WO2002094260A1 - Nouvelle utilisation de vert d'indocyanine en tant qu'agent photosensible - Google Patents

Nouvelle utilisation de vert d'indocyanine en tant qu'agent photosensible Download PDF

Info

Publication number
WO2002094260A1
WO2002094260A1 PCT/BR2002/000010 BR0200010W WO02094260A1 WO 2002094260 A1 WO2002094260 A1 WO 2002094260A1 BR 0200010 W BR0200010 W BR 0200010W WO 02094260 A1 WO02094260 A1 WO 02094260A1
Authority
WO
WIPO (PCT)
Prior art keywords
indocyanine green
fact
accordance
laser
light
Prior art date
Application number
PCT/BR2002/000010
Other languages
English (en)
Inventor
Michel Eid Farah
Rogério ALVES COSTA
José Augusto CARDILLO
Original Assignee
Michel Eid Farah
Alves Costa Rogerio
Cardillo Jose Augusto
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Michel Eid Farah, Alves Costa Rogerio, Cardillo Jose Augusto filed Critical Michel Eid Farah
Publication of WO2002094260A1 publication Critical patent/WO2002094260A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/10—Ophthalmic agents for accommodation disorders, e.g. myopia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts

Definitions

  • the present invention relates to a new use of indocyanine green as a photosensitive agent in dynamic photot ⁇ iermQtherapy and Selective Dynamic Thermotherapy for occlusion of choroidal neovascularization, in patients with age-related macular degeneration, pathological myopia, angiod strias, syndrome of presumed ocular histoplasmosis, inflammatory or idiopathic causes, henceforth named i-PTT and i-TTD; also refers to a new use of a Laser Therapy System and Delivery of Wavelength Light in the Infrared Spectrum for achieving Photodyna ic Effect, and Selective Vascular Choroidal Occlusion using indocyanine green in its original formula; as well as, in modified presentations with Liposo e Encapsulation, with the objective of increasing its half- life, reducing aggregation and larger intra- uscular selectivity, as well as other chemical modifications or the synthesis route, and refers to a photothermodynamic therapy and Selective Dynamic Thermotherapy
  • Indocyanine green an anionic tricarbocyanine dye has been used for imaging retina and choroidal vasculature for over 30 years. There are several scientific works showing improvements in this technique or in imaging by digital video-angiographies, and that detach several computer programs with the objective of working the image achieved by this recording method.
  • indocyanine green dye causing minimal damages to under laying tissue, like other second-generation agents used in photodynamic therapy, is characterized by low skin phototoxicity, high tissue targetability, rapid biodistribution and clearance, as well as technically easy administration and monitoring, indispensable qualities for an ideal photosensitizer to be applied in photodynamic therapy.
  • indocyanine green in combination with infrared light has been appointed as photosensitizing agent for photodynamic therapy of colonic cancer cells.
  • Boumler W Abels C, Karrer S, et al . Photo-oxidative killing of human colonic cancer cells using indocyanine green and infrared light. Br J Cancer 1999;80:360-363).
  • Photodynamic therapy leads to cell death due to the generation of singlet type oxygen and the subsequent formation of oxidative substances as lipid peroxides, post- photoactivation by a wavelength diode laser at 805 nm.
  • Photodynamic therapy can be applied by a therapeutic modality that involves the excitation of a dye by light of a specific wavelength, with the release of excited oxygen and consequent activation of clotting reaction in cascade.
  • Age-related Macular Degeneration is the leading cause of legal blindness in people over 60 years in the developed countries.
  • bearers of choroidal neovascularization in the subfoveal region have several options for their treatment; however, there are various limitations regarding the results achieved.
  • Laser photocoagulation of subretinal vascular membrane in Exudative Macular Degeneration is a well-studied procedure, this therapeutic modality is the only treatment accepted, until recently, but usually with negative results.
  • Another disadvantage is related with the high cost of photosensitizing agent, mainly because the need of f equent applications occurs invariably at an average of 3.4 in the first year and 2.1 in the second year that constitutes important and limiting aspects of the indications and maintenance of this treatment over time.
