CA2012175A1 - Photochemical treatment of blood vessels - Google Patents
Photochemical treatment of blood vesselsInfo
- Publication number
- CA2012175A1 CA2012175A1 CA002012175A CA2012175A CA2012175A1 CA 2012175 A1 CA2012175 A1 CA 2012175A1 CA 002012175 A CA002012175 A CA 002012175A CA 2012175 A CA2012175 A CA 2012175A CA 2012175 A1 CA2012175 A1 CA 2012175A1
- Authority
- CA
- Canada
- Prior art keywords
- blood vessel
- photoreactive compound
- blood
- compound
- photoreactive
- Prior art date
- Legal status (The legal status 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 status listed.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/0613—Apparatus adapted for a specific treatment
- A61N5/062—Photodynamic therapy, i.e. excitation of an agent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N5/00—Radiation therapy
- A61N5/06—Radiation therapy using light
- A61N5/067—Radiation therapy using light using laser light
Abstract
PHOTOCHEMICAL TREATMENT OF BLOOD VESSELS
Abstract of the Disclosure A method for treating blood vessels to destroy the blood vessel without damaging surrounding tissue. The method involves introducing a photoreactive compound into the blood flowing through the blood vessel and allowing the photoreactive compound to accumulate in the blood vessel wall. The photoreactive compound is activated by exposure to radiation prior to accumulation of the reactive compound into surrounding tissues. The activation of the photoreactive compound prior to movement into surrounding tissues provides selective destruction of blood vessels while limiting destruction of surrounding tissues.
Abstract of the Disclosure A method for treating blood vessels to destroy the blood vessel without damaging surrounding tissue. The method involves introducing a photoreactive compound into the blood flowing through the blood vessel and allowing the photoreactive compound to accumulate in the blood vessel wall. The photoreactive compound is activated by exposure to radiation prior to accumulation of the reactive compound into surrounding tissues. The activation of the photoreactive compound prior to movement into surrounding tissues provides selective destruction of blood vessels while limiting destruction of surrounding tissues.
Description
' 2~21~5 ,~ .?`
: ~ocket No. 72-21G
PHOTOCHEMICAL TREATMENT OF BLOOD VESSELS
:
Back~round of the Invention 1. Field of the Invention The present invention relates generally to the use of photoreactive dyes to treat vascular tissue. More particularly, the present invention involves using photoreactive dyes to selectively destroy unwanted blood vessels in normal tissue.
: ~ocket No. 72-21G
PHOTOCHEMICAL TREATMENT OF BLOOD VESSELS
:
Back~round of the Invention 1. Field of the Invention The present invention relates generally to the use of photoreactive dyes to treat vascular tissue. More particularly, the present invention involves using photoreactive dyes to selectively destroy unwanted blood vessels in normal tissue.
2. Description of Related Art In the mid-1960's, researchers began using photosensitive agents to treat malignant tumors. One of the most popular photosensitive agents used in such treatments is a dye known as hematoporphyrin derivative (HPD). In purified form, HPD is known as Photofrin II.
It was found that the HPD preferentially congregates in cancer celis or in vessels feeding the malignant tumor.
The HPD has no effect on the tumor until it is energized by radiation. The energized HPD creates toxic molecules that selectively kill the tissue where the ~PD is located. The use of such photoreactive dyes to destroy abnormal tissue is commonly referred to as photodynamic therapy.
HPD has been used to treat patients for many kinds of solid tumors, including those of the skin, lung, bladder, eye, neck, and esophagus. Usually, the patient who is being treated will receive about two milligrams of Photofrin II per kilogram of body weight. The Photofrin is typically injected into the bloodstream of the patient over a period of about five minutes. The patient must be immediately protected from bright light to prevent undesirable non-selective photoactivation of the Photofrin II. The physician then waits two to three days for the Photofrin II to congregate in the malignant tumor while the remainder of the Photofrin II is washed ;' '~
, ~: .: '~
! ~ .
2 0 ~ 2 ~
from normal tissues by the patient's system. The physician generally then uses an argon-pumped dye laser to shine liyht on the patient's tumor and surrounding area. The laser is focused directly on exterior tumors or those located within 3 to 10 mm of the skin surface.
When tumors are located inside the body, the doctor utilizes an optical fiber to deliver the radiation to the tumor.
The use of photodynamic therapy has been limited to the treatment of malignant tissues. The limitation is due, for the most part, because of the unique ability of malignant tissues to retain HPD long after it has been :, :
washed from normal tissues. Even so, there is a continuing need to use this valuable form of therapy to treat other disorders which are not malignant.
There is presently a need to provide improved therapeutics for treating hypervascular dermal lesions, such as port-wine stains. Hypervascular dermal lesions and other non-malignant tissue disorders are presently treated with lasers. The treatment utilizes photothermal ablation whereby absorbed energies are converted to heat. The lesion is destroyed either by direct thermal denaturization or by propagated shock waves due to near instantaneous heating provided by the laser. A problem with this type of treatment is confining and localizing the thermal injury to a specific tissue location.
