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Journal Drug Design, Development and Therapy

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Drug Design, Development and Therapy; doi:10.2147/dddt

Abstract:An international, peer-reviewed, Open Access journal that spans the spectrum of drug design and development through to clinical applications. The journal is characterized by the rapid reporting of application notes, reviews, original research and clinical studies in all therapeutic areas.
Qingquan Wei, Rui Chen, Qiyang Lou, Jing Yu
Drug Design, Development and Therapy, Volume 13, pp 301-307; doi:10.2147/dddt.s184520

Abstract:Intravitreal corticosteroid implant vs intravitreal ranibizumab for the treatment of macular edema: a meta-analysis of randomized controlled trials Qingquan Wei,1,2,* Rui Chen,1,2,* Qiyang Lou,1,2 Jing Yu1,2 1Department of Ophthalmology, Ninghai First Hospital, Zhejiang 315600, People’s Republic of China; 2Department of Ophthalmology, Shanghai Tenth People’s Hospital Affiliated with Tongji University, Shanghai 200072, People’s Republic of China *These authors contributed equally to this work Purpose: The purpose of this meta-analysis was to compare the efficacy and safety of corticosteroid implant and intravitreal ranibizumab for the treatment of macular edema (ME).Materials and methods: PubMed, Embase, Web of Science, and the Cochrane Central Register of Controlled Trials were comprehensively searched for studies comparing dexamethasone implant with ranibizumab in patients with ME. Best-corrected visual acuity (BCVA), central subfield thickness (CST), and adverse events were extracted from the final eligible studies. RevMan 5.3 software was used to analyze the data, and the modified Jadad assessment tool was used to access the quality of outcomes.Results: Three randomized controlled trials (RCTs) were included in our analysis. The types of causes of ME include central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), and diabetic retinopathy (DR). The ranibizumab treatment group had significantly better BCVA compared with the corticosteroid treatment group (standard mean difference [SMD] -0.80; 95% CI -1.08, -0.53; P<0.00001). The ranibizumab treatment group also had higher CST reduction compared with the corticosteroid treatment group, and there was a significant difference (weighted mean difference [WMD] 167.58; 95% CI 125.21–209.95; P<0.00001). There was no significant difference in serious adverse effects between the two groups (SMD 1.67; 95% CI 0.69, 4.05; P=0.26). However, the use of corticosteroid implant had a higher risk of intraocular pressure (IOP) (OR 6.88; 95% CI 4.53–10.44; P<0.00001) elevation and cataract (OR 3.98; 95% CI 1.89–8.37; P=0.0003) than ranibizumab treatment and fewer injections.Conclusions: Compared with ranibizumab, corticosteroid implant did not have greater improved BCVA, but corticosteroid implant had less CST reduction. The advantages of corticosteroids are fewer injections, while the advantages of ranibizumab include fewer side effects. Keywords: macular edema, dexamethasone implant, ranibizumab, meta-analysis
Hui Tong, Kai Zhao, Jingyu Zhang, Jinxin Zhu, Jianqi Xiao
Drug Design, Development and Therapy, Volume 13, pp 317-326; doi:10.2147/dddt.s185514

