DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO
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Rose Bengal disodium
4 ,5,6,7-Tetrachloro-2′,4′,5′,7′-tetraiodo-3-oxo-3H-spiro[2-benzofuran-1,9′-xanthene]-3′,6′-diolate disodium salt
| cas | 632-69-9 |
C20 H2 Cl4 I4 O5 . 2 Na, mw 1017.36, PH 10
| innovator | Provectus |
The FDA has granted PV-10 Orphan Drug Status for the treatment of highly lethal metastatic melanoma and metastatic liver cancer. It has a successful and expanding Compassionate Use Program in operation and successfully completed trials on metastatic cancer of the breast, liver and melanoma, with positive results in all three. Positive effects in this context is that, if you inject PV-10 into a solid tumor, it kills cancer cells, usually within a week and doesn’t harm normal tissue. Many injected tumors actually disappear while others shrink and stop growing. The dual action of the drug is that the destruction of the cancer by direct injection of PV-10 serves to sensitize the patient’s immune system to seek out and kill similar cancer throughout the body. There is convincing evidence that untreated cancer distant from the treated cancer is attacked by the patient’s immune system after treatment.
PROVECTUS COMPANY OVERVIEW
Provectus (PVCT) is a clinical stage bio-pharmaceutical drug development company. There are 3 key scientific managers running the business along with the CFO, who is also the Chief Operating Officer. They preside over a stable of expert and specialized consultants. The company has two lead drug candidates: PH-10 for significant, often severe, and common skin disorders and PV-10, a dual action, local ablation and immunological anti-cancer drug. PH-10 is currently the subject of post-Phase II trial research into mode of action. PV-10 has successfully completed Phase II trials for malignant melanoma, is currently the subject of independent research on mode of actioRose Bengal disodium is in early clinical trials at Provectus for the topical treatment of psoriasis and atopic dermatitis. An intralesional injectable formulation is also in early clinical development as breast cancer, liver cancer and melanoma therapy. Development for the treatment of actinic keratosis had been ongoing; however, no recent development for this indication has been reported. The company is seeking approval in the U.S. to begin clinical evaluation of this formulation for the treatment of liver and prostate cancer. A compassionate use program is under way for Rose Bengal disodium for the treatment of non-visceral cancers.
The drug’s mechanism of action is believed to be characterized by the creation of free radicals upon activation, which eliminate diseased cells. The compound concentrates in tumors at cytotoxic levels while quickly dissipating from healthy tissue. Simultaneously, the drug triggers an immune response that can eliminate metastatic tumor tissue.
In 2007, orphan drug designation was assigned to Rose Bengal disodium by the FDA for the treatment of metastatic melanoma. This designation was also assigned to the compound in the U.S. in 2011 for the treatment of hepatocellular carcinoma.n and efficacy in conjunction with radiation, and it will have a Phase III pivotal trial starting shortly.
SUMMARY
1. If PV-10 and the Chemotherapies act as the prior data indicate, an NDA for melanoma may be submitted by Provectus in the first half of 2015.
2. If this occurs, the FDA denial of the Breakthrough Therapy designation will not have slowed PV-10’s progress to commercialization.
3. Given the relative safety and efficacy of the different drugs, if the trial is not stopped very early for humanitarian reasons, the planned Interim Analysis is likely to result in the cancellation of the trial, prior to the end of 2015.
4. Given PV-10’s superior safety and lack of significant side effects, if it is only as good as Chemotherapy, it will deserve FDA approval.
The Phase III pivotal trial will demonstrate the safety and efficacy of PV-10 to the market and to prospective acquirers a lot earlier than many have presumed.
Rose bengal (4,5,6,7-tetrachloro-2′,4′,5′,7′-tetraiodofluorescein) is a stain. Its sodium salt is commonly used in eye drops to stain damaged conjunctival and corneal cells and thereby identify damage to the eye. The stain is also used in the preparation of Foraminifera for microscopic analysis, allowing the distinction between forms that were alive or dead at the time of collection.
A form of Rose Bengal is also being studied as a treatment for certain cancers and skin conditions. The cancer formulation of the drug, known as PV-10, is currently undergoing clinical trials for melanoma and breast cancer. The company also has formulated a drug based on Rose Bengal for the treatment of eczema and psoriasis; this drug, PH-10, is currently in clinical trials as well.
| Rose bengal | |
|---|---|
 |
|
| Identifiers | |
| CAS number | 11121-48-5  |
| ATC code | S01 |
| Jmol-3D images | Image 1 |
| Properties | |
| Molecular formula | C20H4Cl4I4O5 |
| Molar mass | 973.67 g mol−1 |
Chemical applications
Light microscopy image of the undescribed species of Spinoloricus from Loricifera stained with Rose Bengal.