In order to reduce injury to surrounding tissues, shorter laser pulse durations have been used which produce a more confined shock wave effect and less thermal conductivity. Although some success has been achieved in reducing injury to the surrounding tissues, there continues to be a "photothermal overflow" which causes injury to surrounding tissues. The thermal injury to surrounding tissues is especially undesirable - :-~ . .-, ,.,. ~. . . ~:
,',: ~:' ' ':. , . ' ~' ~21 7.~
. . .
when dealing with skin lesions where cosmetic appearance is an important consideration.
The use of photosensitive dyes in combination with laser treatment would appear to be desirable in reducing the thermal damage to normal tissues surrounding the hypervascular dermal lesions. ~lowever, photosensitive dyes have not been shown to selectively congregate at such non-malignant dermal lesions. Accordingly, photodynamic therapy has not been suggested for use in treating such non-malignant dermal lesions. It would be desirable, however, to provide a process based on -photodynamic therapy for treating such blood vessel disorders, even though the photosensitive dyes do not selectively migrate to such tissues. ~ ~-` -Summarv of the Invention In accordance with the present invention, it was discovered that blood vessels can be photochemically ~ `-treated to provide selective destruction while, at the 20 same time, limiting damage to surrounding tissues. -The present invention is based on a method wherein a therapeutic amount of a photoreactive compound is introduced into the blood flowing through the blood vessel. It was discovered that photoreactive compounds ~ ;
associate with the blood vessel wall. The photoreactive compound is allowed to accumulate in the blood vessel wall for a sufficient time to provide a sufficient amount of photoreactive compound within the blood vessel wall to destroy the blood vessel when the photoreactive compound is activated by radiation from a laser or other source.
As a feature of the present invention, the -~
photoreactive compound associated with the blood vessel wall is activated prior to the time at which the 35 photoreactive compound leaves the vessel and either -~
enters the surrounding tissue or is washed away. It was 2~217~
discovered that sufficient photoreactive compound is present within blood vessel walls to allow photodynamic destruction of the blood vessel tissue withou-t affectiny surrounding tissue. As a result, the method of the present invention allows the destruction of undesirable blood vessels while limiting the amount of harm to surrounding tissues.
The method of the present invention is particularly well suited for treating hypervascular dermal lesions, such as port-wine stains. The method eliminates many of the cosmetic problems associated with thermal destruction of surrounding tissue. Further, the method takes advantage of the selectivity of tissue destruction provided when using photoreactive compounds.
The above discussed and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.
Brief Description of the Drawings The drawing is a schematic representation of a preferred exemplary method in accordance with the present invention.
Detailed Descri~tion of the Preferred Embodiments The present invention involves photochemical therapy which may be used to treat a wide variety of abnormal blood vessel conditions. The method may be used for a wide variety of situations wherein it is desired to selectively destroy or-e or more blood vessels. The invention is particularly well suited for treating hypervascular dermal lesions. Accordingly, the following description of a preferred embodiment will be limited to describing the treatment of hypervascular dermal lesions with it being understood that the method ~11 217~
, . .. .
may be used for photochemically treating other blood vessel abnormalities.
Hypervascular dermal lesions, such as port-wine-stains or spider veins are abnormal assemblies of blood vessels located within the dermis. The drawiny depicts schematically the process in accordance with the present invention for treating such abnormal blood vessel assemblies. A portion of the skin to be treated is shown at 10. The skin is shown as an extremely simplified cross section showing the epidermis 12 and dermis or corium 14.
The dermis 14 includes blood vessels 16 which are shown in the simplified cross section. 'l`~le various structures present in the dermis, such as nerve endings, sweat glands, hair follicles and sebaceous glands are not depicted in order to simplify the pictorial description of the method. The blood vessels 16 include a blood vessel wall 18 which is made up of blood vessel tissue cells. The blood vessels 16 have an interior surface 20 which defines a blood flow zone 22 through which blood flows. The blood vessels 16 also include an exterior surface 24 which defines the outer perimeter of the blood vessel 16.
The first step in the method involves introducing a therapeutic amount of a photoreactive compound into the blood flowing through the blood flow zone 22. The photoreactive compound is shown schematically as dots within the blood vessel 16. The photoreactive compound can be any of the known photosensitive dyes which are suitable for use in photodynamic therapy. These compounds include hematoporphyrin derivative (llPD) and the purified form of HPD known as Photofrin II. These compounds are commercially available. These compounds and other porphyrin derivatives for use in photodynamic therapy are described in United States Patents Nos.
4,649,151; 4,699,903; 4,692,439; and 4,753,958. The ~2~7~
contents of these United States Patents are ~ e~y incorporated by reference. Although a variety of porphyrin based compounds are available, Photofrin II is -a preferred photoreactive compound. Other suitable -~
5 photoreactive compounds include chlorins, -~
.:. : .
phthalocyanines and purpurin.
The photoreactive compound is injected intravenously into the patient. The dosage level should be between about 1 milligram per kilogram of body weight to about 3 milligrams per kilogram of body weight. The dosage level may vary depending upon the compound being administered and the lesion being treated. The particular dosage levels which will be most effective can be established by routine experimentation. Such dosage levels may be as low as 0.1 milligram per kilogram of body weight or as high as 5 milligra]ns per kilogram of body weight. The photoreactive compound is injected as a solution in which the photoreactive compound is dissolved in a suitable pharmaceutical carrier. Any of the pharmaceutical carriers which have been used in the past for injecting porphyrin dyes for photodynamic therapy may be used. These pharmaceutical carriers include physiological saline which is a preferred pharmaceutical carrier.
