Fahl W.E.,University of Wisconsin - Madison |
Fahl W.E.,ProCertus BioPharm
International Journal of Cancer | Year: 2014
Topical application of the alpha adrenergic vasoconstrictors norepinephrine, phenylephrine or epinephrine to skin or mucosa in alcohol:water-based delivery vehicles minutes before irradiation has recently been shown to protect skin and mucosa cells against radiotherapy-induced toxicities in both preclinical and clinical studies. The protective mechanism is thought to involve transient skin or mucosal vasoconstriction with secondary, transient hypoxia and associated radioprotection. Regarding possible protection of tumor cell nests within the radiotherapy field, the endothelial cell-abnormal stroma constructed blood vessels generally found in human tumors commonly lack adrenergic receptor-containing smooth muscle cells that are required to achieve vasoconstriction. Consistent with this, we show here that topical application of norepinephrine or phenylephrine to broken or intact skin over human Cal-27 or A-431 xeonograft, or mouse solid L1210 allograft tumors growing subcutaneously in nude mice, showed no effect upon radiation-induced tumor growth inhibition. Although vasoconstrictor-induced nude mouse skin blanch was seen minutes after topical application of 600 mM norepinephrine, no blanching was seen within the A-431 xenograft tumors. Radiation dermatitis was severe 11 days post-irradiation (2 × 13.8 Gy) in the irradiated field containing xenograft tumors in mice that received topical delivery vehicle, but was absent in mice that received topical norepinephrine. Topical vasoconstrictor-conferred prevention of radiation dermatitis without discernible radioprotection of three histologically diverse xenograft or allograft tumors supports further development of the topical vasoconstrictor therapeutic strategy in humans. © 2014 UICC.
ProCertus BioPharm | Date: 2012-03-09
Aspects of the present disclosure are directed to formulations that permit the solubilization and long term, stable storage of adrenergic agonist vasoconstrictors in organic solvents. Provided herein are formulations comprising about 250 mM to about 3000 mM of an acid salt of an adrenergic agonist vasoconstrictor dissolved in a pharmaceutically acceptable topical delivery vehicle comprising a water miscible, organic solvent having a water content of less than 40% by weight. Also provide are methods for using and kits containing such formulations.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 97.50K | Year: 2003
DESCRIPTION (provided by applicant): Several recent clinical studies have described the side effect of radiation-induced dermatitis that occurs in the majority of cancer patients who receive radiotherapy. These same studies also report the lack of effective agents to prevent or treat this dermatitis. In some of these patients, the side effects are severe enough that they withdraw from further radiotherapy. Nonetheless, radiotherapy remains a standard and essential part of cancer treatment and cure. ProCertus has developed a topically applied treatment to diminish or eliminate the dermatitis associated with radiotherapy. In current animal proof of concept studies, ProCertus has shown a >90% reduction in radiation-induced dermatitis by pretreating animals with ProDermX, which is currently a research stage human pharmaceutical. This technology consists of a carrier vehicle that delivers a single active agent to the stem cells of the epidermis. The active agent, a proprietary "chemoprotective polyamine," physically protects cellular DNA while also inducing a G1 phase, cell cycle block. This strategy enables the stem cells within the stratum germinativum of the epidermis to survive the radiation exposure, and to continue to replenish the outer layers of the skin and thus maintain a patent skin surface. Though ProCertus scientists have already carried this product through animal model proof of concept, there remain several biological and pharmacological questions that need to be answered before human studies can be initiated. Three Specific Aims have been designed to address and answer these questions during the course of this Phase I SBIR project, which will then enable initial studies in human populations in future research.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase II | Award Amount: 1.45M | Year: 2005
Numerous clinical studies have described the negative impact of radiotherapy-induced dermatitis on cancer patients during and after their 5-6 week course of radiotherapy. Virtually all patients develop at least a mild dermatitis, and for almost half it's a painful side effect lasting weeks. There can be scarring, limitations on more aggressive radiotherapy, and can result in patients quitting radiotherapy, with a significant effect upon tumor recurrence. There are no products on the market that prevent or treat this dermatitis. ProCertus, an early-stage biotech company, has developed a topically-applied small molecule drug for a product, DermX, that confers complete protection against the Grade 1->4 dermatitis seen in a rodent radiodermatitis model, a model that closely reflects the human experience. Based upon market analysis, ProCertus has concluded that a topical preventive for radiodermatitis would be well-received by cancer patients, and yield annual revenues in the range of $250 million. A DermX product would reduce radiotherapy-associated pain, could potentially enable more aggressive radiotherapy where dermatitis is dose-limiting, and could reduce the drop-out rate late in radiotherapy courses. Phase II funds will enable us to address the key, remaining issues in DermX scientific development, which are: i) ensure that topicallyapplied DermX does not affect external beam radiation killing of tumor cell xenografts in nude mice, ii) optimize a topical delivery vehicle that enables full radioprotection of skin stem cells while allowing insignificant levels of DermX active agent to enter systemic circulation, and iii) complete cGMP-certified batch synthesis of DermX that is required for studies prior to filing for its Investigational New Drug (IND) status. At the end of this Phase II project, ProCertus envisions a DermX product ready for clinical trials that: i) is a topical solution devoid of systemic side effects, ii) is applied 1-2 times in the 30 min before radiotherapy, and iii) is expected to prevent the Grade 1-4 dermatitis normally experienced by radiotherapy patients.
Copp R.R.,ProCertus BioPharm |
Peebles D.D.,ProCertus BioPharm |
Soref C.M.,ProCertus BioPharm |
Fahl W.E.,ProCertus BioPharm |
Fahl W.E.,University of Wisconsin - Madison
International Journal of Radiation Biology | Year: 2013
Purpose: A family of 17 new nucleophilic-polyamine and aminothiol structures was designed and synthesized to identify new topical or systemic radioprotectors with acceptable mammalian toxicity profiles. Design elements included: (i) Length and charge of the DNA-interacting, alkylamine backbone, (ii) nucleophilicity of the reactive oxygen species (ROS)-scavenging group, and (iii) non-toxic drug concentration achievable in animal tissues. Materials and methods: Mouse maximum tolerated doses (MTD) were determined by increasing intraperitoneal (IP) doses. To assess radioprotective efficacy, mice received IP 0.5 MTD doses prior to an LD95 radiation dose (8.63 Gy), and survival was monitored. Topically applied aminothiol was also scored for prevention of radiation-induced dermatitis (17.3 Gy to skin). Results: The most radioprotective aminothiols had 4-6 carbons and 1-2 amines, and unlike amifostine and its analogs, displayed a terminal thiol from an alkyl side chain that projected the thiol away from the DNA major groove into the environment surrounding the DNA. The five carbon, single thiol, alkylamine, PrC-210, conferred 100% survival to an otherwise 100% lethal dose of whole-body radiation and achieved 100% prevention of Grade 2-3 radiation dermatitis. By mass spectrometry analysis, the one aminothiol that was tested formed mixed disulfides with cysteine and glutathione. Conclusions: Multiple, highly radioprotective, aminothiol structures, with acceptable systemic toxicities, were identified. © 2013 Informa UK, Ltd.