  • the first modality of treatment with laser photocoagulation had the function of burning the damaged region; such technique, therefore, showed the great disadvantage of leaving a turbidity or permanent marker in the central visual field of the patient, besides definitely damaging the neurosensory retina of the region treated.
  • This invention has the purpose of using a laser system modified under pressure of the effect of photodynamic therapy for vascular occlusion of choroidal vessels or neovascularization originating from choroids that invade the subretinal tissue or neurosensory tissue itself, in a selective form, achieving the intravascular coagulation by photothermo-dyna ic effect without significantly damaging and/or by heating tissues and/or by hyperthermy of adjacent tissues, that is, the treatment spot until the outgoing of new use of the dye and photosensitizer indocyanine green as an agent in the photodynamic therapy to be used in the diseases: age-related macular degeneration, pathological myopia, angiod strias, syndrome of presumed ocular histoplasmosis, inflammatory or idiopathic causes and other abnormalities that may generate enlargement of abnormal vessels in ocular tissues.
  • the Dynamic Photother otherapy and the Selective Dynamic Thermotherapy process uses a photochemical interaction and photophysics, infrared wavelength light emitted by a diode laser, exposure area of up to 8.6 mm diameter, and using only one round and/or modified beam, customized in accordance with the targeted tissue.
  • the Dynamic Photothermotherapy process in this invention is directed to the use in abnormal vessels of ocular tissues, particularly in choroids, retina and/or between the choroids and the retina, which are leaking fluid and/or blood to the referred tissues, and thereby, increasing the risk and/or causing visual decay.
  • the process uses infrared laser in wavelength band, which has more affinity or absorption with the photosensitizing dye used.
  • the procedures are based on administration of a photosensitizing agent in intravenous form, waiting until the dye has reached a proper maximum distribution and localization inside the pre-selected area for treatment, the injection can be repeated according to the case and/or cause of the vascular alteration to be treated.
  • a medical instrument is used associated with an infrared laser light source, and thereby inducing the interaction between the light and the photosensitizing agent, during specific time determined. Excitation of the photosensitizing agent concentrated in the targeted tissue, during the predetermined time while observing the tissues being treated and eventually any visible direct or indirect effect by means of an optical instrument coupled to the emitting source of laser light.
  • the present invention constitutes in the use associated of the photosensitizing agent that will be exposed to the brightness by the projection of the light of the infrared laser in wavelength strip capable to promote the absorption of the used dye, in that the heat generated by the luminous stimulation it happens in controlled thermal conditions, and with great photo-physic and photochemical interactions, so that it doesn't cause characteristic thermal photocoagulation reaction, but just causing photodynamic effect and/or insufficient hyperthermy to cause damages to the adjacent tissues.
  • the photosensitizing agent in predefined conditions, the Indocyanine Green, associated to the exposure to the luminous agent, the light of the infrared laser, to reach the Dynamic Photothermotherapy (i-PTT) and the Selectively Dynamic Thermotherapy (i-TTD) for occlusion of choroidal neovascularization.
  • the photosensitizing agent will be exposed to the brightness by the projection of the light of the infrared laser in wavelength strip capable to promote the absorption of the used dye, in that the heat generated by the luminous stimulation it happens in controlled thermal conditions, and with great photophysics and photochemical interactions, so that it doesn't cause characteristic thermal photocoagulation reaction, but just causing photodynamic effect and/or insufficient hyperthermy to cause damages to the adjacent tissues.