. : -.. ,, ,. ,:, The top portion of the drawing at (l) depicts a -~
portion of skin immediately after intravenous injection of the photoreactive compound. As can be seen, the dots ~ -representing the photoreactive compound are limited to ~ s~
the interior of the blood vessels 16. The photoreactive 30 compound is then allowed to accumulate in the blood ;`~
vessel wall 18 for a sufficient time to provide a sufficient amount of photoreactive compound within the blood vessel wall 18 to destroy the blood vessel when the photoreactive compound is activated by a laser in ; ;, 35 accordance with known techniques. This condition is i shown in the middle of the drawing at (2) where the : ~ ~: ~ : ,: .
: ` - ', ' "' ~ 217~
.
.
photoreactive compound, as represented by the dots, has migrated from the interior of the blood vessel 22 out into the blood vessel walls 18. At this point, the laser 30 is directed onto the blood vessel 16 to activate the photoreactive compound and destroy the blood vessel. The irradiation of the vessels by laser 30 is represented by arrows 32. The laser does not have to focus on individual blood vessels. In fact, any light source of correct color absorbed by the dye is suitable.
It was discovered in accordance with the present invention that sufficient quantities of photoreactive compound are present in the blood vessel wall to cause destruction of the blood vessel even when accumulation of the photoreactive compound is limited to the blood vessel. Limitation of accumulation is achieved by irradiating the skin with laser 30 after only a relatively short period of time. As was previously discussed, conventional photodynamic therapy of tumors requires a waiting period of at least twenty-four hours prior to irradiation. In the present method, the skin is irradiated within one to four hours after intravenous injection of the photoreactive compound. Shorter or longer waiting periods may be used depending upon the type of patient being treated and the particular compound being used. A waiting period of about two hours is preferred. The two-hour time period was found to optimize blood vessel destruction while limiting damage to surrounding tissues.
The wavelength and intensity of laser radiation directed at the blood vessels 16 can be varied within the range of intensities and wavelengths commonly used in photodynamic therapy. Wavelengths of between about 400 to 700 nanometers are acceptable. The preferred wavelength range for HPD is between 00 to 650 nanometers. Wavelengths in this range are preferred since they have sufficient energy to activate hemato 23121~
..:
porphyrin compounds to destroy the blood vessels while at the same time being able to penetrate throuyh the skin to depths sufficient to reach the blood vessels.
630 nanometer laser light has been found to be particularly effective in treating blood vessels located in the skin. For blood vessels located at locations other than in the dermis, suitable means must be used for focusing laser light onto blood vessels. Various optical fiber devices commonly used to direct laser light onto tumors can be used for this purpose. The controlling consideration is to match the wavelength with the absorption by the dye and the location of the lesions. For example, shorter wavelengths which penetrate less deeply into the tissue, are more suitable for superficial lesions.
Destruction of the blood vessels as represented at (2) in the drawing, results in hemorrhaging and coloration of the skin 10. However, after normal healing, the skin 10 remains devoid of the abnormal blood vessels as represented at (3) at the bottom of the drawing.
Examples of a practice are as follows:
Example 1 The effectiveness of the present invention was demonstrated by treating chicken combs. It has been shown that chicken combs provide an accurate model which represents the hypervascular lesions which are found in abnormal human skin. Accordingly, demonstration that the method is effective in destroying chicken comb blood vessels is indicative of the effectiveness of the method in connection with treating human hypervascular lesions.
Twenty chickens weighing 2-1/2 to 3-1/2 kg underwent anesthesia with methohexitone sodium 1%
solution at 10 mg/kg/ IV 2 cc. Some of the chickens were not anesthetized because the procedure is painless due to the lower power densities which are used.
; ~ : ,.:
, ~ ' . ~, ': -2~2~7~
,~ ~
g Photofrin II (DHE) was obtained and prepared by the method of Nelson et al. and injected without dilution intravenou~ly at lo mg/kg. Tl-e Photofrill II was injected as a solution of 2.45 mg Photof'rin per 1 ml of solu. The laser used was a Krypton laser coherent Innova so of 405 nm wavelength. Using a 1 sq cm circular hole stencilled in a cardboard template, 3 chicken combs were irradiated immediately post-injection. 3 additional combs were each rradiated at post-injection times of 1 hr., 2 hr., 3 hr., and 4 hr.
Irradiation parameters were 90 mW for 3 min. 42 sec. for a total energy of 30 j. Animals were examined and ..; . , photographed for a period of 2 weeks.
Post-injection intervals prior to irradiation were compared by observing the chronological extent of persistent comb blanching. Blanching of the chicken comb is recognized as an effective measure of blood ;~
vessel destruction. The 2 hr. areas showed the most prominent blanching effects which persisted for 7, 9 and 20 14 days. All other post-injection intervals areas had ~ -less pronounced blanching and returned to baseline within 2 to 4 days. ;~
After determining the optimal post-injection interval of 2 hours, two different portions of 10 chicken combs underwent 2 irradiations, each after a 2-hour injection interval. The radiation levels were:
-9OmW for 554 seconds for a total irradiation of -~
50 joules -90mW for 828 seconds for a total irradiation of 75 joules Animals were photographed prior to being - ;~
sacrificed. Two animals were then sacrificed at post-irradiation times of 1 hr., 24 hr., 72 hr., and 1 week. ~ ~ -Samples of the 50 joule regions were sectioned for light microscopy (LM), scanning electron microscopy (SEM) and transmission (TEM) electron microscopy (TEM). , -` 2~2~7~ ~:
.~. .
