A Prospective Double-Blinded Clinical Trial Using Apatone®B for Care and Treatment of Proven Non-Infected Symptomatic Postoperative Total Joint Arthroplasties

This research study is being conducted to determine if taking oral (by mouth in pill form) Apatone®B (a combination of Vitamins C and K3) will reduce chronic joint discomfort and improve function of non-infected symptomatic postoperative total joint replacements.

开始日期2010-10-01

申办/合作机构

Ic Medtech Corp.

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100 项与维生素C/甲萘醌相关的临床结果

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100 项与维生素C/甲萘醌相关的转化医学

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100 项与维生素C/甲萘醌相关的专利（医药）

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项与维生素C/甲萘醌相关的文献（医药）

2020-11-02·Oxidative Medicine and Cellular Longevity2区 · 生物学

Selective Targeting of Cancerous Mitochondria and Suppression of Tumor Growth Using Redox-Active Treatment Adjuvant

2区 · 生物学

ArticleOA

作者: Ivanova, Donika ; Takeshima, Tsuguhide ; Higashi, Tatsuya ; Shibata, Sayaka ; Semkova, Severina ; Zhelev, Zhivko ; Lazarova, Dessislava ; Aoki, Ichio ; Bakalova, Rumiana ; Miller, Thomas

Redox-active substances and their combinations, such as of quinone/ascorbate and in particular menadione/ascorbate (M/A; also named Apatone®), attract attention with their unusual ability to kill cancer cells without affecting the viability of normal cells as well as with the synergistic anticancer effect of both molecules. So far, the primary mechanism of M/A-mediated anticancer effects has not been linked to the mitochondria. The aim of our study was to clarify whether this “combination drug” affects mitochondrial functionality specifically in cancer cells. Studies were conducted on cancer cells (Jurkat, Colon26, and MCF7) and normal cells (normal lymphocytes, FHC, and MCF10A), treated with different concentrations of menadione, ascorbate, and/or their combination (2/200, 3/300, 5/500, 10/1000, and 20/2000 μM/μM of M/A). M/A exhibited highly specific and synergistic suppression on cancer cell growth but without adversely affecting the viability of normal cells at pharmacologically attainable concentrations. In M/A-treated cancer cells, the cytostatic/cytotoxic effect is accompanied by (i) extremely high production of mitochondrial superoxide (up to 15-fold over the control level), (ii) a significant decrease of mitochondrial membrane potential, (iii) a decrease of the steady-state levels of ATP, succinate, NADH, and NAD+, and (iv) a decreased expression of programed cell death ligand 1 (PD-L1)—one of the major immune checkpoints. These effects were dose dependent. The inhibition of NQO1 by dicoumarol increased mitochondrial superoxide and sensitized cancer cells to M/A. In normal cells, M/A induced relatively low and dose-independent increase of mitochondrial superoxide and mild oxidative stress, which seems to be well tolerated. These data suggest that all anticancer effects of M/A result from a specific mechanism, tightly connected to the mitochondria of cancer cells. At low/tolerable doses of M/A (1/100-3/300 μM/μM) attainable in cancer by oral and parenteral administration, M/A sensitized cancer cells to conventional anticancer drugs, exhibiting synergistic or additive cytotoxicity accompanied by impressive induction of apoptosis. Combinations of M/A with 13 anticancer drugs were investigated (ABT-737, barasertib, bleomycin, BEZ-235, bortezomib, cisplatin, everolimus, lomustine, lonafarnib, MG-132, MLN-2238, palbociclib, and PI-103). Low/tolerable doses of M/A did not induce irreversible cytotoxicity in cancer cells but did cause irreversible metabolic changes, including: (i) a decrease of succinate and NADH, (ii) depolarization of the mitochondrial membrane, and (iii) overproduction of superoxide in the mitochondria of cancer cells only. In addition, M/A suppressed tumor growth in vivo after oral administration in mice with melanoma and the drug downregulated PD-L1 in melanoma cells. Experimental data suggest a great potential for beneficial anticancer effects of M/A through increasing the sensitivity of cancer cells to conventional anticancer therapy, as well as to the immune system, while sparing normal cells. We hypothesize that M/A-mediated anticancer effects are triggered by redox cycling of both substances, specifically within dysfunctional mitochondria. M/A may also have a beneficial effect on the immune system, making cancer cells “visible” and more vulnerable to the native immune response.