Abstract:YB-1 modulates the drug resistance of glioma cells by activation of MDM2/p53 pathway Hui Tong,1,* Kai Zhao,2,* Jingyu Zhang,3 Jinxin Zhu,4 Jianqi Xiao2 1Department of Neurosurgery, Linyi Central Hospital, Linyi, Shandong 276400, People’s Republic of China; 2Department of Neurosurgery, The First Hospital of Qiqihar City, Qiqihar, Heilongjiang 161005, People’s Republic of China; 3Department of Internal Medicine, Jiangpu District Health Center of Huai’an, Huai’an, Jiangsu, 223001, People’s Republic of China; 4Department of Neurosurgery, Lianshui County People’s Hospital, Huai’an, Jiangsu 223400, People’s Republic of China *These authors contributed equally to this work Background: Y-box-binding protein-1 (YB-1) is aberrantly expressed in a variety of cancers. However, the biological functional role of YB-1 in glioma is not yet clear. Methods: The expression of MDM2 and YB-1 was analyzed by real time PCR. Overexpression and knockdown of YB-1 in glioma cells were created by transfection of pcDNA-YB-1 and siRNA against YB-1, respectively. Cell viability was performed by CCK8 assay.Results: Our findings showed that glioma tissues had higher expressions of YB-1 than that in cancer-free tissues in 54 glioma patients, which were also positively correlated with Murine MDM2 expression. Overexpression of YB-1 or MDM2 renders a drug resistance feature in glioma cell exposed to temozolomide (TMZ), by directly targeting p53. Genetic or chemical inhibition of MDM2 significantly blocked YB-1-modulated response of glioma cells to TMZ. Moreover, inhibition of YB-1 or MDM2 reduced glioma cells metastasis and mortality in mice. Conclusion: YB-1 facilitates the resistance of glioma cells to TMZ by direct activation of MDM2/p53 signaling and represents a promising molecular target for glioma treatment. Keywords: glioma, p53, Murine double minute 2, Y-box binding protein-1, drug resistance, temozolomide
Kerolos Ashraf, Kaveh Yasrebi, Emmanuel Tola Adeniyi, Tobias Hertlein, Knut Ohlsen, Michael Lalk, Frank Erdmann, Andreas Hilgeroth
Drug Design, Development and Therapy, Volume 13, pp 275-283; doi:10.2147/dddt.s184965

Abstract:Antistaphylococcal evaluation of indole-naphthalene hybrid analogs Kerolos Ashraf,1 Kaveh Yasrebi,1 Emmanuel Tola Adeniyi,2 Tobias Hertlein,2 Knut Ohlsen,2 Michael Lalk,3 Frank Erdmann,1 Andreas Hilgeroth1 1Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany; 2Institute of Molecular Infection Biology, Julius Maximilians University Würzburg, Würzburg, Germany; 3Institute of Biochemistry, Ernst Moritz Arndt University Greifswald, Greifswald, Germany Resistance developments against established antibiotics are an emerging problem for antibacterial therapies. Infections with Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) have become more difficult to treat with standard antibiotics that often fail, especially against MRSA. In consequence, novel antibiotics are urgently needed. Antibiotics from natural sources own complicated structures that cause difficulties for a chemical synthetic production. We developed novel small-molecule antibacterials that are easily accessible in a simple one-pot synthesis. The central indolonaphthalene core is substituted with indole residues at various positions. Both the varied indole substitutions and their positions at the molecular scaffold influence the determined antibacterial activity against the evaluated Staphylococcus strains. Best activities have been found for 5-chloro, -cyano, and -hydroxyl indole substitutions. Therefore, first promising lead compounds could be identified that are nontoxic in human HEK and SH-SY5Y cells and exceed the activity of used standard antibiotics, especially against MRSA. Keywords: structure-dependent activity, lead structure, antibacterial activity, compound evaluation, MRSA
Ricardo Costa, Saif Zaman, Susan Sharpe, Irene Helenowski, Colleen Shaw, Hyo Han, Hatem Soliman, Brian Czerniecki
Drug Design, Development and Therapy, Volume 13, pp 309-316; doi:10.2147/dddt.s188925

Abstract:A brief report of toxicity end points of HER2 vaccines for the treatment of patients with HER2+ breast cancer Ricardo Costa,1 Saif Zaman,2 Susan Sharpe,3 Irene Helenowski,4 Colleen Shaw,1 Hyo Han,1 Hatem Soliman,1 Brian Czerniecki1 1Department of Breast Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 2Morsani College of Medicine, University of South Florida, Tampa, FL, USA; 3Moffitt Biomedical Library, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; 4Department of Preventive Medicine, Northwestern University, Chicago, IL, USA Human epidermal growth factor receptor 2 (HER2)-targeted vaccines are under development, but have so far demonstrated only modest clinical efficacy. Additionally, there has been a lack of adequate safety assessment in large-scale prospective clinical trials. Therefore, we performed a meta-analysis of available clinical trial data to summarize the toxicity profiles of these treatments. Literature search was conducted in February 2018. The trials analyzed had at least one study arm consisting of HER2 vaccine monotherapy. Heterogeneity across studies was analyzed using I2 statistics. Data were analyzed using random-effects meta-analysis for absolute risk (AR). Eight trials and 248 patients were included. There was no evidence of heterogeneity between studies for grades 3/4 adverse events (AEs) or for death. The AR for treatment-related serious AEs was 5% with no treatment-related deaths. The AR of all-grade fatigue, injection site reaction, and fever/chills/rigors was 33%, 23%, and 31%, respectively. Asymptomatic drop in left ventricle ejection fraction was rare (8%). HER2 vaccines are well tolerated with increased AR of fatigue, injection site reactions, and fever/chills/rigors. Keywords: HER2, vaccines, immunity, dendritic cells, toxicity
Qiuzhen Liang, Xinghua Song, Shengli She, Zhen Wang, Chong Wang, Dawei Jiang
Drug Design, Development and Therapy, Volume 13, pp 373-384; doi:10.2147/dddt.s190696