,. .
Comparative histology was achleved by examininy combs in which Baseline - no Photofrin II or irrad.ation administered 5Control - (LM) and transmission (EM) were compared to a control group that underwent the same irradiation protocol but without prior sensitization with DHE.
Evaluation of the epidermal effect was performed by SEM on each area irradiated with 50 joules. In addition lo to comparison with the baseline micrographs, each area was compared to a neighboring un-irradiated zone.
All of the combs showed immediate post-irradiation darkening which persisted for 15 to go minutes before gradual conversion to blanching. Initial blanching was more prominent in the 75 joule group. For the ensuing several days that blanching persisted; zones of intermittent darkening and blanching were observed.
Return to baseline color was more rapid in the 50 joule group which had nearly returned to baseline by 4 to 5 days. The 75 joule group had scattered areas of persistent blanching at 1 week.
It was noted that the changes occurred specifically in the region of the comb vasculature. Dramatic swelling of erythrocytes and apparent ballooning of the vessels was noted on both LM and EM corresponding to the period of darkening. There was subsequent progression to prominent vessel wall swelling with absence of intraluminal erythrocytes and presence of enlarged endothelial cells which corresponded to the development of gross blanching. From 24 hours to 1 week, histologic sections revealed zones of patent vessels alternating with zones of persistent occlusion. At one week, there was both areas of patent vasculature and areas of occlusion. ~owever, open vessels re~ealed persistent stasis and crowding of normal RBC's. The epidermal - 2~217~
-11- , .
:
layer remained unchanged compared to the baseline epidermal layer.
The blanching of the combs remained for up to 12 days followed by a gradual return to normal coloration.
Example 2 The same method as Example 1 was used to treat a number of chicken combs except that 630 mm red light from a dye laser was used instead of 405 nm light and all times between injections and irradiation were 2 hours. The results were similar except that permanent blanching of the chicken combs was achieved. As in Example 1, there was no damage found to the epidermis or other tissue of the comb surrounding the destroyed blood vessels.
15Having thus described exemplary embodiments of the ~
present invention, it should be noted by those skilled -~ -in the art that the within disclosures are exemplary -only and that various other alternatives, adaptations, and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.
,.,',.....
''"' ~'-~"~""'.'"'
It was found that the HPD preferentially congregates in cancer celis or in vessels feeding the malignant tumor.
The HPD has no effect on the tumor until it is energized by radiation. The energized HPD creates toxic molecules that selectively kill the tissue where the ~PD is located. The use of such photoreactive dyes to destroy abnormal tissue is commonly referred to as photodynamic therapy.
HPD has been used to treat patients for many kinds of solid tumors, including those of the skin, lung, bladder, eye, neck, and esophagus. Usually, the patient who is being treated will receive about two milligrams of Photofrin II per kilogram of body weight. The Photofrin is typically injected into the bloodstream of the patient over a period of about five minutes. The patient must be immediately protected from bright light to prevent undesirable non-selective photoactivation of the Photofrin II. The physician then waits two to three days for the Photofrin II to congregate in the malignant tumor while the remainder of the Photofrin II is washed ;' '~
, ~: .: '~
! ~ .
2 0 ~ 2 ~
from normal tissues by the patient's system. The physician generally then uses an argon-pumped dye laser to shine liyht on the patient's tumor and surrounding area. The laser is focused directly on exterior tumors or those located within 3 to 10 mm of the skin surface.
When tumors are located inside the body, the doctor utilizes an optical fiber to deliver the radiation to the tumor.
The use of photodynamic therapy has been limited to the treatment of malignant tissues. The limitation is due, for the most part, because of the unique ability of malignant tissues to retain HPD long after it has been :, :
washed from normal tissues. Even so, there is a continuing need to use this valuable form of therapy to treat other disorders which are not malignant.
There is presently a need to provide improved therapeutics for treating hypervascular dermal lesions, such as port-wine stains. Hypervascular dermal lesions and other non-malignant tissue disorders are presently treated with lasers. The treatment utilizes photothermal ablation whereby absorbed energies are converted to heat. The lesion is destroyed either by direct thermal denaturization or by propagated shock waves due to near instantaneous heating provided by the laser. A problem with this type of treatment is confining and localizing the thermal injury to a specific tissue location.
In order to reduce injury to surrounding tissues, shorter laser pulse durations have been used which produce a more confined shock wave effect and less thermal conductivity. Although some success has been achieved in reducing injury to the surrounding tissues, there continues to be a "photothermal overflow" which causes injury to surrounding tissues. The thermal injury to surrounding tissues is especially undesirable - :-~ . .-, ,.,. ~. . . ~:
,',: ~:' ' ':. , . ' ~' ~21 7.~
. . .
when dealing with skin lesions where cosmetic appearance is an important consideration.
