WO2001017561A1 - Angiographie a colorants fluorescents et photocoagulation utilisant des colorants - Google Patents

Angiographie a colorants fluorescents et photocoagulation utilisant des colorants Download PDF

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Publication number
WO2001017561A1
WO2001017561A1 PCT/US2000/024160 US0024160W WO0117561A1 WO 2001017561 A1 WO2001017561 A1 WO 2001017561A1 US 0024160 W US0024160 W US 0024160W WO 0117561 A1 WO0117561 A1 WO 0117561A1
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Prior art keywords
dye
blood
animal
vessel
fluorescent dye
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PCT/US2000/024160
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English (en)
Inventor
Robert W. Flower
Abu Alam
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Akorn, Inc.
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Publication date
Priority claimed from US09/393,456 external-priority patent/US6351663B1/en
Application filed by Akorn, Inc. filed Critical Akorn, Inc.
Priority to AU71064/00A priority Critical patent/AU7106400A/en
Publication of WO2001017561A1 publication Critical patent/WO2001017561A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0063—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres
    • A61K49/0069—Preparation for luminescence or biological staining characterised by a special physical or galenical form, e.g. emulsions, microspheres the agent being in a particular physical galenical form
    • A61K49/0097—Cells, viruses, ghosts, red blood cells, viral vectors, used for imaging or diagnosis in vivo
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A61K49/0034—Indocyanine green, i.e. ICG, cardiogreen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0041—Xanthene dyes, used in vivo, e.g. administered to a mice, e.g. rhodamines, rose Bengal
    • A61K49/0043—Fluorescein, used in vivo

Definitions

  • the present invention relates generally to methods for diagnosing and treating conditions associated with abnormal vasculature. BACKGROUND OF THE INVENTION
  • Fluorescent dyes such as indocyanine green (ICG) have been used for years in connection with angiography to diagnose and treat vascular abnormalities that occur in the eye, e.g., choroidal neovascularization (CNV).
  • CNV is a cause of Age- Related Macular Degeneration (ARMD), which is the leading cause of significant visual impairment in the elderly.
  • ICG indocyanine green
  • CNV originates in the choroidal blood vessels, the latter lying adjacent the retina of the eye. When CNV forms, it may intrude into and displace a portion of the sensory retina from its normal position, thereby distorting vision. Vision may also be blocked entirely if hemorrhage of the CNV occurs.
  • One method of diagnosing and treating ARMD is by laser photocoagulation of the CNV. This treatment, however, is successful to the extent that the CNV can be accurately mapped. This is because the CNV is, by definition, in the macular area and often encroaches on the fovea. Application of photocoagulation close to the fovea can result in the destruction of high acuity vision and/or accelerated growth of the CNV.
  • mapping of CNV is completed using angiograms.
  • Angiograms are images of blood vessels, obtained by injecting a fluorescent dye into the blood stream prior to obtaining an image.
  • a radiation source that emits light (radiation) at that particular wavelength (e.g.. a low-powered laser provided using fiber optic cables incorporated into a fundus camera) is used to illuminate the eye.
  • a light source is part of a fundus camera, which also includes a CCD video camera.
  • the fundus camera begins capturing images, i.e., angiograms, of the eye at specific time intervals.
  • the angiograms provide a record of the extent of dye movement within the ocular vasculature at each specific time interval.
  • the dye after the dye is injected into the body, the dye enters the vasculature of the eye and begins to fluoresce due to the presence of the appropriate excitation radiation (light).
  • the fluorescing dye being mixed with the ocular blood, provides each angiogram with an accurate illustration of the extent of ocular blood flow through the ocular vasculature at that moment.
  • a series of angiograms of the same vasculature over a given time period one is able to map the vasculature and determine the location of a CNV, and may then move to treat this abnormality, e.g., by laser photocoagulation of the CNV itself.
  • the present invention meets the foregoing and other needs in a variety of ways.
  • the present invention provides a method for enhancing the clarity of fluorescent dye angiograms using relatively high dye concentrations, leading to more accurate targeting of vessels during treatment.
  • the present invention provides a method that allows blood vessels feeding various types of abnormalities to be more readily identified, and thereafter treated.
  • Several other aspects of the present invention provide new methods of diagnosis and treating abnormalities and conditions using fluorescent dyes. All of the inventive aspects may be used on animals, e.g., humans, dogs, cats, but are preferably used in connection with the diagnosis and treatment of human subjects.