  • the Searchers have been seeking to identify new photosensitizers for photodynamic therapy that can be efficiently used in larger groups of patients bearers of Age- Related Macular Degeneration and that are able to improve the visual acuity in this disease and in others that have the development of choroidal neovascularization and/or subretinal and/or retinal.
  • this invention consists of the determination of conditions under proceeding phases to achieve an evaluation of the vascular tissues response, in particular, choriocapillaris and choroidal neovascularization, in relation to the indocyanine green, in photophysics and photochemistry (photodynamic) in relation/interaction of indocyanine green and of the light in 810 nm length. Studies were carried out in pigmented and non- pigmented rabbits eyes.
  • Indocyanine Green used here as photosensitizer can be modified by several means for treatment by dynamic photothermotherapy, can as well be associated with other forms of photocoagulating hyperthermy, that is, being unable to induce tissue burns, also becoming selective, thereby.
  • this invention is proposing a new photother o-sensitizing process, which involves an intravenous injection of Indocyanine Green at doses from 0,5 to 5,0 mg/Kg, preferably, 2 g/Kg and focal activation with laser light of 810 nm in a retinal irradiance, where the energy absorb by the molecule is not primarily converted to heat (photo-oxidation type I), but transferred to molecular oxygen via triplet state (photo-oxidation reaction type II) .
  • choriocapillaris response choroidal vascular tissue topographically situated in choroidal inner layer, near Bruch's membrane, with wavelength light at 810 nm and Indocyanine Green in pigmented and non-pig ented rabbits eyes
  • choroidal vascular tissue topographically situated in choroidal inner layer, near Bruch's membrane, with wavelength light at 810 nm and Indocyanine Green in pigmented and non-pig ented rabbits eyes achieved positive results in order to evaluate the medicinal and technological potential of the present invention and dynamic photothermotherapy, for choroidal neovascularization occlusion, vascular tissue bellow the retina, which includes choriocapillaris and external deep vessels, where it originates the neovascularization lately noted in humans
  • the choriocapillaris occlusion was achieved with Indocyanine at doses of 10 to 20 mg/Kg and irradiation as low as 7,2 Joules/cm 2 .
  • the present invention reports for the first time a case of occult type choroidal neovascularization due to Related Macular Degeneration that was successfully treated by the dynamic photothermotherapy with Indocyanine Green (i-PTT) .
  • Indocyanine Green is a water-soluble tricarbocyanine molecule that does not contain more than 5% sodium chloride, chemically is N-hydro-3, 3' , 3 '-tetrametyl-1, 1 '-di- ( sulphobutyl) -4, 5, 4 ' , 5'-hidroxy of benzoindotricarbocyanine with molecular weight of 775.
  • Green shows high bound level to plasma lipoproteins (approximately 98%, warranting intravascular retention properties) .
  • Fluorescence properties assure the exact contrast localization in subretinal neovascular lesion, prior to positioning the laser beam for application of activating light.
  • indocyanine green after administration of indocyanine green during the semiologic process, and after observing the concentration of this substances in the neovascular membrane itself, we are certain of the bio-assessibility of the medication to achieve the desired effect of photothermo- dynamic and neovascularization selective occlusion of which the substance is concentrated.
  • Indocyanine Green constitute a medicament relatively cheap and safety that has a very low local and systemic toxicity and a favorable biodistribution, as well as fluorescence properties already known, which detection technology was largely improved in late years through reaching digital images and video angiography cameras able to actuate in infrared band.
  • detection technology was largely improved in late years through reaching digital images and video angiography cameras able to actuate in infrared band.
  • the medication is easily administered, and is rapidly distributed and excreted.
  • Indocyanine Green was not shown for photodynamic therapy treatment, until the authors of the present invention could show in vivo ( Costa et al , unpublished data, 2000) .