The use of photosensitive dyes in combination with laser treatment would appear to be desirable in reducing the thermal damage to normal tissues surrounding the hypervascular dermal lesions. ~lowever, photosensitive dyes have not been shown to selectively congregate at such non-malignant dermal lesions. Accordingly, photodynamic therapy has not been suggested for use in treating such non-malignant dermal lesions. It would be desirable, however, to provide a process based on -photodynamic therapy for treating such blood vessel disorders, even though the photosensitive dyes do not selectively migrate to such tissues. ~ ~-` -Summarv of the Invention In accordance with the present invention, it was discovered that blood vessels can be photochemically ~ `-treated to provide selective destruction while, at the 20 same time, limiting damage to surrounding tissues. -The present invention is based on a method wherein a therapeutic amount of a photoreactive compound is introduced into the blood flowing through the blood vessel. It was discovered that photoreactive compounds ~ ;
associate with the blood vessel wall. The photoreactive compound is allowed to accumulate in the blood vessel wall for a sufficient time to provide a sufficient amount of photoreactive compound within the blood vessel wall to destroy the blood vessel when the photoreactive compound is activated by radiation from a laser or other source.
As a feature of the present invention, the -~
photoreactive compound associated with the blood vessel wall is activated prior to the time at which the 35 photoreactive compound leaves the vessel and either -~
enters the surrounding tissue or is washed away. It was 2~217~
discovered that sufficient photoreactive compound is present within blood vessel walls to allow photodynamic destruction of the blood vessel tissue withou-t affectiny surrounding tissue. As a result, the method of the present invention allows the destruction of undesirable blood vessels while limiting the amount of harm to surrounding tissues.
The method of the present invention is particularly well suited for treating hypervascular dermal lesions, such as port-wine stains. The method eliminates many of the cosmetic problems associated with thermal destruction of surrounding tissue. Further, the method takes advantage of the selectivity of tissue destruction provided when using photoreactive compounds.
The above discussed and many other features and attendant advantages of the present invention will become better understood by reference to the following detailed description when considered in conjunction with the accompanying drawings.
Brief Description of the Drawings The drawing is a schematic representation of a preferred exemplary method in accordance with the present invention.
Detailed Descri~tion of the Preferred Embodiments The present invention involves photochemical therapy which may be used to treat a wide variety of abnormal blood vessel conditions. The method may be used for a wide variety of situations wherein it is desired to selectively destroy or-e or more blood vessels. The invention is particularly well suited for treating hypervascular dermal lesions. Accordingly, the following description of a preferred embodiment will be limited to describing the treatment of hypervascular dermal lesions with it being understood that the method ~11 217~
, . .. .
may be used for photochemically treating other blood vessel abnormalities.
Hypervascular dermal lesions, such as port-wine-stains or spider veins are abnormal assemblies of blood vessels located within the dermis. The drawiny depicts schematically the process in accordance with the present invention for treating such abnormal blood vessel assemblies. A portion of the skin to be treated is shown at 10. The skin is shown as an extremely simplified cross section showing the epidermis 12 and dermis or corium 14.
The dermis 14 includes blood vessels 16 which are shown in the simplified cross section. 'l`~le various structures present in the dermis, such as nerve endings, sweat glands, hair follicles and sebaceous glands are not depicted in order to simplify the pictorial description of the method. The blood vessels 16 include a blood vessel wall 18 which is made up of blood vessel tissue cells. The blood vessels 16 have an interior surface 20 which defines a blood flow zone 22 through which blood flows. The blood vessels 16 also include an exterior surface 24 which defines the outer perimeter of the blood vessel 16.
The first step in the method involves introducing a therapeutic amount of a photoreactive compound into the blood flowing through the blood flow zone 22. The photoreactive compound is shown schematically as dots within the blood vessel 16. The photoreactive compound can be any of the known photosensitive dyes which are suitable for use in photodynamic therapy. These compounds include hematoporphyrin derivative (llPD) and the purified form of HPD known as Photofrin II. These compounds are commercially available. These compounds and other porphyrin derivatives for use in photodynamic therapy are described in United States Patents Nos.
4,649,151; 4,699,903; 4,692,439; and 4,753,958. The ~2~7~
contents of these United States Patents are ~ e~y incorporated by reference. Although a variety of porphyrin based compounds are available, Photofrin II is -a preferred photoreactive compound. Other suitable -~
5 photoreactive compounds include chlorins, -~
.:. : .
phthalocyanines and purpurin.
The photoreactive compound is injected intravenously into the patient. The dosage level should be between about 1 milligram per kilogram of body weight to about 3 milligrams per kilogram of body weight. The dosage level may vary depending upon the compound being administered and the lesion being treated. The particular dosage levels which will be most effective can be established by routine experimentation. Such dosage levels may be as low as 0.1 milligram per kilogram of body weight or as high as 5 milligra]ns per kilogram of body weight. The photoreactive compound is injected as a solution in which the photoreactive compound is dissolved in a suitable pharmaceutical carrier. Any of the pharmaceutical carriers which have been used in the past for injecting porphyrin dyes for photodynamic therapy may be used. These pharmaceutical carriers include physiological saline which is a preferred pharmaceutical carrier.