  • the present invention is able to provide angiograms of enhanced clarity by administering a plurality of relatively small boluses at relatively high dye concentrations to an animal undergoing an angiographic procedure.
  • the method includes introducing boluses of about 0.1 ml to about 1.0 ml of a liquid composition at spaced time intervals into the animal to at least partially fill the blood vessels with the composition, wherein the liquid composition comprises a relatively high fluorescent dye and a carrier.
  • the dye concentration would be at least about 30 mg/ml, preferably at least about 40 mg/ml and most preferably at least about 50 mg/ml.
  • Light energy of a type and in an amount sufficient to cause the dye in each bolus to fluoresce as the dye flows through the blood vessels is then applied, and angiographic images obtained.
  • Another aspect of the present invention provides a method for determining the direction of blood flow within a vessel. This may allow a physician to more readily determine whether a particular vessel is feeding an abnormality, indicating that it should be treated.
  • the method includes at least the steps of administering a liquid composition comprising a fluorescent dye and a carrier into the animal to at least partially fill the blood vessel with the composition. Energy of a type and in an amount sufficient to cause the dye in the blood vessel to fluoresce is then applied. Subsequently, energy of a type and in an amount in excess of that required to cause the dye to fluoresce is applied to a portion of the fluorescing dye passing through the blood vessel to cause that portion of the fluorescing dye to stop fluorescing.
  • a series of angiographs of both the fluorescing dye, and of the subsequent non-fluorescing portion thereof are obtained, and those angiograms are compared to determine the direction of relative movement of the bleached dye.
  • the direction of relative movement of the bleached dye portion indicates the direction of relative movement of the blood flow in the blood vessel.
  • one indication permits a physician to locate a tumor in or adjacent to the wall of a body cavity of an animal.
  • This method includes administering a liquid composition comprising a fluorescent dye and a carrier into the animal to at least partially fill the blood vessels of the body cavity with the composition; applying energy of a type and in an amount sufficient to cause the dye to fluoresce as the dye flows through the blood vessels of the body cavity; obtaining at least one angiographic image of the fluorescing dye as the dye flows through the blood vessels of the body cavity; and analyzing the angiographic image obtained in the prior step to determine whether a tumor is present in or adjacent to the wall of the body cavity.
  • the present invention provides methods for treating the aforementioned conditions.
  • One exemplary method reduces the blood flow through a vessel that carries blood into a tumor of an animal.
  • This method comprises administering a liquid composition comprising a fluorescent dye and a carrier into the animal to at least partially fill a blood vessel that carries blood into a tumor with the composition, and applying energy to the blood vessel of a type and in an amount sufficient to excite the dye in the blood vessel, thereby increasing the temperature of any liquid adjacent the dye, the increase in temperature causing the blood within the vessel to coagulate relatively quickly, thereby reducing (and preferably halting completely) the rate of blood flow through that vessel into the tumor.
  • Other related aspects of the present invention include methods for reducing or eliminating tumors. These methods are preferably used after the tumors have been located using fluorescent dye angiography, the latter providing a means for precisely locating a tumor in a subject.
  • a single session can include dye-enhanced photocoagulation of those vessels feeding blood into the tumor using an endoscope, followed by injection of chemotherapeutic and anti-angiogenesis agents via the endoscope directly into the tumor itself (as opposed to conventional IV administration).
  • a further aspect of the present invention provides a related method for reducing the rate of blood flow through a vessel that carries blood into a lesion.
  • This aspect allows a physician, after treating a vessel using dye-enhanced photocoagulation, to provide further treatment to the same vessel without administering additional fluorescent dye, and without the need for obtaining another angiogram prior to the additional treatment.
  • This method is predicated in substantial part on the discovery that, when at least partial obstruction of a vessel is obtained using dye-enhanced photocoagulation, a sufficient amount of dye is entrapped within the partial obstruction to permit one or more additional dye-enhanced photocoagulation treatments to be administered without requiring additional administration of dye, and preferably without obtaining another angiogram.
  • the method comprises administering to the animal sufficient fluorescent dye to at least partially fill the target blood vessel with the dye; creating at least a partial obstruction in the vessel by applying energy to the vessel of a type and in an amount sufficient to excite the fluorescent dye; and applying energy of a type and in an amount sufficient to excite fluorescent dye entrapped in the partial obstruction, wherein no additional fluorescent dye is administered to the animal after creation of the at least partial obstruction.
  • a first aspect of the present invention provides a method for enhancing the resolution of angiograms.