2014-10-01·Ultrastructural Pathology4区 · 工程技术

Pro-oxidant Treatment of Human Prostate Carcinoma (DU145) Induces Autoschizis Cell Death: Autophagosomes Build up out of Injured Endomembranes and Mitochondria

4区 · 工程技术

Article

作者: Jack L. Summers ; Jacques Gilloteaux ; James M. Jamison

One hour after pro-oxidative treatment by either ascorbate (VC), menadione (VK3), or VC: VK3 combination followed by 24-h incubation in culture medium, DU145 human prostate carcinoma cells developed ultrastructural-dependent organelle damage with the sequence Sham > VC > VK3 > VC: VK3. Along the nuclear alterations and the cytoplasm self-excisions reducing cell size, other induced injuries concerned mitochondria and endomembranes that associated with lysosomes. Damaged organelles surrounded by specialized endoplasmic membranes formed autophagosomes out of phagophores that also captured pieces of glycogen-rich cytoplasm. Most autophagosomes amassed in the diminished-size perikarya and corroborated the enhanced cytotoxicity of the VC: VK3 treatment. These accumulations did not initiate cell death, instead were merely signs of excessive "recycling" of damaged organelles. These features may reflect that high lysosomal activities provided foodstuffs in an ultimate strategy of survival of the tumor cells already devastated by reactive oxidative species (ROS) energetic sites. As such they became transient markers preceding cell death induced to occur by autoschizis and not by apoptosis or other cell deaths. This report could provide more support for the usage of this vitamin combination named APATONE as inexpensive potent adjuvant or treatment in prostate cancers.

2010-07-01·Journal of Histochemistry & Cytochemistry4区 · 生物学

Nucleolar Changes and Fibrillarin Redistribution Following Apatone Treatment of Human Bladder Carcinoma Cells

4区 · 生物学

Article

作者: Neal, Deborah ; McGuire, Karen ; Summers, Jack L. ; Thiry, Marc ; Perlaky, Laszlo ; Jamison, James M. ; Smetana, Karel ; Gilloteaux, Jacques

Ascorbate and menadione (Apatone) in a ratio of 100:1 kills tumor cells by autoschizis. In this study, vitamin-induced changes in nucleolar structure were evaluated as markers of autoschizis. Human bladder carcinoma (T24) cells were overlain with vitamins or with culture medium. Supernatants were removed at 1-hr intervals from 1 to 4 hr, and the cells were washed with PBS and prepared for assay. Apatone produced marked alterations in nucleolar structure including redistribution of nucleolar components, formation of ring-shaped nucleoli, condensation and increase of the proportion of perinucleolar chromatin, and the enlargement of nucleolar fibrillar centers. Immunogold labeling of the nucleolar rRNA revealed a granular localization in treated and sham-treated cells, and immunogold labeling of the rDNA revealed a shift from the fibrillar centers to the condensed perinucleolar chromatin. Fibrillarin staining shifted from the fibrillar centers and adjacent regions to a more homogeneous staining of the entire nucleolus and was consistent with the percentage of autoschizic cells detected by flow cytometry. Because autoschizis entails sequential reactivation of DNase I and DNase II, and because the fibrillarin redistribution following DNase I and Apatone treatment is identical, it appears that the nucleolar and fibrillarin changes are markers of autoschizis.

100 项与维生素C/甲萘醌相关的药物交易

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
水肿	临床2期	美国	Ic Medtech Corp.	2010-10-01
异物反应	临床2期	美国	Ic Medtech Corp.	2010-10-01
骨质溶解	临床2期	美国	Ic Medtech Corp.	2010-10-01
滑膜炎	临床2期	美国	Ic Medtech Corp.	2010-10-01
关节疾病	临床2期	-	Summa Health System (Ohio)	-
多囊肾	临床2期	美国	-	-
前列腺癌	临床2期	-	Ic Medtech Corp.	-
前列腺癌	临床2期	-	Summa Health System (Ohio)	-
创伤和损伤	临床2期	美国	Summa Health System (Ohio)	-

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT01272830 (Apatone-B, CTgov)	临床2期	骨质溶解 \| 水肿 \| 滑膜炎 \| 异物反应	57	Apatone®B (Oral Apatone®B)	壓襯願壓遞繭壓願願積(糧艱積衊醖艱憲鬱窪網) = 選衊簾願選鬱鏇網夢鹽醖襯淵簾餘獵顧醖餘網 (築鹽醖範壓壓鑰選築觸, 鹽壓鹽壓簾網襯繭餘憲 ~ 鬱襯艱衊構構願衊鬱築) 更多	-	2018-01-31
				Placebo (Placebo)	壓襯願壓遞繭壓願願積(糧艱積衊醖艱憲鬱窪網) = 鹹淵淵衊遞遞艱遞淵鹽醖襯淵簾餘獵顧醖餘網 (築鹽醖範壓壓鑰選築觸, 蓋夢鑰選繭繭衊簾鏇觸 ~ 獵蓋淵範衊淵遞網鬱窪) 更多