. : -.. ,, ,. ,:, The top portion of the drawing at (l) depicts a -~
portion of skin immediately after intravenous injection of the photoreactive compound. As can be seen, the dots ~ -representing the photoreactive compound are limited to ~ s~
the interior of the blood vessels 16. The photoreactive 30 compound is then allowed to accumulate in the blood ;`~
vessel wall 18 for a sufficient time to provide a sufficient amount of photoreactive compound within the blood vessel wall 18 to destroy the blood vessel when the photoreactive compound is activated by a laser in ; ;, 35 accordance with known techniques. This condition is i shown in the middle of the drawing at (2) where the : ~ ~: ~ : ,: .
: ` - ', ' "' ~ 217~
.
.
photoreactive compound, as represented by the dots, has migrated from the interior of the blood vessel 22 out into the blood vessel walls 18. At this point, the laser 30 is directed onto the blood vessel 16 to activate the photoreactive compound and destroy the blood vessel. The irradiation of the vessels by laser 30 is represented by arrows 32. The laser does not have to focus on individual blood vessels. In fact, any light source of correct color absorbed by the dye is suitable.
It was discovered in accordance with the present invention that sufficient quantities of photoreactive compound are present in the blood vessel wall to cause destruction of the blood vessel even when accumulation of the photoreactive compound is limited to the blood vessel. Limitation of accumulation is achieved by irradiating the skin with laser 30 after only a relatively short period of time. As was previously discussed, conventional photodynamic therapy of tumors requires a waiting period of at least twenty-four hours prior to irradiation. In the present method, the skin is irradiated within one to four hours after intravenous injection of the photoreactive compound. Shorter or longer waiting periods may be used depending upon the type of patient being treated and the particular compound being used. A waiting period of about two hours is preferred. The two-hour time period was found to optimize blood vessel destruction while limiting damage to surrounding tissues.
The wavelength and intensity of laser radiation directed at the blood vessels 16 can be varied within the range of intensities and wavelengths commonly used in photodynamic therapy. Wavelengths of between about 400 to 700 nanometers are acceptable. The preferred wavelength range for HPD is between 00 to 650 nanometers. Wavelengths in this range are preferred since they have sufficient energy to activate hemato 23121~
..:
porphyrin compounds to destroy the blood vessels while at the same time being able to penetrate throuyh the skin to depths sufficient to reach the blood vessels.
630 nanometer laser light has been found to be particularly effective in treating blood vessels located in the skin. For blood vessels located at locations other than in the dermis, suitable means must be used for focusing laser light onto blood vessels. Various optical fiber devices commonly used to direct laser light onto tumors can be used for this purpose. The controlling consideration is to match the wavelength with the absorption by the dye and the location of the lesions. For example, shorter wavelengths which penetrate less deeply into the tissue, are more suitable for superficial lesions.
Destruction of the blood vessels as represented at (2) in the drawing, results in hemorrhaging and coloration of the skin 10. However, after normal healing, the skin 10 remains devoid of the abnormal blood vessels as represented at (3) at the bottom of the drawing.
Examples of a practice are as follows:
Example 1 The effectiveness of the present invention was demonstrated by treating chicken combs. It has been shown that chicken combs provide an accurate model which represents the hypervascular lesions which are found in abnormal human skin. Accordingly, demonstration that the method is effective in destroying chicken comb blood vessels is indicative of the effectiveness of the method in connection with treating human hypervascular lesions.
Twenty chickens weighing 2-1/2 to 3-1/2 kg underwent anesthesia with methohexitone sodium 1%
solution at 10 mg/kg/ IV 2 cc. Some of the chickens were not anesthetized because the procedure is painless due to the lower power densities which are used.
; ~ : ,.:
, ~ ' . ~, ': -2~2~7~
,~ ~
g Photofrin II (DHE) was obtained and prepared by the method of Nelson et al. and injected without dilution intravenou~ly at lo mg/kg. Tl-e Photofrill II was injected as a solution of 2.45 mg Photof'rin per 1 ml of solu. The laser used was a Krypton laser coherent Innova so of 405 nm wavelength. Using a 1 sq cm circular hole stencilled in a cardboard template, 3 chicken combs were irradiated immediately post-injection. 3 additional combs were each rradiated at post-injection times of 1 hr., 2 hr., 3 hr., and 4 hr.
Irradiation parameters were 90 mW for 3 min. 42 sec. for a total energy of 30 j. Animals were examined and ..; . , photographed for a period of 2 weeks.
Post-injection intervals prior to irradiation were compared by observing the chronological extent of persistent comb blanching. Blanching of the chicken comb is recognized as an effective measure of blood ;~
vessel destruction. The 2 hr. areas showed the most prominent blanching effects which persisted for 7, 9 and 20 14 days. All other post-injection intervals areas had ~ -less pronounced blanching and returned to baseline within 2 to 4 days. ;~
After determining the optimal post-injection interval of 2 hours, two different portions of 10 chicken combs underwent 2 irradiations, each after a 2-hour injection interval. The radiation levels were:
-9OmW for 554 seconds for a total irradiation of -~
50 joules -90mW for 828 seconds for a total irradiation of 75 joules Animals were photographed prior to being - ;~
sacrificed. Two animals were then sacrificed at post-irradiation times of 1 hr., 24 hr., 72 hr., and 1 week. ~ ~ -Samples of the 50 joule regions were sectioned for light microscopy (LM), scanning electron microscopy (SEM) and transmission (TEM) electron microscopy (TEM). , -` 2~2~7~ ~:
.~. .