  • This enhancement is provided by the introduction of a plurality of relatively small, yet highly dye-concentrated, boluses of a fluorescent dye composition into an animal, and subsequently obtaining angiograms as the composition passes through the vasculature of interest.
  • the use of this method provides for a greater degree of fluorescence in the composition, and hence greater resolution in the associated angiogram, as compared to angiograms obtained using a composition having a conventional dye concentration.
  • ICG fluorescent dye
  • IC- GREENTM ICG, manufactured by Akorn, Inc., Decatur, Illinois
  • this aspect of the invention includes introducing boluses of a liquid composition comprising a fluorescent dye at a concentration that is higher than that previously used.
  • This concentration should be at least about 1.5 times (e.g., about 30 mg/ml for ICG), preferably at least about 2 times (e.g., about 40 mg/ml for ICG) and most preferably about 2.5 times (e.g., at least about 50 mg/ml for ICG) the highest known angiographic diagnostic concentration.
  • the boluses are advantageously small in volume, about 0.1 ml to about 1.0 ml, and may be of the same or different volume.
  • the boluses are introduced at spaced time intervals into an animal to at least partially fill the blood vessels of interest with the composition.
  • angiographic images are obtained.
  • the images obtained provide higher levels of resolution than those obtained using conventional dye (e.g., ICG) compositions. While not being bound to any particular theory, it is believed that the enhancement of resolution is due to the greater number of dye molecules present in a given wave front transiting a blood vessel, and a recognition that CCD cameras (typically used to obtain angiographic images) generate relatively high signal-to-noise ratios. With the relatively greater number of dye molecules being present in a particular dye "wave front,” a greater the number of photons are generated by the dye upon exposure to radiation, providing better image quality even when the relatively high signal-to-noise ratio CCD cameras are used.
  • the total quantity of the liquid composition administered through a plurality of boluses should be sufficient to permit readable angiographic images to be obtained and analyzed when using a CCD camera.
  • This quantity may equal that administered using conventional formulations, but is advantageously greater, e.g., at least about 1.5 times the amount of dye administered using conventional formulations. More advantageously, at least twice that amount, preferably at least three times that amount, and most preferably, at least five times the amount of conventional formulations is administered.
  • a saline flush can be administered to aid the circulation of the liquid composition throughout the blood vessels of interest.
  • the dyes useful in the present invention should be able to fluoresce in the presence of radiation of a certain wavelength, and to permit angiographic images of blood vessels of higher quality to be obtained as compared to angiograms obtained using conventional dye concentrations.
  • the dyes should also be able to generate thermal energy when exposed to radiation.
  • the dyes should therefore be selected to at least permit diagnostic procedures, while preferred dyes function for both diagnostic and treatment procedures.
  • Treatment methods using dye-enhanced photocoagulation discussed herein comprise applying radiation of a certain wavelength (based upon the dye used) on a portion of an undesirable dye-carrying blood vessel. The radiation wavelength is selected to "excite" the dye; the absorption of such radiation by the dye causes the temperature of the dye to increase.
  • the dye-containing composition used in this and the other treatment methods disclosed herein may vary widely.
  • One limit on the dye concentration is that sufficient dye should be present in composition, and more importantly the targeted vessel, to permit at least partial obstruction of the target vessel by the dye-enhanced photocoagulation methods discussed herein.
  • the novel diagnostic methods disclosed in the following paragraphs may also use a wide range of dye concentrations, with the limitation that sufficient dye should be present in the composition (and targeted vessels) to permit the angiograms taken in conjunction with those methods to be analyzed.
  • One method of determining the degree of vessel obstruction is by analyzing angiograms taken after treatment is completed, and after the dye has left the treated vessel. For example, if the treatment results in total obstruction of a CNV feeder vessel, an angiogram of the downstream portion of the vessel, e.g., the CNV itself, will not reveal any dye fluorescence. Partial obstruction should reveal a lower degree of fluorescence.
  • fluorescent dyes are known that are acceptable for use in the composition of the various inventive methods described herein.
  • Exemplary dyes include fluorescein, rose bengal, ICG and analogue members of the tricarbocyanine dyes, and any other dye which meets the criteria described herein for diagnosis and/or treatment procedures.
  • the preferred fluorescent dye is ICG because it is readily available, has long been approved for administration to humans for ophthalmic angiography and other unrelated indications, and is suitable for both diagnosis and treatment procedures.
