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【medical-news】治疗青光眼的新药物新方法

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New drugs, techniques promising, but more data needed

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.

"It improves bleb survival in this model without disruption of the cytoarchitecture," Dr. Lama said.

Another agent being tested is the MMP inhibitor ilonostat, he said, adding that "it has been shown to rival mytomycin C in an animal (rabbit) model, but without the destructive effects that mitomycin C has on the conjunctival architecture."

PDT is being explored for selective targeting of choroidal neovascular membranes without disruption of adjacent tissue, Dr. Lama said.

"We can exploit the same concept in a wound-healing model by giving a photosynthesizer, which is selectively taken up by fibroblasts, and applying blue light to irradiate it," he said. "Unlike the previously mentioned investigational agents, we actually have human data for PDT in glaucoma surgery. One was a pilot study, and another was a prospective, non-randomized, non-controlled trial in which IOP <21 mm Hg was able to be achieved in 60% of the patients, without glaucoma medication."

But much information is lacking, Dr. Lama said. "We don't know the dose of photosynthesizer needed, the proper wavelength of light, the amount of area to be exposed, or the length of light exposure," he said. "It begs for randomized studies."

He concluded: "We can suppress fibroblasts early on. We hope to get chronic suppression of fibroblasts, and in that way we get improved bleb survival. What we've done so far is change the way we apply antiproliferatives. Where we go from here is better standardization of doses and development of these novel agents so we can reduce toxicity and get more healthy-appearing blebs."

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2007-02-26 23:01 浏览 : 1581 回复 : 5

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• 笑死，除了妇产只招男性的医院你见过吗？

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本人已认领该文编译，48小时后若未提交译文，请其他战友自由认领。

2007-03-22 13:02

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• 新冠疫苗的奥秘——如何选择疫苗抗原？（转载）

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New drugs, techniques promising, but more data needed
治疗青光眼的新药物新方法，但需要更多的数据
Future could include gene therapy, MMP regulators and inhibitors, PDT
将来可能包括基因治疗，MMP调节剂和抑制剂，PDT
Feb 15, 2007
By: Ed Edelson
2007.2.15
作者：Ed Edelson

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.
纽约----Paul J. Lama医学博士在青光眼2006年会上告诉与会者，一些抗纤维化药物和疗法对青光眼的治疗似乎带来希望，但仍需要更多的特别是人类的对照试验数据。

"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.
青光眼部联合主任和纽瓦克新泽西医学和牙科大学-新泽西医学院的眼科和视科学研究所助理教授Lama博士说，“如果这些药物有结果的话，那么我们将获得可以联合使用的整系列的药物，就像治疗癌症一样”。

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.
他说，处于研发早期的方法包括基因疗法，光动力疗法（PDT）及天然蛋白多糖和基质金属蛋白酶（MMP）抑制剂ilonostat，但是临床实践的事实是眼科医师目前必须依赖局部的类固醇和两种抗增殖活性的药物，5-氟尿嘧啶 (5-FU)和丝裂霉素C，而这些都有其不足之处。

"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."
Lama博士说，“5-FU和丝裂霉素C在改善青光眼滤过手术的手术结果方面很成功，”“但是这些强效药物的毒性很大，在使用强效的抗增殖剂时要付出代价。”

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."
他说青光眼手术是“自相矛盾的”，“因为手术的成功依赖于手术伤口愈合不完全来允许房水通过人为制造的通道排出。因此，当我们说到手术失败，即意味着房水不能流出。基本意思就是说，在青光眼手术中，你需要保持通路管道的滤过性，且这意味着伤口愈合将开始起作用。”

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."
Lama博士说，当使用5-FU时，“可能遇到例如小片的点状角膜病变这样轻微的问题，但也可能很严重，而且可能出现上皮缺损不愈合及复发性糜烂”。“当愈合充分后，滤泡就鼓起并凹凸不平，因为瘢痕形成出现角膜表面润湿不完全及不舒适。异常的滤泡形态除了有自发泄漏倾向外，也可能会出现囊状及无血管。这可能导致低眼压，滤泡炎甚至是化脓性眼内炎。”

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.
他说，理想的滤泡是一种有渗透性，多血管而非无血管的滤泡。“因此，在青光眼手术中除了采用以穹窿为基底的结膜瓣小梁切除术而非角膜缘为基底的结膜瓣小梁切除术外，另出现一种使用抗增殖剂的趋势，这不同于我们通常的做法”Lama博士说。

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.
伦敦Moorfields眼科医院的Peng Khaw医学博士，已经指出广泛的应用抗纤维化药物联合以穹窿为基底的结膜瓣小梁切除术能达到更广泛的抑制成纤维细胞作用，而没有以角膜缘为基底的结膜瓣小梁切除术产生的疤痕导致的房水流动限制。

"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.
Lama博士说，“这些适应性变化的基本原理是创造一种理想的滤泡，没有流动性限制的渗透性，”而且，仅有一项回顾性研究比较了联合以穹窿为基底的结膜瓣小梁切除术和以角膜缘为基底的结膜瓣小梁切除术在达到更理想的滤泡形态及降低感染风险方面的不同。他说，“在英国的此项研究中，似乎以穹窿为基底的结膜瓣小梁切除术出现囊状滤泡和后期感染的几率更小。然而目前缺乏针对滤泡形态比较这两种小梁切除术的随机前瞻性临床研究”。