Rose Bengal is also used in synthetic chemistry to generate singlet oxygen from triplet oxygen. The singlet oxygen can then undergo a variety of useful reactions, particularly [2 + 2] cycloadditions with alkenes and similar systems.
Rose Bengal can be used to form many derivatives that have important medical functions. One such derivative was created so to be sonosensative but photoinsensative, so that with a high intensity focused ultrasound, it could be used in the treatment of cancer. The derivative was formed by amidation of Rose Bengal, which turned off the fluorescent and photosensitive properties of Rose Bengal, leading to a usable compound, named in the study as RB2.[1]
Salts of Rose Bengal can also be formed, with the molecular formula C20 H4 Cl4 I4 O5 . 2 Na, molecular weight of 1017.64 g/mol and CAS # 632-69-9. Known as Rose Bengal Sodium Salt, this compound has its own unique uses and properties, but also functions as a dye.[2]
Biological applications
PV-10 was found to cause an observable response in 60 percent of tumors treated, according to researchers in a phase II melanoma study. Locoregional disease control was observed in 75 percent of patients. Also confirmed was a “bystander effect”, previously observed in the phase I trial, whereby untreated lesions responded to treatment as well, potentially due to immune system response. These data were based on the interim results of the first 40 patients treated in an 80 patient study.[3] Rose Bengal has been shown to not just prevent the growth and spread of ovarian cancer, but also to cause apoptotic cell death of the cancer cells. This has been proven in vitro, in order to prove that Rose Bengal is still a possible option in the treatment of cancer, and further research should be done.[4]
Rose Bengal is also used in animal models of ischemic stroke (photothrombotic stroke models) in biomedical research. A bolus of the compound is injected into the venous system. Then the region of interest (e.g., the cerebral cortex) is exposed and illuminated by LASER light of 561 nm. A thrombus is formed in the illuminated blood vessels, causing a stroke in the dependent brain tissue.[5][6]
Rose bengal has been used for 50 years to diagnose liver and eye cancer. It has also been used as an insecticide.[7][8]
Rose Bengal is able to stain cells whenever the surface epithelium is not being properly protected by the preocular tear film, because Rose Bengal has been proven to not be able to stain cells because of the protective functioning of these preocular tear films.[9] This is why Rose Bengal is often useful as a stain in diagnosing certain medical issues, such as conjunctival and lid disorders.[10]
Rose Bengal has been used for ocular surface staining to study the efficacy of punctal plugs in the treatment of keratoconjunctivitis sicca. [11]
Rose Bengal is being researched as an agent in creating nano sutures.[12] Wounds are painted on both sides with it and then illuminated with an intense light. This links the tiny collagen fibers together sealing the wound.[13][14][15] Healing is faster and the seal reduces chances of infection.[16][17]
Rose Bengal is used in several microbiological media, including Cooke’s Rose Bengal agar, to suppress bacterial growth.
Rose Bengal has been used as a protoplasm stain to discriminate between living and dead micro-organisms, particularly Foraminifera, since the 1950s when Bill Walton developed the technique.[18]
Electronic applications
Rose Bengal demonstrates at least six distinct electronic properties[19] which are otherwise hidden in the molecule. Rose Bengal is a double planar molecule and relative rotation of the planes generate unique electronics. Therefore, Rose Bengal is a suitable candidate for molecular electronics.
History
Rose Bengal was originally prepared in 1884 by Gnehm, as an analogue of fluorescein.[20] The name is due to its similarity to alta, a dye that women in Bengal have used for centuries to colour their feet red during weddings and festivals.
References
- Kim, Y; Valentina Rubio, Jianjun Qi, Rongmin Xia, Zheng-Zheng Shi, Leif Peterson, Ching-Hsuan Tung, and Brian E. O’Neill (2012). “Cancer treatment using an optically inert Rose Bengal derivative combined with pulsed focused ultrasound”. AIP Conference Proceedings 1481: 175.
- “Rose Bengal Sodium Salt”. Sigma-Aldrich. Sigma Aldrich Co. Retrieved 12 November 2013.
- Metastatic Melanoma PV-10 Trial Results Encouraging Says Drug Company, Medical News Today, 09 Jun 2009
- Koevary, S (2012). “Selective toxicity of rose bengal to ovarian cancer cells in vitro”. International Journal of Physiology, Pathophysiology and Pharmacology 4: 99–107.