,. .
Comparative histology was achleved by examininy combs in which Baseline - no Photofrin II or irrad.ation administered 5Control - (LM) and transmission (EM) were compared to a control group that underwent the same irradiation protocol but without prior sensitization with DHE.
Evaluation of the epidermal effect was performed by SEM on each area irradiated with 50 joules. In addition lo to comparison with the baseline micrographs, each area was compared to a neighboring un-irradiated zone.
All of the combs showed immediate post-irradiation darkening which persisted for 15 to go minutes before gradual conversion to blanching. Initial blanching was more prominent in the 75 joule group. For the ensuing several days that blanching persisted; zones of intermittent darkening and blanching were observed.
Return to baseline color was more rapid in the 50 joule group which had nearly returned to baseline by 4 to 5 days. The 75 joule group had scattered areas of persistent blanching at 1 week.
It was noted that the changes occurred specifically in the region of the comb vasculature. Dramatic swelling of erythrocytes and apparent ballooning of the vessels was noted on both LM and EM corresponding to the period of darkening. There was subsequent progression to prominent vessel wall swelling with absence of intraluminal erythrocytes and presence of enlarged endothelial cells which corresponded to the development of gross blanching. From 24 hours to 1 week, histologic sections revealed zones of patent vessels alternating with zones of persistent occlusion. At one week, there was both areas of patent vasculature and areas of occlusion. ~owever, open vessels re~ealed persistent stasis and crowding of normal RBC's. The epidermal - 2~217~
-11- , .
:
layer remained unchanged compared to the baseline epidermal layer.
The blanching of the combs remained for up to 12 days followed by a gradual return to normal coloration.
Example 2 The same method as Example 1 was used to treat a number of chicken combs except that 630 mm red light from a dye laser was used instead of 405 nm light and all times between injections and irradiation were 2 hours. The results were similar except that permanent blanching of the chicken combs was achieved. As in Example 1, there was no damage found to the epidermis or other tissue of the comb surrounding the destroyed blood vessels.
15Having thus described exemplary embodiments of the ~
present invention, it should be noted by those skilled -~ -in the art that the within disclosures are exemplary -only and that various other alternatives, adaptations, and modifications may be made within the scope of the present invention. Accordingly, the present invention is not limited to the specific embodiments as illustrated herein, but is only limited by the following claims.
,.,',.....
''"' ~'-~"~""'.'"'
Claims (19)
1. A method for photochemically treating an area of the skin that contains at least one blood vessel wherein said blood vessel includes a blood vessel wall comprising blood vessel tissue cells, said blood vessel wall having an interior surface defining a blood flow zone through which blood flows and an exterior surface which defines the outer perimeter of said blood vessel, wherein the method comprises:
introducing a therapeutic amount of a photoreactive compound into the blood flowing through said blood flow zone wherein said photoreactive compound is capable of accumulating in said blood vessel wall from said blood vessel interior surface toward said blood vessel exterior surface and wherein said photoreactive compound destroys blood vessel tissue and other tissue cells upon activation;
allowing said photoreactive compound to accumulate in said blood vessel wall for a sufficient time to provide a sufficient amount of photoreactive compound within said blood vessel wall to destroy said blood vessel when said photoreactive compound is activated;
and activating said photoreactive compound in said blood vessel wall prior to movement of said photoreactive compound past the outer perimeter of said blood vessel to thereby limit destruction of tissue surrounding said blood vessel by said photoreactive compound.
introducing a therapeutic amount of a photoreactive compound into the blood flowing through said blood flow zone wherein said photoreactive compound is capable of accumulating in said blood vessel wall from said blood vessel interior surface toward said blood vessel exterior surface and wherein said photoreactive compound destroys blood vessel tissue and other tissue cells upon activation;
allowing said photoreactive compound to accumulate in said blood vessel wall for a sufficient time to provide a sufficient amount of photoreactive compound within said blood vessel wall to destroy said blood vessel when said photoreactive compound is activated;
and activating said photoreactive compound in said blood vessel wall prior to movement of said photoreactive compound past the outer perimeter of said blood vessel to thereby limit destruction of tissue surrounding said blood vessel by said photoreactive compound.
2. A method according to claim 1 wherein said photoreactive compound is a hematoporphyrin compound.
3. A method according to claim 2 wherein said photoreactive compound is hematoporphyrin derivative.
4. A method according to claim 2 wherein said photoreactive compound is Photofrin II.
5. A method according to claim 2 wherein said hematoporphyrin compound is activated by irradiation with light having a wavelength of between about 400 to 700 nanometers.
6. A method according to claim 5 wherein the wavelength of said radiation is between about 700 and 650 nanometers.
7. A method according to claim 6 wherein said photoreactive compound is Photofrin II.
8. A method according to claim 1 wherein said blood vessels are located in the skin of a mammal.
9. A method according to claim 8 wherein said blood vessels are located in a hypervascular dermal lesion.
10. A method according to claim 9 wherein said photoreactive compound is hematoporphyrin compound.
11. A method according to claim 10 wherein said photoreactive compound is hematoporphyrin derivative.
12. A method according to claim 11 wherein said photoreactive compound is Photofrin II.
13. A method according to claim 9 wherein said photoreactive compound is activated by exposure to radiation having a wavelength of between about 400 to 700 nanometers.
