.3% （105/156） and 56.3% （27/48）, respectively. By univariate analysis, the higher rate of SVR was significantly related to HCV genotype non-1b （P〈0.001）, younger ages （P = 0.014）, lower pretreatment levels of HCV RNA （P = 0.019） and higher histological activity index （HAI） score for intralobular regeneration and focal necrosis （P= 0.037）. By multivariate analyses, HCV genotype non-lb, younger age and lower pretreatment HCV RNA levels were significantly associated with HCV SVR （odds ratio （OR）/95% confidence interval （CI）： 12.098/0.02-0.19, 0.936/0.890-0.998, and 3.131/1.080-9.077, respectively）. The SVR of SENV-D was higher among patients clearing SENV-D than those who had viremia at the end of therapy （P = 0.04）.CONCLUSION： Coexistent SENV-D infection, apparently associated with higher ages, is found in more than onethird Taiwan Residents CHC patients. Both HCV and SENV-D are highly susceptible to combination therapy with high-dose IFN and ribavirin and SENV-D co-infection does not affect the HCV response. HCV genotype, pretreatment HCV RNA levels and age are predictive factors for HCV SVR.
基金The study was supported by DOD Prostate Cancer Research Program PC150221,R.Stephenson Family Fund.
文摘Androgen deprivation therapy(ADT)has been the standard of care for the last 75 years in metastatic hormone sensitive prostate cancer(PCa).However,this approach is rarely curative.Recent clinical trials have demonstrated that ADT combined with other agents,notably docetaxel and abiraterone,lead to improved survival.The mechanisms surrounding this improved cancer outcomes are incompletely defined.The response of cancer cells to ADT includes apoptosis and cell death,but a significant fraction remains viable.Our laboratory has demonstrated both in vitro and in vivo that cellular senescence occurs in a subset of these cells.Cellular senescence is a phenotype characterized by cell cycle arrest,senescenceassociated b-galactosidase(SA-b-gal),and a hypermetabolic state.Positive features of cellular senescence include growth arrest and immune stimulation,although persistence may release cytokines and growth factors that are detrimental.Senescent tumor cells generate a catabolic state with increased glycolysis,protein turnover and other metabolic changes that represent targets for drugs,like metformin,to be applied in a synthetic lethal approach.This review examines the response to ADT and the putative role of cellular senescence as a biomarker and therapeutic target in this context.
基金partly supported by BPM Bulk Medicine and Pharmaceuticals Production,TROPMED GMbH,Neuhofer Welche 48,D-19370 Parchtm,Germany,courtesy of Dr Alain J.Bourdichon
文摘The present study evaluated the in vitro activity and in vivo efficacy of diminazene combined with chloroquine as a potential drug against Leishmania donovani. Amphotericin B was used as a positive control drug. In vitro activity involved incubation of various drug concentrations with promastigotes or vero cells in culture before determination of parasite growth inhibition or cell death while in vivo evaluations involved infection of various mice groups with virulent L. donovani parasites and treatment with test drug compounds following disease establishment. Weight changes in experimental mice were also evaluated before infection and throughout the experiment. The results indicated that the diminazene-chloroquine combination was at least nine times more efficacious than individual drugs in killing promastigotes in culture. The diminazene-chloroquine combination was safer （Ld50=0.03±0.04） than Amphotericin B （Ld50=0.02±0.01）. Body weight in infected mice increased significantly （P=0.0007） from day 7 to day 37 following infection （P=0.026）. However, body weight remained comparable in all mice groups during treatment （P=0.16）. The diminazene-chloroquine combination significantly reduced splenic parasite numbers as compared to individual drug therapies （P=0.0001） although Amphotericin B was still more efficacious than any other treatment （P=0.0001）. Amongst the test compounds, the diminazene-chloroquine combination showed the lowest level of IgG antibody responses with results indicating significant negative correlation between antileishmanial antibody responses and protection against disease. These findings demonstrate the positive advantage and the potential use of a combined therapy of diminazene-chloroquine over the constituent drugs. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.
基金This project was supported by the National Natural Science Foundation of China(81972832)Project supported by College Students’innovation and entrepreneurship training program of Fujian Province(S202010386051).
文摘Sorafenib,a molecular targeted multi-kinase inhibitor,has received considerable interests in recent years due to its significant profiles of efficacy in cancer therapy.However,poor pharmacokinetic properties such as limited water solubility,rapid elimination and metabolism lead to low bioavailability,restricting its further clinical application.Over the past decade,with substantial progress achieved in the development of nanotechnology,various types of smart sorafenib nanoformulations have been developed to improve the targetability as well as the bioavailability of sorafenib.In this review,we summarize various aspects from the preparation and characterization to the evaluation of antitumor efficacy of numerous stimuli-responsive sorafenib nanodelivery systems,particularly with emphasis on their mechanism of drug release and tumor microenvironment response.In addition,this review makes great effort to summarize the nanosystem-based combination therapy of sorafenib with other antitumor agents,which can provide detailed information for further synergistic cancer therapy.In the final section of this review,we also provide a detailed discussion of future challenges and prospects of designing and developing ideal sorafenib nanoformulations for clinical cancer therapy.