- Salber D, et al. (2006). “Differential uptake of [18F]FET and [3H]l-methionine in focal cortical ischemia”. Nuclear Medicine and Biology 33 (8): 1029–1035. doi:10.1016/j.nucmedbio.2006.09.004. PMID 17127177.
- Watson BD, Dietrich WD, Busto R, Wachtel MS, Ginsberg MD (1985). “Induction of reproducible brain infarction by photochemically initiated thrombosis”. Ann Neurol 17 (5): 497–504. doi:10.1002/ana.410170513. PMID 4004172.
- Capinera, John L.; Squitier, Jason M. (2000). “Insecticidal Activity of Photoactive Dyes to American and Migratory Grasshoppers (Orthoptera: Acrididae)”. Journal of Economic Entomology 93 (3): 662–666. doi:10.1603/0022-0493-93.3.662. PMID 10902313.
- Martin, Phyllis; Mischke, Sue; Schroder, Robert (1998). “Compatibility of Photoactive Dyes with Insect Biocontrol Agents”. Biocontrol Science and Technology 8 (4): 501–508. doi:10.1080/09583159830018.
- Feenstra, R; Tseng, S (July 1992). “What is actually stained by rose bengal?”. Arch Ophthalmol 110: 984–993. doi:10.1001/archopht.1992.01080190090035.
- Yokoi, Norihiko (2012). “Vital staining for disorders of conjunctiva and lids”. Atarashii Ganka 29: 1599–1605.
- Ervin AM, Wojciechowski R, Schein O (2010). “Punctal occlusion for dry eye syndrome”. Cochrane Database Syst Rev 9: CD006775. doi:10.1002/14651858.CD006775.pub2. PMID 20824852.
- Chan, B; Chan, O; So, K (2008). “Effects of photochemical crosslinking on the microstructure of collagen and a feasibility study on controlled protein release”. Acta Biomaterialia 4 (6): 1627–1636. doi:10.1016/j.actbio.2008.06.007. PMID 18640085.
- O’Neill A.C., Winograd J.M, Zeballos J.M., Johnson T.S., Randolph M.A., Bujold K.E., Kochevar I.E., Redmond R.W. (2007). “Microvascular anastomosis using a photochemical tissue bonding technique”. Lasers in Surgery and Medicine 39 (9): 716–722. doi:10.1002/lsm.20548. PMID 17960755.
- Mulroy L., Kim J., Wu I., Scharper P., Melki S.A., Azar D.A., Redmond R.W., Kochevar I.E. (2000). “Photochemical keratodesmos for repair of lamellar corneal incisions”. Invest Ophthalmol Vis Sci 41 (11): 3335–3340. PMID 11006222.
- Proano C.E., Mulroy L., Erika Jones E., Azar D.A., Redmond R.W., Kochevar I.E. (2004). Invest Ophthalmol Vis Sci: 2177–2181.
- Laser Show in the Surgical Suite, Technology Review, March/April 2009
- Laser Show in the Surgical Suite, Technology Review, 02.11.2009
- Walton, W. (1952), Techniques for recognition of living foraminifera, Contrib. Cushman Found. Foraminiferal Res., 3, 56 – 60
- A new approach to extract multiple distinct conformers and co-existing distinct electronic properties of a single molecule by point-contact method Anirban Bandyopadhyay, Satyajit Sahu, Daisuke Fujita and Yutaka Wakayama, Phys. Chem. Chem. Phys., 2010 view highlights in Royal Society of Chemistry,
- Alexander, Walter (2010). “American Society of Clinical Oncology, 2010 Annual Meeting and Rose Bengal: From a Wool Dye to a Cancer Therapy”. Pharmacy and Therapeutics 35 (8): 469–474. PMC 2935646. Retrieved 5 November 2013.
- US 2010021566
- WO 2011050164
- US 2011250296
External links
- Rose Bengal at the US National Library of Medicine Medical Subject Headings (MeSH)
- Absorption and extinction data
New Drug Approvals 
A cogent summary of this underreported-upon intratumoral anti-cancer agent. It’s “too-good-to-true” efficacy and safety have held it back in skeptic’s eyes, but it appears that it will make a big splash later this year. In the current trials it will finally be administered to all tumors, multiple times as needed, instead of to just one tumor and/or just one injection per tumor. The tumor ablation causes apoptosis which allows all the internal antigens to be presented to the patient’s immune system, thereby allowing T cell education to attack any metas tiding cells to be be attacked anywhere in the body. A second current study already underway combines PV-10 with a checkpoint inhibitor (also for melanoma). Watch for the results of these two studies of PV-10. These are exciting times for solid tumor oncology.
In your summary about PV-10 you say 2015 in point 1 and point 3. I think you meant 2016. Thanks.