  • a modified wavelength diode laser at 810 nm similar to the one used for photodynamic therapy with Indocyanine Green, was used with safety to deliver irradiances of about 7.000 milliwatts/cm 2 in 60 seconds for treatment of occult subfoveal subretinal neovascularization. Activation of about 805 nm is also advantageous due to the deep large light penetration.
  • indocyanine green shows, as other second- generation agents used for photodynamic therapy, a low phototoxicity for the skin, selectivity for the targeted tissue, rapid delivery and biodistribution, easy administration and monitored.
  • the present invention arises with great impact to reveal a new use for indocyanine green that is normally used in achieving the angiography image with indocyanine green, for recording retinal vasculature, mainly choroidal (vascular tissue situated right behind the retina and is responsible for nutrition of inner retinal layers) .
  • neovascular membranes of patients with age-related macular degeneration, pathologic myopia, angiod strias of idiopathic and/or traumatic or inflammatory causes and/or related to dystrophies primarily through photo-oxidation reactions type II, with generation of singlet oxygen through braking out a thrombosis cascade by disintegration of red blood cells, release of active oxygen, oxidative radicals, fibrin and circulation obstruction in choriocapillaris, reaching, thereby, an efficiency of 100% positive results (obstruction of targeted vessels) in present technique.
  • the photosensitizer molecule that has absorbed laser light energy can reach the ground state activated by radioactive or non- radioactive mechanism.
  • the molecule looses the energy absorbed by the molecule and can be converted to heat, by internal conversion or transferred to other molecules by means of a photo-oxidation reaction type I, thereby damaging cells by raising their infracellular temperature, created by the use of photocoagulation implemented by indocyanine green (Reichel E, Puliafito C, Duker J, Guyer D. Indocyanine green dye enhanced diode photocoagulation of poorly defined subfoveal choroidal neovascularization. Ophthalmic Surg 1994; 25:195-201) or tissue welding (Decoste S, Farinelli W, Flotte T, Anderson R. Dye-enhanced laser welding for skin closure. Laser Surg Med 1992; 12:25-32).
  • indocyanine green dye may release the energy absorbed by the photosensitizer, transfer it to the oxygen molecule by means of a photo-oxidation type II, via a triplet state, and other components to form reactive intermediates as singlet oxygen, which can cause irreversible destruction in biological substrates.
  • Other reactive species such as superoxide, hydroperoxyl, or hydroxyl radicals may also be involved in the irreversible damage mediated by biological components (Henderson BW, Dougherty TJ. How does photodynamic therapy work? Photochem Photobiol 1992; 55:145-157, Roberts W, Hasan T. Role of neovasculature and vascular permeability on the tumor retention of photodynamic agents. Cancer Res 1992; 52:924-930) .
  • indocyanine green is an efficient photosensitizing agent for normal choriocapillaris occlusion in pig ented or non-pigmented rabbits.
  • indocyanine green the subretinal vasculature was efficaciously closed, with minimal alteration in adjacent neurosensory retina with light doses, as low as 7,2 J/cm 2 . More intense choroidal effects were noted at the highest doses of light tested.
  • Clinical examination and fundus photography revealed no retinal color change during and immediately following the use of dynamic photothermotherapy treatment, although a mild grayishing of the neurosensory retina was noted on the next day.
  • fluorescein angiography applied to group V of the experiment showed choroidal occlusion evidently larger after 24 hours in comparison to the early fluorescein angiography performed 6 hours after light exposure.
  • the delayed response is also a sign that the mechanism of vascular occlusion action was photochemical and not thermal.
  • choriocapillaris occlusion was associated with a mild damage at level of retinal pigment epithelium in our study, this alteration also occurred in several other studies.
  • the extent of the damage depended on the dose of light administered and was noted in the treatment field. Any extension in its vicinity, as noted in other types of treatment, caused by lateral, deep and superficial heat transference, which arises with thermal photocoagulation. (Wilson CA, Royster AJ, Tiedeman JS, Hatchell DL. Exudative Retinal detachment after photodynamic injury.