Abstract:Development of dual delivery antituberculotic system containing rifapentine microspheres and adipose stem cells seeded in hydroxyapatite/tricalcium phosphate
Junbei Wu, Yunhong Lu, Xiaofei Cao
Drug Design, Development and Therapy, Volume 13, pp 365-372; doi:10.2147/dddt.s188728

Abstract:Different effects of oxycodone and remifentanil in patients undergoing ultrasound-guided percutaneous radiofrequency ablation of hepatic cancer: a randomized trial
Shiyu Mao, Junfeng Zhang, Yadong Guo, Ziwei Zhang, Yuan Wu, Wentao Zhang, Longsheng Wang, Jiang Geng, Yang Yan, Xudong Yao
Drug Design, Development and Therapy, Volume 13, pp 291-300; doi:10.2147/dddt.s181122

Abstract:Hyperprogression after anti-programmed cell death ligand-1 therapy in a patient with recurrent metastatic urothelial bladder carcinoma following first-line cisplatin-based chemotherapy: a case report Shiyu Mao,1,* Junfeng Zhang,1,* Yadong Guo,1,* Ziwei Zhang,1 Yuan Wu,2 Wentao Zhang,2 Longsheng Wang,1 Jiang Geng,1 Yang Yan,1 Xudong Yao1 1Department of Urology, Shanghai Tenth People’s Hospital, Tongji University, Shanghai 200072, PR China; 2Department of Urology, Shanghai Tenth People’s Hospital, Anhui Medical University, Hefei 230032, PR China *These authors contributed equally to this work Background: Immune checkpoint blockade targeting programmed cell death ligand-1 (PD-L1)/programmed death-1 (PD-1) signaling was approved recently for locally advanced and metastatic urothelial bladder carcinoma (UBC). Some patients experience a very rapid tumor progression, rather than clinical benefit, from anti-PD-L1/PD-1 therapy.Case presentation: A 58-year-old male diagnosed with non-muscle-invasive bladder cancer 3 years ago received transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy. TURBT was repeated a year later for recurrent and progressive UBC. Following further disease progression, he received a radical cystectomy (RC), pathologically staged as T2bN2M0, and adjuvant cisplatin-containing combination chemotherapy. When his disease progressed to metastatic UBC, he was started on anti-PD-L1 monotherapy and experienced ultrarapid disease progression within 2 months; imaging scans ruled out pseudoprogression. We observed a fourfold increase in tumor growth rate, defined as the ratio of post- to pretreatment rates. Next-generation sequencing of formalin-fixed paraffin-embedded RC tissues showed MDM2 amplification without MDM4 amplification, EGFR aberrations, or DNMT3A alterations. Immunohistochemistry showed grade 2+ PD-L1 labeling intensity of the RC tissues, with 15%–25% and 5%–10% PD-LI immunopositive tumor cells and tumor-infiltrating immune cells, respectively.Conclusion: Even in cases with PD-L1-positive tumors, MDM2 gene amplification may result in failure of anti-PD-L1 immunotherapy and rapid tumor growth. Therefore, genomic profiling may identify patients at risk for hyperprogression before immunotherapy. Keywords: urothelial bladder carcinoma, programmed cell death ligand-1, immune checkpoint blockade, hyperprogression, MDM2
Haitao Ren, Yuan Li, Yan Chen, Liang Wang
Drug Design, Development and Therapy, Volume 13, pp 285-290; doi:10.2147/dddt.s191617