  • a light source emitting such wavelengths should be used when obtaining angiographic images during diagnosis, as well as during any subsequent treatment procedure.
  • the dye compositions may further include a pharmaceutically-acceptable carrier.
  • the carrier enhances the administration of the fluorescent dye to a patient, the latter being either intravenously or by other suitable means.
  • the choice of carrier will be determine in part by the particular fluorescent dye used, as well as by the particular route of administration of the liquid composition.
  • the carrier should be compatible with both the fluorescent dye and the tissues and organs of the subject that come into contact with the liquid composition. Moreover, the carrier should not interfere with the energy applied or angiographic images obtained following administration.
  • suitable carriers include water, saline, alcohols, red blood cells (RBC), glycerin, polyethylene glycol, propylene glycol, polysorbate 80, Tweens, liposomes, amino acids, lecithin, dodecyl sulfate, lauryl sulfate, phospholipid, Cremophor, desoxycholate, soybean oil, vegetable oil, safflower oil. sesame oil, peanut oil, cottonseed oil, sorbitol, acacia, aluminum monstearate, polyoxyethylated fatty acids, povidone and mixtures thereof.
  • the carrier is water.
  • the composition will include components that increase the degree of dye fluorescence, e.g., alcohols such as ethanol and surfactants such as the Tweens.
  • Optional components that may be present in the composition include tonicity and/or pH adjusters, e.g., NaOH, HC1, tribuffer phosphate, tris buffer and the like.
  • the composition may include thrombin or other known blood clotting compounds that would function to further enhance blood clotting during and after treatment.
  • the fluorescent dye composition may initially be provided as a lyophilizate for reconstitution before use, or as a pre-mix, in a vial or syringe.
  • RBCs may be used as a carrier for the fluorescent dye.
  • This technique is referred to herein as RBC doping.
  • the RBC as a carrier has advantages in that it is a normal constituent of circulating blood and, despite the relative large volume (and hence large dye- carrying capacity) of each RBC, RBCs can nevertheless readily move throughout the circulatory system — deforming to enable movement through even the small diameter capillaries. Further, and while not desiring to be bound to any particular theory, the use of doped RBCs provides additional advantages pertaining to clot formation.
  • the size of clot formed during the treatment methods described herein depends upon the amount of dye present at the vessel treatment site, the amount of radiation energy delivered thereto and the distribution of the dye molecules associated with the RBCs.
  • vessel closure will be permanent.
  • the clot will resolve, requiring additional treatment.
  • the doping of dye in RBCs reduces the variability in clot formation because it increases the fraction of dye molecules associated with RBCs at the treatment site, thereby increasing the probability that a sizable clot is formed during treatment.
  • the object of the procedure is to remove the content of the RBCs, and then refill the RBCs with hemoglobin and dye, e.g., ICG, and, if desired, other clot potentiating compounds, e.g., fibrin.
  • hemoglobin and dye e.g., ICG
  • other clot potentiating compounds e.g., fibrin.
  • the following exemplary procedure may be followed to provide the doped composition for use in the various inventive methods described herein.
  • a small amount of the subject's blood is withdrawn (about 10-15 ml), although any compatible blood may be used, and is centrifuged to permit removal of the serum.
  • the remaining RBCs are washed in normal PBS to remove proteins from the RBC surface.
  • the washed RBCs are placed in a cooled hemolizing solution, and incubated therein for about 5 min.
  • the pH of the solution is readjusted to 7.2, and ICG is added.
  • the solution is again incubated at 37°C for about 45-60 min. If desired, other compounds that assist in clotting, e.g., fibrin, may be added at this stage.
  • the solution is then centrifuged at about 500 g for about 6 min, and the supernatant is removed. The resulting cells are washed several times to remove ICG not associated with the RBCs.
  • ICG-doped RBCs are provided, which may then be injected into a subject as a bolus for diagnostic purposes, and preferably for purposes of effecting treatment, in accordance with the methods described herein.
  • uptake of the radiation should be potentiated to ensure that a relatively high number of RBCs are exploded at the target site in the vessel.
  • Liposomes may also be used in connection with the present invention as a carrier for the dye. As technology providing for the formation of liposomes is well known, such will not be repeated herein. However, the following are illustrative of components that are expected to provide suitable dye-carrying liposomes: cholesterol, stearic acid, egg phosphotidyl choline, and stearyl amine. It should be appreciated that in connection with the various novel indications
  • the concentration of the fluorescent dye present in the liquid composition, and the injection of relatively small boluses of the composition is not critical. At a minimum, however, the amount of fluorescent dye used in those methods must be present in the composition at a concentration that permits the dye to fluoresce when radiation at appropriate wavelength is applied, providing useful angiographic images. The same standard is applicable to the treatment methods; sufficient dye should be utilized to enable the desired treatment.