  • Indocyanine green is not significantly toxic in animals, since its lethal dose (LD50) after intravenous administration ranges from 50 to 80 g/kg. There are no equivalent data in humans; the disappearance rate of indocyanine green in healthy human subjects is 18 to 24% per minute. The normal biologic half-life was determined finding the value of 2.5 to 3 minutes so that blood samples taken from healthy patients 20 minutes after the injection of indocyanine green does not contain more than 4% of the initial concentration of the dye (Villeneuve JP, Huot R, Marleau D, Huet PM. Estimation of hepatic blood flow with indocyanine green: Comparison between the continuous infusion and single injections methods. Am J Gastroenterol 1982; 77:233-237) eliminating the need for a 24-hour period of light abstinence as required for photodynamic therapy with verteporfin.
  • LD50 lethal dose
  • Indocyanine green is not metabolized after an intravenous injection, and is excreted exclusively through hepatic via. It is not absorbed from the intestine and does not stay in enterohepatic circulation. The dye is taken from the plasma by the hepatic parenchyma cells and secreted into the bile. Negligible uptake of the dye occurs in the kidneys, lungs, cerebrospinal fluid, and peripheral circulation. Renal excretion does not occur. The safety of intravenous administration of indocyanine green in humans was already well documented, with severe adverse reactions occurring in only 0.05% of patients.
  • Photodynamic therapy with existing ophthalmic agents is mainly limited by poor aqueous solubility, needing intralipid or liposome formulation and consequent intravenous administration by slow infusion, in contrast with the application of indocyanine green that is a water-soluble substance and can be rapidly infused, thereby avoiding long intervals of 10 minutes or more, required for slow infusion of a preparation for suspension with lissome and/or with intralipid formulation.
  • indocyanine green that is a water-soluble substance and can be rapidly infused, thereby avoiding long intervals of 10 minutes or more, required for slow infusion of a preparation for suspension with lissome and/or with intralipid formulation.
  • This property also enhances treatment practicality and avoids the fact of increasing patient compliance and comfort, in addition, modification of indocyanine green with encapsulation can and other chemical modification can also be rapidly administered, thereby enhancing the photothermodynamic effect.
  • indocyanine green is bound rapidly and almost completely (98%) to plasma proteins.
  • Albumin is its major carrier; however, in human serum, 80% of indocyanine green can be bound to globulins, probably alpha-1 lipoproteins
  • the hyperproliferative neovascular tissue exhibits an enhanced permeability and elevated levels of specific albumin and LDL receptors (Schmidt U, Birngruber R, Hasan T. Selective occlusion of ocular neovascularization by photodynamic therapy. Ophthalmology 1992; 89:391-394) as well as LDL receptors ( Rutledge J, Curry F, Blanche P, Krauss R. Solvent drag of LDL across mammalian endothelial barriers with increased permeability. Am J Physiol 1995; 268:H1982-H19910 leading to increased LDL transport across endothelial junctions (Schnitzer J, Carley W, Palade G. Albumin interacts with a 60-kDa icrovascular endothelial glycoprotein. Proc Natl Acad Sci 1988;85:6773-6777 ).
  • the photosensitizer In order that a dye can have a photodynamic action, the photosensitizer must be irradiated by a non-thermal low intensity light, and at the wavelength of greater absorption for the photosensitizer.
  • Indocyanine green reveals a high absorption in the infrared spectrum region around 805 nm. Infrared light penetrates deeper into tissue of red light, thereby conferring advantages in the selectivity for treatment of subretinal or choroidal neovascular membranes.
  • indocyanine green in its regular and/or single conventional form and in presentations with modifications is a safety photosensitizer that can be widely used in ophthalmology with very low local or systemic toxicity effect and is easily administered and is rapidly distributed and excreted.
  • the present invention reveals a new use of indocyanine green, in any form of presentation, as an efficient photosensitizer substance for use in the dynamic photothermo therapy and in the selective dynamic thermotherapy for selective occlusion of subretinal neovascular membranes, mainly by means of photooxidation reactions type II.
