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【medical-news】治疗青光眼的新药物新方法
Future could include gene therapy, MMP regulators and inhibitors, PDT
Feb 15, 2007
By: Ed Edelson
Dr. Lama
New York—Some antifibrosis drugs and techniques on the horizon appear promising, but more data, especially from controlled human trials, are needed, Paul J. Lama, MD, told those attending the Glaucoma 2006 meeting here.
"If these agents come to fruition, then we will have a whole array of agents that could be used in combination, like cancer chemotherapy," said Dr. Lama, associate director of the glaucoma division and an assistant professor at the Institute of Ophthalmology and Visual Science of the University of Medicine and Dentistry of New Jersey-New Jersey Medical School, Newark.
Methods in the early stage of development include gene therapy, photodynamic therapy (PDT), and the naturally occurring proteoglycan decorin and the matrix metalloproteinase (MMP) inhibitor ilonostat, he said, but the reality of clinical practice is that ophthalmologists now must rely on topical steroids and two antiproliferative agents, 5-fluorouracil (5-FU) and mitomycin C, which have their weaknesses.
"5-FU and mitomycin C both have been highly successful in improving outcome in terms of filtering surgery," Dr. Lama said, "but these potent agents can be highly toxic, and there is no free lunch when it comes to use of potent antiproliferatives."
Glaucoma surgery is "paradoxical," he said, "because the success of surgery depends on incomplete wound healing to allow aqueous to flow through an artificially created drainage pathway. So when we talk about failed surgery, it means no flow. The bottom line is that, in glaucoma surgery, you need to maintain filtration through the drainage channel, and that means wound healing will come into play."
When 5-FU is used, "you can get mild problems such as a little bit of punctate keratopathy, but it also can be severe, and you can get non-healing epithelial defects and recurrent erosions," Dr. Lama said. "When there is exuberant healing, the bleb becomes elevated and lumpy, you get incomplete wetting of the surface of the cornea with dellen formation, and discomfort. Aberrant filtering bleb morphology also may be cystic and avascular as well as prone to spontaneous leakage. This can lead to hypotony, blebitis, or even endophthalmitis."
The ideal bleb, he said, is a bleb that is diffuse and hypervascular but not avascular. "Thus, there has been a growing trend for glaucoma surgeons to apply the antiproliferative agents differently from what we have been accustomed to doing, as well as creating a fornix-based rather than a limbal-based flap," Dr. Lama said.
Peng Khaw, MD, of Moorfields Eye Hospital, London, has suggested broad application of the antifibrosis agent with a fornix-based flap to achieve more widespread fibroblastic suppression without a posterior flow delimiting scar that forms from a limbus-based incision, Dr. Lama said.
"The rationale with these adaptations is to create the ideal bleb that is diffuse without flow limitations," Dr. Lama said, adding that only one retrospective study has compared fornix-based and limbus-based conjunctival flaps with respect to achieving more ideal bleb morphology and risk of infection. "In this study from the United Kingdom, it appears that fornix-based flaps are less prone to cystic bleb formation and late infection. Randomized prospective clinical trials comparing these two methods of trabeculectomy surgery from the standpoint of bleb morphology, however, are currently lacking," he said.
"The bottom line is that you can't live on 5-FU and mytomycin C alone," Dr. Lama said. "If you just inspect the survival curve with 5-FU or no 5-FU, you see that those who received 5-FU did best in the first 6 months. After that, the survival curves are parallel, indicating similar rates of bleb failure. Antiproliferatives are thus good at suppressing the wound-healing response early on after filtering surgery but less effective at suppressing the ongoing healing response. Thus, single application of these antifibrotics at the time of surgery does not appear to be enough for the long term."
Interest is growing in research to discover new modalities that would inhibit fibroblasts without disrupting the normal cytoarchitecture, he said, adding that many novel antiproliferative agents and techniques are being developed, with most still at the experimental level.
Gene therapy is being investigated, for instance, Dr. Lama said.
"You can transfect a gene into a fibroblast," he said. "There are preliminary data studying the p53 suppressor gene and the downstream p21 gene. Both have been shown to inhibit DNA synthesis and arrest fibroblast growth without apoptosis and thus preserve the cytoarchitecture."
Another agent of interest is decorin, which is a naturally occurring proteoglycan that affects wound healing by regulating extracellular matrix formation and by inhibiting transforming growth factor beta, which is a potent stimulator of wound healing, he said. It has been studied only in a rabbit model, however.
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作者:admin@医学,生命科学 2011-01-16 05:14
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