  • This information may be readily determined by those skilled in the art, and should be at least that concentration currently accepted for use in ophthalmic angiography, e.g., for diagnosis, 2 ml of a 20 mg/ml ICG solution (IC-GREENTM).
  • concentration currently accepted for use in ophthalmic angiography e.g., for diagnosis, 2 ml of a 20 mg/ml ICG solution (IC-GREENTM).
  • IC-GREENTM 20 mg/ml ICG solution
  • any suitable source of radiation that causes the particular dye to fluoresce as it flows through the vessels of interest may be used in the present methods.
  • the type and amount of energy applied to the blood vessels of interest must be sufficient to cause the fluorescent dye present in these blood vessels to fluoresce.
  • the energy applied must be within the limits of the maximum flux density or irradiance which can be applied to the blood vessels of interest within a particular time span without causing excessive damage to the normal surrounding tissue. The longer the duration of exposure to the energy source, the lower the allowable level of irradiance.
  • the particular energy source and amount of energy applied will depend upon the type of fluorescent dye administered to the subject.
  • the radiation used in the methods described herein is preferably applied using a laser, and, most preferably, using a pulsed laser.
  • the pulsing of the laser provides the advantage of generating a greater number of photons for image formation in the shortest time interval.
  • Various devices, preferably fundus cameras can be adapted for providing an appropriate level and type of radiation in accordance with the teachings provided herein. The latter include, for example, those described in U.S. Patents 5,279,298, 5,394,199 and 5,400,791.
  • a fundus camera having two sources of radiation e.g., lasers
  • one laser can be used to irradiate the general area of interest so any vessels requiring treatment can be identified, while the second laser can be used almost immediately upon identification of the vessel to be treated to hasten the coagulation of the blood therein, i.e., dye-enhanced photocoagulation.
  • the ability to aim the treatment laser using the identical view used to obtain the angiograms is a significant advantage. Further, the ability to complete the diagnosis and treatment steps within minutes, e.g., advantageously in less than about 30 and preferably less than about 15 minutes, lessens patient trauma and increases overall treatment efficiency.
  • the present invention further provides novel methods for visualizing blood vessels at locations other than in the eye.
  • the method now permits angiograms of blood vessels and other abnormalities associated with blood vessels to be obtained at any location in an animal in which readable angiographic images can be obtained.
  • the interior wall of the bladder, stomach, colon may be explored, as well as the exterior walls of those organs.
  • This permits the diagnosis and treatment of abnormal blood vessels, such as aneurysms, ruptured blood vessels, e.g., those associated with a stroke or physical trauma, as well as the diagnosis and treatment of tumors and other such lesions associated with those and other body cavity tissues.
  • An endoscope may advantageously be used to obtain the previously mentioned angiograms. The endoscope would be inserted into the body and positioned adjacent the area of interest.
  • a first instrument would be used with the endoscope to provide radiation at an appropriate wavelength, e.g., a laser optic cable, to cause the dye within the subject vessels to fluoresce so an angiogram can be obtained.
  • a second instrument would be used with the endoscope that would permit an angiographic image of the fluorescing dye within the vessels to be obtained.
  • an optical device connected to a CCD camera such as those used to perform a colonoscopy and other invasive procedures to permit a physician to view the interior of a body cavity, presently exists, and such technology may be readily adapted for use in conjunction with the endoscopic procedures of the present invention.
  • body cavity includes any cavity that permits the introduction of an endoscope or other instrument that permits the use of appropriate radiation and imaging equipment required to obtain an angiogram.
  • body tissues associated with suitable cavities are the eye, lung, gastrointestinal tract, bladder, pancreas, gall bladder, sinus, heart, cervix, brain, ovaries, prostate, stomach and skin.
  • Treatment is preferably effected by applying radiation upstream of the lesion, e.g., upstream of the ruptured blood vessel, the vessel feeding the tumor, or adjacent and upstream of the abnormal blood vessels, after administration of the dye composition.
  • the temperature of any liquid adjacent the dye receiving the radiation is raised, and the blood clotting is hastened, thereby reducing, e.g., partially or completely preventing, the flow of blood through the vessel.