  • the referred substance is applied in photosensitizing compound form.
  • Indocyanine green in its photosensitizing form, was reconstituted into solution form, using 0.5 to 10 ml, preferably 2 ml of sterile distilled water for 50 mg of indocyanine green in its powder form. The solution reached was maintained and protected from light during the handling of the indocyanine green to prevent inadvertent activation.
  • the objective of the present invention refers to the use in treatment of subretinal neovascular membranes, through photooxidation reactions type II (photodynamic therapy) reached with the use of indocyanine green and a laser delivery system with modified diode and slit-lamp.
  • the diode laser has the wavelength of 810 nm in infrared spectrum band, near the maximum absorption peak of indocyanine green and has a diaphragm mechanism with different openings for exposure of beams with different diameters 0.8, 1.0, 1.2, 1.5, 2.5 and 4.3 mm, coupled to the co-observation system with biomicroscope in slit-lamp form.
  • the indocyanine green as the photosensitizing agent in the treatment of dynamic photothermotherapy and of selective dynamic thermotherapy for occlusion of neovascularization of the cor ⁇ ide, its presentation in packages from 100 to 200mg, in one or two flasks, being used in therapeutic dosage from 1 to 5 mg/kg per weigth, more preferable from 2 to 3mg/Kg, being the package linked during the treatment above refered, in flasks containing from 125 to 150 of the powder of the dye.
  • the dye can be administered in three ways in relation to the time of application of the laser: - immediately before, 30 minutes before and another combined (30 minutes before and immediately before) , in that to occur the accumulation of the dye to obtain higher effect, the two applications overlaying itself.
  • the filling of photosensitizing agent could be made by the packaging of the volume foreseen in one or in two flasks.
  • FIGURE 1 For illustrative purposes the following figures are presented, and above procedures can be noted for a better understanding of the present invention that has the essential photodynamic effect as basis, with a laser delivery system at 810 nm with beams of large diameters (over 1500 micros in the retina) .
  • FIGURE 1 For illustrative purposes the following figures are presented, and above procedures can be noted for a better understanding of the present invention that has the essential photodynamic effect as basis, with a laser delivery system at 810 nm with beams of large diameters (over 1500 micros in the retina) .
  • FIGURE 2 is a diagrammatic representation of FIGURE 1
  • FIGURE 3 is a diagrammatic representation of FIGURE 3
  • FIGURE 4
  • Light micrograph nine days after light treatment .
  • FIGURE 5
  • FIGURE 6 is a diagrammatic representation of FIGURE 6
  • the pigment epithelium cells were disrupted (uranyl acetate; original magnification x ⁇ OOO, bar: 1 urn) . (Bottom left and right) Lesion of 14.2 J/cm 2 of group 4 (20 mg/kg of indocyanine green, 90 mW) . Choriocapillaris endothelial cells showed cytoplasm projections, folding and infoldings further to vacuolization.
  • FIGURE 7 (arrows) (uranyl acetate; original magnification xl2k/x40k, bar: 500/100 nm) .
  • the melanosomes were intact, and having some degree of lesion in pigment epithelium cells. Br ⁇ ch/ s membrane remained intact, but there was damage to the outer retina layer, and with photoreceptors forming rings (uranyl acetate; original magnification x3000, bar: 2 ⁇ ) . (Bottom left) The photoreceptor segments in higher magnification showed degeneration characterized by fusion of disc membranes with convoluted aspect, sometimes associated with the disruption of internal segment (uranyl acetate; original magnification x8000, bar: 1 ⁇ m) .
  • the outer nuclear layers showed piknosis and vacuolization
  • the photosensitizer dye indocyanine green was reconstituted into solution form using 2,0ml of distilled water at 5°C during one hour, reaching a reconstitution in aqueous solution form.
  • the solution was maintained protected from light and immediately reconstituted prior to its use and protected from light during all handling period, in order to prevent inadvertent activation.