Abstract:Endostatin attenuates PDGF-BB- or TGF-beta1-induced HSCs activation via suppressing RhoA/ROCK1 signal pathways Haitao Ren,1 Yuan Li,2 Yan Chen,3 Liang Wang4 1Department of Burns and Wound Care Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China; 2Department of Ultrasound, Women’s Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China; 3Emergency Department, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, P.R. China; 4Department of Hepatobiliary and Pancreatic Surgery, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310009, P.R. China Aim: To testify the hypothesis that endostatin exerts antifibrotic effects in hepatic stellate cells (HSCs) by modulating RhoA (ras homolog gene family, member A)/ROCK 1 (Rho-associated protein kinase 1) signal pathways.Materials and methods: HSCs-T6 of passages 3–5 were cultured in DMEM and serum starved for 48 hours. HSCs were grouped as follows: control group, TGF-β1 (transforming growth factor β1) group, endostatin+TGF-β1 group, PDGF-BB (platelet-derived growth factor-BB) group, and endostatin+PDGF-BB group. In the PDGF-BB group, HSCs were treated with PDGF-BB (200 ng/mL) for 72 hours; in the TGF-β1 group, they were treated with TGF-β1 (10 ng/mL) for 72 hours. In the Endostatin+TGF-β1 group or Endostatin+PDGF-BB group, HSCs were treated with TGF-β1 (10 ng/mL) or PDGF-BB (200 ng/mL) for 72 hours after pretreatment with endostatin (5 µg/mL) for 1 hour. In the control group, HSCs were only treated with serum-free DMEM for 72 hours. Collagen I was analyzed with ELISA. F-actin was detected with immunofluorescent staining. The mRNAs and proteins of β-smooth muscle actin, RhoA, and ROCK1 were analyzed by using real-time PCR and Western blot, respectively.Results: TGF-β1 and PDGF-BB promote the proliferation of HSCs significantly at 48 and 72 hours. Endostatin inhibits the proliferation effect induced by TGF-β1 or PDGF-BB significantly (P
Zhi-Yong Pan, Yu-Hang Zhao, Wen-Hong Huang, Zhi-Ze Xiao, Zhi-Qiang Li
Drug Design, Development and Therapy, Volume 13, pp 265-273; doi:10.2147/dddt.s192633

Abstract:Effect of progesterone administration on the prognosis of patients with severe traumatic brain injury: a meta-analysis of randomized clinical trials Zhi-Yong Pan, Yu-Hang Zhao, Wen-Hong Huan, Zhi-Ze Xiao, Zhi-Qiang Li Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, PR China Purpose: The aim of this study was to assess the neuroprotective effect of progesterone administration on severe traumatic brain injury (TBI) for different follow-up periods and administration route by completing a meta-analysis of randomized clinical trials (RCTs).Methods: A systematic literature search of PubMed, Embase, and Cochrane databases and the Web of Science (from establishment of each to September 1, 2018) was performed to identify original RCTs that evaluated the associations between progesterone treatment and the prognosis of patients with severe TBI.Results: Eight RCTs enrolling 2,251 patients with severe TBI were included. Within 3 months post-injury, patients with progesterone administration had a lower mortality (risk ratio [RR] =0.59; 95% CI [0.42–0.81], P=0.001) and better neurologic outcomes (RR =1.51; 95% CI [1.12–2.02], P=0.007) than those who received placebo. However, these differences did not persist at 6 months post-injury for mortality (RR =0.96; 95% CI [0.65–1.41], P=0.83) or neurologic outcomes (RR =1.09; 95% CI [0.93–1.27], P=0.31). The analysis stratified by administration route showed that beneficial effects were only observed in patients who received progesterone intramuscularly (RR =1.61, 95% CI [1.19–2.18], P=0.002); no benefit was observed with intravenous administration (RR =0.99, 95% CI [0.91–1.07], P=0.75).Conclusion: Progesterone administration improved the clinical outcomes of severe TBI patients within 3 months but may not have significant long-term benefits 6 months post-injury. Keywords: progesterone, severe traumatic brain injury, neuroprotection
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