  • Varicose veins may also be treated using the aforementioned treatment methods.
  • the method of the present invention is preferably used in combination with other treatment agents.
  • therapeutically-effective amounts of chemotherapeutic agents such as cisplatin, carboplatin, doxorubicin, paclitaxel, taxotere, methotrexate, fluorouracil, camptothecin, cyclophosphamide and mixtures thereof, may be administered, as well as therapeutically-effective amounts of anti-angiogenesis agents, either alone or in combination, may be administered.
  • chemotherapeutic agents such as cisplatin, carboplatin, doxorubicin, paclitaxel, taxotere, methotrexate, fluorouracil, camptothecin, cyclophosphamide and mixtures thereof.
  • anti-angiogenesis agents either alone or in combination, may be administered.
  • suitable anti-tumor and anti-angiogenesis agents and associated dosage regimens are well known, and as such will not be repeated herein.
  • the timing of administration of these agents may occur at any time so long as the administration does not interfere with the treatment method of the present invention.
  • the agents may be administered in combination with the dye-enhanced photocoagulation treatment methods described herein.
  • the agents can be administered immediately after dye-enhanced photocoagulation of tumor feeder vessels, and preferably are injected directly into the tumor. This provides several advantages including the reduction of trauma to the patient because multiple treatment agents are administered in a single procedure, the chemotherapeutic and anti-angiogenesis agents are delivered directly to the tumor thereby limiting the exposure of healthy tissue to these toxic agents (as would be the case using conventional IV administration), and conventional radiation can be narrowly focused on the tumor itself, as opposed to conventional methods that irradiate an area surrounding the tumor.
  • the location and boundaries of the tumor may be determined with a high degree of precision, without resort to the use of more harmful diagnostic procedures, e.g., X-rays.
  • the precision provided by the present invention permits the treatment agents described previously to be more efficient because they are applied with a high degree of precision onto just the tumor itself, as compared to conventional methods, e.g., systemic administration of chemotherapeutic agents and application of radiation, which are applied over a more general area. This precise focus, in turn, lessens trauma to the subject by minimizing the side effects of these toxic agents.
  • the present invention also provides a method for determining the direction of blood flow in a blood vessel of a patient.
  • This method is of significance in identifying those arteries that are providing blood to a lesion, e.g., CNV, tumor or other blood vessel abnormality.
  • a lesion e.g., CNV, tumor or other blood vessel abnormality.
  • the preferred dye-enhanced photocoagulation treatment described herein can be used to at least partially preclude, or preferably completely preclude, the flow of blood through the arteries. This would have the effect of "starving" the CNV, lesion, tumor or other abnormality, causing a reduction in size or complete elimination.
  • the method which uses a technique referred to herein as "bleaching,” comprises administering the aforesaid liquid dye composition to the subject to at least partially fill the blood vessels in the area to be examined with the composition. Thereafter, radiation of a type and in an amount sufficient to cause the dye in the blood vessel to fluoresce is applied.
  • angiograms are obtained at selected time intervals, and these angiograms are compared to determine the direction of relative movement of that portion of the dye no longer fluorescing, i.e., the "bleached" dye. This comparison can be made by reviewing the angiograms taken using a CCD video device, wherein the relative movement of the bleached portion of the dye indicates the direction of relative movement of the blood flow in the blood vessel.
  • a method for reducing the rate of blood flow through a vessel that carries blood into a lesion, e.g., CNV, tumor.
  • This method comprises administering to the animal sufficient fluorescent dye, advantageously in combination with a pharmaceutically-acceptable carrier, to at least partially fill the targeted blood vessel with the dye. Thereafter, at least a partial obstruction in the blood vessel is created by applying energy to the vessel of a type and in an amount sufficient to excite the fluorescent dye, as described previously herein.
  • a quantity of fluorescent dye becomes entrapped in the at least partial obstruction.
  • This entrapped dye permits at least one further dye-enhanced photocoagulation treatment to be undertaken without a prior (further) administration of fluorescent dye.
  • the dye becomes trapped within the obstructing clot formed during treatment, and in sufficient quantity, to permit additional dye-enhanced photocoagulation treatments to be successfully administered. Such further treatments lead to complete obstruction of the vessel.
  • the method further comprises applying energy of a type and in an amount sufficient to excite fluorescent dye entrapped in the partial obstruction.
  • the at least partial obstruction is converted to a complete obstruction of the vessel during this single additional treatment. However, more than additional treatments may be used to obtain complete obstruction.