  • Example II The laser delivery system consisted of a laser in infrared diode spectrum and a bio icroscope in slit-lamp form.
  • a diode laser (TTT 1500, QPTQ, Sao Carlos, Brazil) with wavelength at 810 nm, near the maximum absorption peak of indocyanine green.
  • the application beams consisted of diaphragms with 0.8, 1.0, 1.2, 1.5, 2.5, and 4.3 mm diameters.
  • a fundus contact lens Prior to light application, a fundus contact lens
  • each light stimulating shot in the retina was equal to 4000 ⁇ m.
  • the intensity used was 50 mW (Group 1 and 2) , 90 mW
  • Light irradiation started 10 seconds following the intravenous injection of either indocyanine green or distilled water. After treatment, the animals were returned to their housing and raised under ordinary fluorescent lights, 30 lux for 9 days. Fundus photography and fluorescein angiography were performed 24 hours after treatments, using a fundus camera (TRC-50IA/IMAGEnet, Topcon, Tokyo, Japan) . Additional photography and angiography were performed 6 hours after light treatments in the group 5. The photography was performed with 10% sodium fluorescein (0.1 ml/kg) via marginal ear vein injection.
  • Example V Histological analysis By the ninth day, the eyes were enucleated and the rabbits were euthanatized. Additional analyses were also performed two days after light exposure in one animal of group 5. Immediately after enucleating, the eye was incised at the equator and the vitreous was removed. All specimens were fixed by immersion in 2.5% glutaraldehyde in 0.1M cacodylate buffer (pH 7.4) for two hours at 25° C. On the next day, the tissue was then transferred to 0.1 M cacodylate buffer. The lesion was individually dissected and post-fixed in 2% osmium tetroxide in 0,1 M cacodylate buffer for one hour at 25°C.
  • the specimen was stained overnight in 0.5% (W/V) aqueous uranyl acetate.
  • the specimen was dehydrated in equal series of alcoholic solution, followed by propylene oxide.
  • the tissue was imbibed in epoxy resin and sectioned at 0.5 ⁇ m.
  • Retinal edema was not present. There was no retinal or subretinal hemorrhage present.
  • the late-phases of angiogram showed hyperfluorescence indicating the breakdown of the outer blood-retinal barrier ( Figure 2) .
  • Specimens from the ninth day post-treatment were obtained from two left eyes of each group and from one right eye of the respective control groups.
  • the Brtich' s membrane was intact, although eventually existing fibroblast infiltration and disappearance of the basal folding and infoldings.
  • Neurosensory retina was well preserved, exhibiting loss of some photoreceptor external segments only ( Figure 5) .
  • Choriocapillaris was filled with a combination of red blood cells and fibrin, whereas choroidal vessels remained open and perfused.
  • Endothelium of choriocapillaris cells showed cytoplasm projections, infoldings and vacuolization.
  • Some choriocapillaris endothelial cells exhibited loss of intercellular junctions.
  • Choriocapillaris occlusion was also achieved in lesions of the group 4 (21. 6 J/cm 2 ) and group 5 (20.0 and
  • the choriocapillaris was filled with a combination of erythrocytes, neutrophilis, platelets and fibrin.
  • Pigmented epithelium cells were fully disrupted in some treated areas.
  • Example VIII A case of occult subfoveal choroidal neovascularization due to age-related macular degeneration was successfully treated with dynamic photothermotherapy, using indocyanine green and light irradiation with a diode laser at 810nm (i-PTT) .
  • indocyanine green solution 1 . 5mg/kg was then infused intravenously as a bolus, followed immediately by a saline solution flush.
  • 3.0 W/cm 2 laser light was applied to the lesion, during 95 seconds , through a contact lens for fundus biomicroscopy with 1 .5X magnification power .
  • the light application caused no alterations, visible by biomicroscopy or ophthalmology, conco itantly monitored to the treatment, and soon after performance of the same.
  • visual acuity had improved to 20/200 and a hypofluorescent area corresponding to the serosanguineous pigment epithelium detachment could be identified by fluorescein angiography.
  • Retinal vessels remained perfused and showed no signs of edema and/or occlusion, even in the peri-foveal circulation.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Ophthalmology & Optometry (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