"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."
Lama博士说“基本意思就是不能单纯依靠5-FU和丝裂霉素C”。“如果仅仅检查使用5-FU或不使用5-FU的滤泡存活曲线，你会发现那些接受5-FU的患者在头6个月表现良好。此后，存活曲线是平行的，表明滤泡失败的几率一样。因此抗增殖剂在青光眼滤过手术早期对于抑制伤口愈合有利，但是对于持续愈合的抑制效果不佳。因此，在手术时单纯使用这些抗纤维化药物，从长期效果来看似乎不够。”

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.
他说，研究兴趣集中在寻找在不破坏正常细胞结构情况下，发现新的可以抑制成纤维细胞的模式，另外，很多新的抗增殖剂和技术被开发出来，但大部分仍停留在试验水平。

Gene therapy is being investigated, for instance, Dr. Lama said.
Lama博士说，如基因治疗就正在被研究。

"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."
他说“你可以将基因转染进成纤维细胞”。“有关于p53抑制基因和下游p21基因的初步研究数据。两者都显示在无细胞凋亡情况下，能抑制DNA合成并阻止成纤维细胞生长，因此可以保护细胞结构。”

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.
他说另一种被关注的药物是蛋白多糖，这是种天然的蛋白多糖，可以通过控制细胞外基质形成及抑制β因子的变异生长来影响伤口愈合，这是种强效的伤口愈合刺激剂。然而，这种研究只在兔子模型中进行过。

"It improves bleb survival in this model without disruption of the cytoarchitecture," Dr. Lama said.
Lama博士说“它在不破坏细胞结构的情况下促进滤泡的存活”。

Another agent being tested is the MMP inhibitor ilonostat, he said, adding that "it has been shown to rival mytomycin C in an animal (rabbit) model, but without the destructive effects that mitomycin C has on the conjunctival architecture."
他说另一种试验物质是MMP组织抑制剂，另外“在动物（兔子）模型中，已经证实其作用比得上丝裂霉素C，但没有联合小梁切除术中使用丝裂霉素C所存在的破坏作用”。

PDT is being explored for selective targeting of choroidal neovascular membranes without disruption of adjacent tissue, Dr. Lama said.
Lama博士说，PDT被用来在不破坏毗邻组织的情况下，寻找选择性的靶向脉络膜新生血管膜。

"We can exploit the same concept in a wound-healing model by giving a photosynthesizer, which is selectively taken up by fibroblasts, and applying blue light to irradiate it," he said. "Unlike the previously mentioned investigational agents, we actually have human data for PDT in glaucoma surgery. One was a pilot study, and another was a prospective, non-randomized, non-controlled trial in which IOP <21 mm Hg was able to be achieved in 60% of the patients, without glaucoma medication."
他说“我们可以利用同样的思想，在伤口愈合模型中，通过给予一种成纤维细胞选择性进行的光能合成物质，并且用蓝光照射”。“与先前提到的研究物质不同，我们有关于PDT在青光眼手术中的实际人类数据。一个是试点研究，另一个是前瞻性、非随机、无对照试验研究，其中60％的患者能达到眼内压<21 mm Hg，并且不需要青光眼药物治疗。”

But much information is lacking, Dr. Lama said. "We don't know the dose of photosynthesizer needed, the proper wavelength of light, the amount of area to be exposed, or the length of light exposure," he said. "It begs for randomized studies."
Lama博士说，但仍缺少很多信息。他说“我们不知道光照量，合适的波长，照射面积，或者光照时间长短”。“这需要进行随机试验。”

He concluded: "We can suppress fibroblasts early on. We hope to get chronic suppression of fibroblasts, and in that way we get improved bleb survival. What we've done so far is change the way we apply antiproliferatives. Where we go from here is better standardization of doses and development of these novel agents so we can reduce toxicity and get more healthy-appearing blebs."
他得出结论：“我们可以在早期抑制成纤维细胞。我们希望能长期的抑制成纤维细胞，同时要改善滤泡的存活性。目前我们所做的是改变我们使用抗增殖剂的方法。我们的目标是使剂量更标准化而且研制新的药物，这样我们可以降低毒性并获得看起来更健康的滤泡。”

2007-03-22 17:19

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ginnyran 编辑于 2007-03-24 07:21

• 新冠疫苗的奥秘——如何选择疫苗抗原？（转载）

guigli

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刚刚学习了一下。
ginnyran 战友翻译的非常好，不过我猜您可能不是眼科的吧？

有一点小小的建议：
“穹窿底结膜瓣、非轮部底结膜并瓣”应该翻译作
“以穹窿为基底的结膜瓣”“以角膜缘为基底的结膜瓣”更准确，这是我们在进行小梁切除术中可选择的两种不同结膜瓣制作方式。limbus在眼科译作“角膜缘”

2007-03-22 20:10

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