  • a physician can obtain an angiogram after the initial treatment to verify the presence of fluorescent dye entrapped within the obstruction before undertaking the foregoing additional dye-enhanced photocoagulation treatments.
  • the present invention further permits additional treatment of the at least partially obstructed vessel without the need for an angiogram prior to such treatment.
  • a physician can_simply use the diagnostic (low power) laser to cause the dye entrapped in the at least partial obstruction to fluoresce, and then apply the treatment (high power) laser thereto. This method precludes the need for further administrations of dye prior to each additional treatment.
  • the foregoing method is advantageously performed during a single visit, e.g., within a few hours, and preferably the additional treatments are conducted within about one hour after the initial treatment.
  • the fluorescent dye, carrier, liquid composition characteristics, administration of the liquid composition, application of radiation for diagnosis and treatment, and obtaining angiographic images described in connection with the method of visualizing and treating blood vessels using relatively high dye concentrations are equally applicable to the foregoing novel methods for visualizing arteries that are providing blood to any type of lesion, e.g., CNV, tumor or other abnormality associated with blood vessels, and treating those blood vessels, as well as determining blood flow direction.
  • references to a single component or step should be construed as also including more than one component or step, i.e., at least one.

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Abstract

L'invention concerne l'utilisation à des fins médicales de colorants fluorescents tels que le vert d'indocyanine (ICG), la fluorescéine et le rose-bengale. Elle concerne plus particulièrement des procédés pour réduire, au moyen de colorants fluorescents, les flux sanguins irriguant des lésions telles que la CNV (néovascularisation choroïdienne) et les tumeurs.
PCT/US2000/024160 1999-09-10 2000-09-05 Angiographie a colorants fluorescents et photocoagulation utilisant des colorants WO2001017561A1 (fr)

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US09/393,456 US6351663B1 (en) 1999-09-10 1999-09-10 Methods for diagnosing and treating conditions associated with abnormal vasculature using fluorescent dye angiography and dye-enhanced photocoagulation
US48797700A 2000-01-20 2000-01-20
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US6915154B1 (en) 1999-09-24 2005-07-05 National Research Council Of Canada Method and apparatus for performing intra-operative angiography
WO2008000403A2 (fr) * 2006-06-29 2008-01-03 Carl Zeiss Meditec Ag Procédé et dispositif de détection optique de l'oeil
US7881777B2 (en) 1999-09-24 2011-02-01 National Research Council Of Canada Method and apparatus for performing intra-operative angiography
US8144958B2 (en) 2008-09-11 2012-03-27 Carl Zeiss Meditec Ag Medical systems and methods
US9421280B2 (en) 2005-04-26 2016-08-23 Novadaq Technologies Inc. Real time imaging during solid organ transplant
US9610021B2 (en) 2008-01-25 2017-04-04 Novadaq Technologies Inc. Method for evaluating blush in myocardial tissue
US9816930B2 (en) 2014-09-29 2017-11-14 Novadaq Technologies Inc. Imaging a target fluorophore in a biological material in the presence of autofluorescence
US10041042B2 (en) 2008-05-02 2018-08-07 Novadaq Technologies ULC Methods for production and use of substance-loaded erythrocytes (S-IEs) for observation and treatment of microvascular hemodynamics
US10219742B2 (en) 2008-04-14 2019-03-05 Novadaq Technologies ULC Locating and analyzing perforator flaps for plastic and reconstructive surgery
US10265419B2 (en) 2005-09-02 2019-04-23 Novadaq Technologies ULC Intraoperative determination of nerve location
US10278585B2 (en) 2012-06-21 2019-05-07 Novadaq Technologies ULC Quantification and analysis of angiography and perfusion
US10434190B2 (en) 2006-09-07 2019-10-08 Novadaq Technologies ULC Pre-and-intra-operative localization of penile sentinel nodes
US10492671B2 (en) 2009-05-08 2019-12-03 Novadaq Technologies ULC Near infra red fluorescence imaging for visualization of blood vessels during endoscopic harvest