La présente invention concerne une nouvelle utilisation de vert d'indocyanine en tant qu'agent photosensible dans une photothermothérapie dynamique et dans une thermothérapie dynamique sélective permettant le traitement de l'occlusion de la néovascularisation choroïdienne.
PCT/BR2002/000010 2001-05-21 2002-01-22 Nouvelle utilisation de vert d'indocyanine en tant qu'agent photosensible WO2002094260A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BRPI0102052-8 2001-05-21
BR0102052-8A BR0102052A (pt) 2001-05-21 2001-05-21 Novo uso da indocianina verde como um agente foto sensitivo em terapia fotodinâmica para oclusão de neovascularização de coróide; nova utilização de um sistema de laser terapia e liberação de comprimento de onda de luz no espectro infravermelho para obtenção de efeito fotodinâmico e oclusão vascular seletiva da coróide e/ou da retina ou do espaço subrretiniano associado a dita indocianina verde e processo de terapia fotodinâmica para oclusão vascular sub-retiniana utilizando sistema de liberação de laser infravermelho e indocianina verde

Publications (1)

Publication Number Publication Date
WO2002094260A1 true WO2002094260A1 (fr) 2002-11-28

Family

ID=3947330

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BR2002/000010 WO2002094260A1 (fr) 2001-05-21 2002-01-22 Nouvelle utilisation de vert d'indocyanine en tant qu'agent photosensible

Country Status (2)

Country Link
BR (1) BR0102052A (fr)
WO (1) WO2002094260A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057259A2 (fr) * 2001-12-27 2003-07-17 Akorn, Inc. Compositions de vert d'indocyanine et procedes d'utilisation correspondants

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6140314A (en) * 1994-12-14 2000-10-31 The Johns Hopkins University Selective and non-invasive visualization or treatment of vasculature

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6140314A (en) * 1994-12-14 2000-10-31 The Johns Hopkins University Selective and non-invasive visualization or treatment of vasculature

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003057259A2 (fr) * 2001-12-27 2003-07-17 Akorn, Inc. Compositions de vert d'indocyanine et procedes d'utilisation correspondants
WO2003057259A3 (fr) * 2001-12-27 2003-09-18 Akorn Inc Compositions de vert d'indocyanine et procedes d'utilisation correspondants

Also Published As

Publication number Publication date
BR0102052A (pt) 2003-02-11

Similar Documents

Publication Publication Date Title
Costa et al. Choriocapillaris photodynamic therapy using indocyanine green
Schmidt-Erfurth et al. Mechanisms of action of photodynamic therapy with verteporfin for the treatment of age-related macular degeneration
Gomer et al. Photodynamic therapy of intraocular tumors examination of hematoporphyrin derivative distribution and long-term damage in rabbit ocular tissue
US6984655B1 (en) Photodynamic therapy for selectively closing neovasa in eyeground tissue
Cerman et al. Clinical use of photodynamic therapy in ocular tumors
Costa et al. Photodynamic therapy with indocyanine green for occult subfoveal choroidal neovascularization caused by age-related macular degeneration
US6443976B1 (en) Methods for treating conditions and illnesses associated with abnormal vasculature
Costa et al. Indocyanine green-mediated photothrombosis as a new technique of treatment for persistent central serous chorioretinopathy
US5707986A (en) Angiographic method using green porphyrins in primate eyes
Reichel et al. Indocyanine green dye-enhanced diode laser photocoagulation of poorly defined subfoveal choroidal neovascularization
Mellish et al. Verteporfin: a milestone in opthalmology and photodynamic therapy
Michels et al. Photodynamic therapy with verteporfin: a new treatment in ophthalmology
Renno et al. Photosensitizer delivery for photodynamic therapy of choroidal neovascularization
ES2304429T3 (es) Terapia fotodinamica con indice de fluencia reducido.
US20080221648A1 (en) Combined photocoagulation and photodynamic therapy
JPH10510807A (ja) 選択的かつ非侵襲的な視覚化または脈管構造の処置
Kim et al. Photodynamic therapy of pigmented choroidal melanomas of greater than 3-mm thickness
US6524330B1 (en) Method of ocular treatment
Kliman et al. Phthalocyanine photodynamic therapy: new strategy for closure of choroidal neovascularization
Berdugo et al. Evaluation of the new photosensitizer Stakel (WST-11) for photodynamic choroidal vessel occlusion in rabbit and rat eyes
CN102325550B (zh) 光动力学疗法和抗vegf剂在治疗有害的脉络膜新血管系统中的联合应用
Mori et al. Angiographic and histologic effects of fundus photodynamic therapy with a hydrophilic sensitizer (mono-L-aspartyl chlorin e6)
GOHTO et al. Photodynamic effect of a new photosensitizer ATX-S10 on corneal neovascularization
Obana et al. Selective occlusion of choroidal neovascularization by photodynamic therapy with a water‐soluble photosensitizer, ATX‐S10
Roberts Techniques to improve photodynamic therapy

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: JP

WWW Wipo information: withdrawn in national office

Country of ref document: JP