文摘Both GLP-1 receptor agonists(GLP-1RA)and SGLT-2 inhibitors(SGLT-2I)are newer classes of anti-diabetic agents that lower HbA1c moderately and decrease body weight and systolic blood pressure(SBP)modestly.Combination therapy with GLP-1RA plus SGLT-2I have shown a greater reduction in HbA1c,body weight,and SBP compared to either agent alone without any significant increase in hypoglycemia or other side effects.Since several agents from each class of these drugs have shown an improvement in cardiovascular(CV)and renal outcomes in their respective cardiovascular outcome trials(CVOT),combination therapy is theoretically expected to have additional CV and renal benefits.In this comprehensive opinion review,we found HbA1c lowering with GLP-1RA plus SGLT-2I to be less than additive compared to the sum of HbA1c lowering with either agent alone,although body weight lowering was nearly additive and the SBP lowering was more than additive.Our additional meta-analysis of CV outcomes with GLP1RA plus SGLT-2I combination therapy from the pooled data of five CVOT found a similar reduction in three-point major adverse cardiovascular events compared to GLP-1RA or SGLT-2I alone,against placebo.Interestingly,a greater benefit in reduction of heart failure hospitalization with GLP-1RA plus SGLT-2I combination therapy was noted in the pooled meta-analysis of two randomized controlled trials.Future adequately powered trials can confirm whether additional CV or renal benefit is truly exerted by GLP-1RA plus SGLT-2I combination therapy.
基金supported by grants from the National Natural Science Foundation of China(Grant 81672758)the Science and Technology Commission of Shanghai Municipality(Grants 16ZR1410400 and 14DZ2270100)the Fundamental Research Funds for the Central Universities(Grant 78260029)
文摘The KRAS gene is frequently mutated in multiple cancer types,but it fell off the drug discovery radar for many years because of its inherent "undruggable" structure and undefined biological properties.As reported in the paper entitled "Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK" in Nature Communications,we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs;we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase markedly suppressed tumor growth in mice.An increase in the expression of the tumor suppressor P21^(WAF1/CIP1) contributed to the synergistic mechanism of the combination therapy.These findings open a novel avenue for the treatment of KRAS-mutant lung cancer.
基金Supported by the Shenzhen Basic Research Project,No.JCYJ20190807155805818the Foundation of Guangdong Provincial Key Laboratory of Sensor Technology and Biomedical Instrument,No.2020B1212060077.
文摘Diabetic wounds(DWs)are a common complication of diabetes mellitus;DWs have a low cure rate and likely recurrence,thus affecting the quality of patients’lives.As traditional therapy cannot effectively improve DW closure,DW has become a severe clinical medical problem worldwide.Unlike routine wound healing,DW is difficult to heal because of its chronically arrested inflammatory phase.Although mesenchymal stem cells and their secreted cytokines can alleviate oxidative stress and stimulate angiogenesis in wounds,thereby promoting wound healing,the biological activity of mesenchymal stem cells is compromised by direct injection,which hinders their therapeutic effect.Hydrogels form a three-dimensional network that mimics the extracellular matrix,which can provide shelter for stem cells in the inflammatory microenvironment with reactive oxygen species in DW,and maintains the survival and viability of stem cells.This review summarizes the mechanisms and applications of stem cells and hydrogels in treating DW;additionally,it focuses on the different applications of therapy combining hydrogel and stem cells for DW treatment.
文摘The long-term success of standard anticancer monotherapeutic strategies has been hampered by intolerable side effects,resistance to treatment and cancer relapse.These monotherapeutic strategies shrink the tumor bulk but do not effectively eliminate the population of self-renewing cancer stem cells(CSCs)that are normally present within the tumor.These surviving CSCs develop mechanisms of resistance to treatment and refuel the tumor,thus causing cancer relapse.To ensure durable tumor control,research has moved away from adopting the monotreatment paradigm towards developing and using combination therapy.Combining different therapeutic modalities has demonstrated significant therapeutic outcomes by strengthening the anti-tumor potential of monotreatment against cancer and cancer stem cells,mitigating their toxic adverse effects,and ultimately overcoming resistance.Recently,there has been growing interest in combining natural products from different sources or with clinically used chemotherapeutics to further improve treatment efficacy and tolerability.Thymoquinone(TQ),the main bioactive constituent of Nigella sativa,has gained great attention in combination therapy research after demonstrating its low toxicity to normal cells and remarkable anticancer efficacy in extensive preclinical studies in addition to its ability to target chemoresistant CSCs.Here,we provide an overview of the therapeutic responses resulting from combining TQ with conventional therapeutic agents such as alkylating agents,antimetabolites and antimicrotubules as well as with topoisomerase inhibitors and non-coding RNA.We also review data on anticancer effects of TQ when combined with ionizing radiation and several natural products such as vitamin D3,melatonin and other compounds derived from Chinese medicinal plants.The focus of this review is on two outcomes of TQ combination therapy,namely eradicating CSCs and treating various types of cancers.In conclusion,the ability of TQ to potentiate the anticancer activity of many chemotherapeutic agents and sensitize cancer cells to radiotherapy makes it a promising molecule that could be used in combination therapy to overcome resistance to standard chemotherapeutic agents and reduce their associated toxicities.