US10631746B2 (en) 2014-10-09 2020-04-28 Novadaq Technologies ULC Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography
US10992848B2 (en) 2017-02-10 2021-04-27 Novadaq Technologies ULC Open-field handheld fluorescence imaging systems and methods
US12028600B2 (en) 2021-10-04 2024-07-02 Stryker Corporation Open-field handheld fluorescence imaging systems and methods

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US8892190B2 (en) 1999-09-24 2014-11-18 National Research Council Of Canada Method and apparatus for performing intra-operative angiography
US6915154B1 (en) 1999-09-24 2005-07-05 National Research Council Of Canada Method and apparatus for performing intra-operative angiography
US7881777B2 (en) 1999-09-24 2011-02-01 National Research Council Of Canada Method and apparatus for performing intra-operative angiography
WO2003057259A3 (fr) * 2001-12-27 2003-09-18 Akorn Inc Compositions de vert d'indocyanine et procedes d'utilisation correspondants
WO2003057259A2 (fr) * 2001-12-27 2003-07-17 Akorn, Inc. Compositions de vert d'indocyanine et procedes d'utilisation correspondants
US9421280B2 (en) 2005-04-26 2016-08-23 Novadaq Technologies Inc. Real time imaging during solid organ transplant
US10265419B2 (en) 2005-09-02 2019-04-23 Novadaq Technologies ULC Intraoperative determination of nerve location
WO2008000403A3 (fr) * 2006-06-29 2008-03-13 Zeiss Carl Meditec Ag Procédé et dispositif de détection optique de l'oeil
WO2008000403A2 (fr) * 2006-06-29 2008-01-03 Carl Zeiss Meditec Ag Procédé et dispositif de détection optique de l'oeil
US10434190B2 (en) 2006-09-07 2019-10-08 Novadaq Technologies ULC Pre-and-intra-operative localization of penile sentinel nodes
US11564583B2 (en) 2008-01-25 2023-01-31 Stryker European Operations Limited Method for evaluating blush in myocardial tissue
US10835138B2 (en) 2008-01-25 2020-11-17 Stryker European Operations Limited Method for evaluating blush in myocardial tissue
US9610021B2 (en) 2008-01-25 2017-04-04 Novadaq Technologies Inc. Method for evaluating blush in myocardial tissue
US9936887B2 (en) 2008-01-25 2018-04-10 Novadaq Technologies ULC Method for evaluating blush in myocardial tissue
US10219742B2 (en) 2008-04-14 2019-03-05 Novadaq Technologies ULC Locating and analyzing perforator flaps for plastic and reconstructive surgery
US10041042B2 (en) 2008-05-02 2018-08-07 Novadaq Technologies ULC Methods for production and use of substance-loaded erythrocytes (S-IEs) for observation and treatment of microvascular hemodynamics
US9357931B2 (en) 2008-09-11 2016-06-07 Carl Zeiss Meditec Ag Medical systems and methods
US8144958B2 (en) 2008-09-11 2012-03-27 Carl Zeiss Meditec Ag Medical systems and methods
US9351644B2 (en) 2008-09-11 2016-05-31 Carl Zeiss Meditec Ag Medical systems and methods
US9320438B2 (en) 2008-09-11 2016-04-26 Carl Zeiss Meditec Ag Medical systems and methods
US9129366B2 (en) 2008-09-11 2015-09-08 Carl Zeiss Meditec Ag Medical systems and methods
US10492671B2 (en) 2009-05-08 2019-12-03 Novadaq Technologies ULC Near infra red fluorescence imaging for visualization of blood vessels during endoscopic harvest
US10278585B2 (en) 2012-06-21 2019-05-07 Novadaq Technologies ULC Quantification and analysis of angiography and perfusion
US11284801B2 (en) 2012-06-21 2022-03-29 Stryker European Operations Limited Quantification and analysis of angiography and perfusion
US9816930B2 (en) 2014-09-29 2017-11-14 Novadaq Technologies Inc. Imaging a target fluorophore in a biological material in the presence of autofluorescence
US10488340B2 (en) 2014-09-29 2019-11-26 Novadaq Technologies ULC Imaging a target fluorophore in a biological material in the presence of autofluorescence
US10631746B2 (en) 2014-10-09 2020-04-28 Novadaq Technologies ULC Quantification of absolute blood flow in tissue using fluorescence-mediated photoplethysmography
US10992848B2 (en) 2017-02-10 2021-04-27 Novadaq Technologies ULC Open-field handheld fluorescence imaging systems and methods
US11140305B2 (en) 2017-02-10 2021-10-05 Stryker European Operations Limited Open-field handheld fluorescence imaging systems and methods
US12028600B2 (en) 2021-10-04 2024-07-02 Stryker Corporation Open-field handheld fluorescence imaging systems and methods

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