14. A method according to claim 9 wherein the wavelength of said radiation is between about 600 and 650 nanometers.
15. A method according to claim 12 wherein said Photofrin II is exposed to radiation having a wavelength of between about 600 and 650 nanometers.
16. A method according to claim 9 wherein said hypervascular dermal lesion is port-wine-stains or spider veins.
17. A method according to claim 8 wherein said mammal is a human.
18. A method according to claim 9 wherein said mammal is a human.
19. A method according to claim 1 wherein said photoreactive compound is allowed to accumulate in said blood vessel wall for about 2 hours prior to activation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US33201589A | 1989-03-31 | 1989-03-31 | |
| US332,015 | 1989-03-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2012175A1 true CA2012175A1 (en) | 1990-09-30 |
Family
ID=23296348
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002012175A Abandoned CA2012175A1 (en) | 1989-03-31 | 1990-03-14 | Photochemical treatment of blood vessels |
Country Status (3)
| Country | Link |
|---|---|
| AU (1) | AU5413490A (en) |
| CA (1) | CA2012175A1 (en) |
| WO (1) | WO1990011797A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5705518A (en) * | 1992-11-20 | 1998-01-06 | University Of British Columbia | Method of activating photosensitive agents |
| WO2006112379A1 (en) * | 2005-04-14 | 2006-10-26 | Takafumi Ohshiro | Drug for treating or diagnosing vascular lesion in the skin or the subcutaneous soft tissue caused by light irradiation |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5425728A (en) * | 1991-10-29 | 1995-06-20 | Tankovich; Nicolai I. | Hair removal device and method |
| US5423803A (en) * | 1991-10-29 | 1995-06-13 | Thermotrex Corporation | Skin surface peeling process using laser |
| US5817089A (en) * | 1991-10-29 | 1998-10-06 | Thermolase Corporation | Skin treatment process using laser |
| US5752949A (en) * | 1991-10-29 | 1998-05-19 | Thermolase Corporation | Hair removal method |
| US5752948A (en) * | 1991-10-29 | 1998-05-19 | Thermolase Corporation | Hair removal method |
| EG20471A (en) | 1993-07-12 | 1999-05-31 | Thermotrex Corp | Hair removal device and method |
| CA2131750C (en) * | 1994-07-26 | 2000-11-21 | Nikolai I. Tankovich | Improved hair removal method |
| US6317616B1 (en) * | 1999-09-15 | 2001-11-13 | Neil David Glossop | Method and system to facilitate image guided surgery |
| US20070299431A1 (en) | 2006-05-02 | 2007-12-27 | Green Medical, Inc. | Systems and methods for treating superficial venous malformations like spider veins |
| US7465312B2 (en) | 2006-05-02 | 2008-12-16 | Green Medical, Inc. | Systems and methods for treating superficial venous malformations like spider veins |
Family Cites Families (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3323365C2 (en) * | 1982-09-04 | 1994-10-20 | Gsf Forschungszentrum Umwelt | Method and device for illuminating cavities |
| US4773899A (en) * | 1982-11-23 | 1988-09-27 | The Beth Israel Hospital Association | Method of treatment of artherosclerosis and balloon catheter the same |
| US4622952A (en) * | 1983-01-13 | 1986-11-18 | Gordon Robert T | Cancer treatment method |
| US4622953A (en) * | 1983-01-13 | 1986-11-18 | Gordon Robert T | Process for the treatment of atherosclerotic lesions |
| US4541438A (en) * | 1983-06-02 | 1985-09-17 | The Johns Hopkins University | Localization of cancerous tissue by monitoring infrared fluorescence emitted by intravenously injected porphyrin tumor-specific markers excited by long wavelength light |
| US4610241A (en) * | 1984-07-03 | 1986-09-09 | Gordon Robert T | Atherosclerosis treatment method |
| US4815447A (en) * | 1985-03-19 | 1989-03-28 | Mills Randell L | Mossbauer cancer therapy |
-
1990
- 1990-03-14 CA CA002012175A patent/CA2012175A1/en not_active Abandoned
- 1990-03-27 WO PCT/US1990/001647 patent/WO1990011797A1/en unknown
- 1990-03-27 AU AU54134/90A patent/AU5413490A/en not_active Abandoned
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5705518A (en) * | 1992-11-20 | 1998-01-06 | University Of British Columbia | Method of activating photosensitive agents |
| US5770619A (en) * | 1992-11-20 | 1998-06-23 | University Of British Columbia | Method of activating photosensitive agents |
| EP0947222A2 (en) | 1992-11-20 | 1999-10-06 | The University Of British Columbia | Method of activating photosensitive agents |
| WO2006112379A1 (en) * | 2005-04-14 | 2006-10-26 | Takafumi Ohshiro | Drug for treating or diagnosing vascular lesion in the skin or the subcutaneous soft tissue caused by light irradiation |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1990011797A1 (en) | 1990-10-18 |
| AU5413490A (en) | 1990-11-05 |
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