Invasive manipulation of the peripheral circulatory system to correct occlusive diseases of the arteries has become more and more routine. Over 200,000 procedures are performed annually in the United States alone which involve blood vessel bypasses, balloon catheters, and other "mechanical" techniques to correct the problem. A serious side effect of these procedures is the subsequent development in the subject of intimal hyperplasia which may, itself, constitute a blockage problem. This appears to be a direct response to the intimal injury caused by the intervention; smooth muscle cells and fibroblasts proliferate and create stenoses in the interior of the vascular wall. The mechanism of this process is evidently not well understood, but a central feature of the development of the problem appears to be unwanted proliferation of smooth muscle cells.
Various methods have been tried to overcome this dangerous side effect. Approaches have included mechanical manipulation as well as administration of chemical agents such as aspirin, dexamethasone, heparins, calcium channel blockers, and a variety of other agents presumed on the basis of various theories to interfere with the development of the stenoses. They have met with very little success and have side effects of their own.
One additional approach is the use of photodynamic therapy (PDT). This form of management, originally applied to cancer treatment, involves the use of photoactive materials which home to tumor tissue, presumably because of the rapidly proliferating nature of the tissue. The photoactive substances, which include psoralen, various porphyrin-based materials, such as Photofrin II.TM. porphyrin aggregate, chlorins, phthalocyanins, and monohydrobenzoporphyrin derivatives, to name but a few, are harmless unless photoactivated. However, when irradiated with light of appropriate wavelength, the drugs apparently effect the formation of a toxic agent, presumably singlet oxygen, although they themselves are chemically unchanged. The resultant toxic agent causes the destruction of the unwanted tumor tissue.
PDT has also been applied with some success to the treatment of atherosclerotic plaques. See, for example, Kessel, D. et al., Photochem Photobiol (1984) 40:59-62; Okunaka, T. et al., Photochem Photobiol (1987) 46:769-775; Spears, J. R. et al., J Clin Invest (1983) 71:395-399; Spokqiny, A. M. et al., J Am Col Cardiol (1986) 8:1387-1392; Copperath, K. et al., Eur Heart J (1989) 10 (Suppl):151; Straight, R. et al., Photodynamic Therapy of Tumors and Other Diseases, (1985) pp. 349-350.
The use of PDT to treat or prevent the restenosis that often accompanies angioplasty has also been studied. These studies have either employed smooth muscle cells in (SMC) in culture, on the theory that SMC proliferation is the sine qua non of restenosis, or have used animal models. In general, PDT appears to show promise in this regard. However, controls run in many of these studies, using the photoactivating agent in the absence of light, have provided contradictory results when smooth muscle cells in culture were used as the model system. Applicants are unaware of any animal studies which showed any indication of positive results for preventing restenosis in the absence of light.
Dartsch, P. C. et al. reported in Advances in Laser Medicine 4: Laser Angioplasty II Biamino, G., et al. (ads) Ecomed Verlagsgesellschaft, Landsberg/Lech, Berlin (1990) 77-80, the results of contracting smooth muscle cells in culture exposed to dihematoporphyrin-ester and -ether (DHE). This porphyrin-based drug is now marketed as Photofrin II.TM.. The report discloses that SMC were isolated by enzymatic disaggregation of either normal or stenosing plaque tissues and cultured in vitro. They were tested in their first, second or third passage by treating them with DHE at concentrations ranging from 0.1-25 .mu.g/ml and irradiated with ultraviolet light. The percentage of viable and still adherent cells was markedly reduced for plaque-derived SMC and much less dramatically reduced for normal SMC. A less dramatic, but nevertheless detectable, effect was observed in the presence of DHE but in the absence of radiation. Specifically, cells treated with 5 .mu.g/ml DHE and light showed a reduction in the number of viable cells to 73% in the case of normal derived cells and 38% for plaque-derived SMC. Using a DHE concentration of 1 .mu.g/ml and an energy density of 1200 mJ/cm2, after 24 hours 80% of the normal SMC and 20% of the plaque-derived SMC were viable. Similar results were reported by this group in related publications: Dartsch, P. C. et al., Atherosclerosis (1990) 10:616-624; Dartsch, P. C. et al., J Am Coll Cardiol (1990) 15:1545-1550.
In two recent reports by Sobeh, M. S. et al., results apparently contradictory to those of Dartsch, et al. were obtained when SMC cultured from the intermedia of human long saphenous vein harvested for coronary artery vein bypass grafting, were used in the tests. These cells were treated with Photofrin II.TM. porphyrin aggregates and irradiated. These reports state that the cells were unaffected by Photofrin II.TM. porphyrin aggregate at 0-100 .mu.g/ml without light. However, when treated with light energy of greater than 3 J/cm2 in the presence at least 2 .mu.g/ml of the drug, a mean cell destruction of over 80% was reported regardless of wavelength. The reports also state that light without prior chromophore sensitization produced no cell damage. (Vascular Surgical Society of Great Britain and Ireland Annual General Meeting, London, November 1992; 13th Annual American Society of Laser Medicine and Surgery, New Orleans, April 1993.)
Asahara, T. et al. reported in Circulation (1992) 86 (Suppl) 1-846, that PDT was able to inhibit restenosis in rabbits that had received balloon injuries of the iliac artery and were fed with a 0.2% cholesterol diet. Hematoporphyrin derivative (HPD) was administered 24 hours before irradiation at various times relative to the injury. The best effects were observed when the treatment was administered one week after angioplasty.
In another in vivo study, Ortu, P. et al., Circulation (1992) 85:1189-1196, reported that photodynamic therapy, with chloraluminum-sulfonated phthalocyanine (CASPc) used as the drug, was effective in inhibiting the intimal hyperplasia response in rats subjected to balloon injury of the carotid artery. Controls consisted of rats irradiated, but not administered the drug. No controls using CASPc without light were reported.
Eton, D. et al., J. Surg. Res. (1992) 53:558-562, reported the effect of photodynamic therapy using Photofrin II.TM. porphyrin aggregates in a rabbit model wherein the rabbits underwent standardized intimal injury to both common carotid arteries with a balloon catheter. The test animals received Photofrin II.TM. porphyrin aggregate and subsequent irradiation; the control groups either received no treatment, or chromophore alone, or light alone. The results were evaluated in terms of arterial cross sections. Only the test group showed a statistically significant improvement over the controls, although the animals treated with light alone or Photofrin II.TM. porphyrin aggregate alone had non-significant lower mean ratios of the area of intimal hyperplasia to the area enclosed by the internal elastic lamina, used as a measure of stenosis in this study.
It would be advantageous to provide a treatment to prevent intimal hyperplasia (IH) following vascular trauma which is independent of PDT, so that the necessity to provide light using specialized equipment is avoided. It has now been found that green porphyrins, administered concurrently with, and for a period of time after, angioplastic procedures, can effectively inhibit the undesired stenoses often accompanying this procedure.