WO2001074389A2 - Improved treatment of neovascularization - Google Patents

Improved treatment of neovascularization Download PDF

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Publication number
WO2001074389A2
WO2001074389A2 PCT/EP2001/003265 EP0103265W WO0174389A2 WO 2001074389 A2 WO2001074389 A2 WO 2001074389A2 EP 0103265 W EP0103265 W EP 0103265W WO 0174389 A2 WO0174389 A2 WO 0174389A2
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WO
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Prior art keywords
administration
inhibitors
angiogenic drug
subject
angiogenic
Prior art date
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PCT/EP2001/003265
Other languages
French (fr)
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WO2001074389A3 (en
Inventor
Romulus Kimbro Brazzell
Original Assignee
Novartis Ag
Novartis-Erfindungen Verwaltungsgesellschaft M.B.H.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to UA2002097520A priority Critical patent/UA75350C2/en
Priority to CA002403612A priority patent/CA2403612A1/en
Priority to KR1020027012287A priority patent/KR20020082487A/en
Priority to AU2001250401A priority patent/AU2001250401B2/en
Priority to HU0300347A priority patent/HUP0300347A3/en
Priority to JP2001572131A priority patent/JP2003528926A/en
Priority to NZ521360A priority patent/NZ521360A/en
Priority to IL15183301A priority patent/IL151833A0/en
Application filed by Novartis Ag, Novartis-Erfindungen Verwaltungsgesellschaft M.B.H. filed Critical Novartis Ag
Priority to PL01359027A priority patent/PL359027A1/en
Priority to BR0109499-8A priority patent/BR0109499A/en
Priority to EP01923695A priority patent/EP1265636A2/en
Priority to AU5040101A priority patent/AU5040101A/en
Priority to EEP200200547A priority patent/EE200200547A/en
Priority to MXPA02009351A priority patent/MXPA02009351A/en
Publication of WO2001074389A2 publication Critical patent/WO2001074389A2/en
Publication of WO2001074389A3 publication Critical patent/WO2001074389A3/en
Priority to NO20024486A priority patent/NO20024486L/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/553—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one oxygen as ring hetero atoms, e.g. loxapine, staurosporine
    • 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
    • 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
    • A61K41/0071—PDT with porphyrins having exactly 20 ring atoms, i.e. based on the non-expanded tetrapyrrolic ring system, e.g. bacteriochlorin, chlorin-e6, or phthalocyanines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the invention relates to an improved method to treat subfoveal choroidal neovascularization (CNV) by use of an anti-angiogenic agent as an adjunct to photodynamic therapy (PDT) also called photodynamic treatment.
  • CNV subfoveal choroidal neovascularization
  • PDT photodynamic therapy
  • the present treatment of age related macular degeneration (AMD) with photodynamic therapy using an appropriate photosensitizer leads to excellent short-term results for treating CNV and is a significant improvement over laser photocoagulation.
  • AMD age related macular degeneration
  • PDT photodynamic therapy
  • a pharmaceutical treatment which could be used in conduction with PDT, and which prevents the growth of new vessels would be a significant advancement and would be advantageous for the treatment of CNV.
  • the prevention of new unwanted neovasculature could reduce the number of PDT treatments required in some subjects.
  • the present techniques may also be useful for treating other types of ocular tissue as well, such as retinal neovascular lesions.
  • the present invention describes in a first aspect a method for an improved treatment of unwanted neovasculature due to CNV in a subject, which method comprises:
  • the present invention relates in a further aspect to the use of an anti-angiogenic drug in conjunction with a photosensitive agent in the preparation of a medicament for the improved photodynamic treatment of unwanted neovasculature due to CNV in a subject, preferably a human subject.
  • the invention relates in a further aspect to the use of an anti-angibgenic drug in conjunction with a photosensitive agent in the preparation of a medicament for the improved photodynamic treatment of unwanted neovasculature due to CNV in a subject, preferably human subject, wherein said improved photodynamic treatment comprises the steps of:
  • PDT as a treatment is well known in the art, and generally involves the use of a photosensitize agent activated by a laser.
  • a preferred PDT treatment having a photosensitize agent and laser treatment protocol is disclosed in the issued European patent EP 680 * 365 B1 and in the International application WO 97/33619.
  • the photosensitive agent lodges in the ocular tissue affected by CNV (i.e., the target occular tissue) and is activated by a laser having a wavelength absorbable by the photosensitive agent.
  • the anti- angiogenic drug is administered before, after and / or simultaneously with the photosensitizer used in the PDT treatment.
  • the combination of PDT and anti-angiogenic drug is referred to as adjunctive PDT.
  • the anti-angiogenic may be administered either sequentially or simultaneously with the photosensitive agent, the preferred method being sequential. Therefore, the term "in conjunction with"shall be construed in accordance to the definitions as provided within this disclosure.
  • sequential treatment an anti-angiogenic drug may be administered for 1 to 4 weeks, more preferably 0.5 to 1.5 weeks before administration of the PDT photosensitizer.
  • the anti-angiogenic may be administered 0 to 4 weeks, more preferably 0 to 1 weeks after administration of the PDT photosensitie agent. If necessary, the anti-angiogenic may be sequentially administered both before and after PDT according to the schedule described above.
  • the treatment is considered simultaneous if the anti-angiogenic is co-administered with the photosensitizer.
  • Particular subjects may require multiple adjunctive PDT treatments or adjunctive PDT treatments with the anti-angiogenic and particular adjunctive PDT treatments may require multiple administrations of the anti-angiogenic drug.
  • Anti-angiogenic drugs as the term is used herein mean drugs that work by preventing, inhibiting or reversing the growth of new blood vessels via the process commonly known as angiogenesis.
  • anti-angiogenic drugs useful in adjunctive PDT include staurosporins, for example N-benzoyl-staurosporine, somatostatins, such as octreotide
  • VEGF inhibitors such as CGP 79987D, CGP 57 148B or CGP 53716,
  • a preferred anti-angiogenic drug is selected from inhibitors of protein kinase C (PKC) (e.g., N- benzoyl-staurosporine), inhibitors of growth hormone and IGF-1 (e.g., octreotide), inhibitors of vascular endothelial growth factor (VEGF) (e.g., CGP 79787, N-benzoyl-staurosporine, CAM 781 ), inhibitors of cyclooxgenase II (e.g., diclofenac, COX 189), inhibitors of angiotensin II (e.g., valsartan), inhibitors of NF-kappa B, and PLA2 antagonists, more preferably from PKC inhibitors, VEGF
  • a highly preferred anti-angiogenic drug is selected from an inhibitor of PKC and VEGF, in particular from an inhibitor of PKC.
  • a highly preferred anti-angiogenic drug is selected from N- benzoyl-staurosporine, CGP 79787 and octreotide and in particular from N-benzoyl- staurosporine.
  • the preferred photosensitizers are selected from the group of a chlorine, a bacteriochlorine, a phthalocyanine, a porphyrin, a purpurin, a merocyanine, a pheophorbide and a psoralen.
  • a highly preferred photosensitizer is selected from the porphyrins and is typically the so-called green porphyrin or BPD-MA.
  • photosensitive compounds described above can be used in the method of the invention.
  • mixtures of two or more photosensitive compounds can also be used; however, the effectiveness of the treatment depends on the absorption of light by the photosensitive compound so that if mixtures are used, components with similar absorption maxima are preferred.
  • the nature of the formulation used to deliver the anti-angiogenic drug or photosensitive agent will depend in part on the mode of administration and on the nature of the anti-angiogenic drug and the photoactive agent selected. Any pharmaceutically acceptable excipient, or combination thereof, appropriate to the particular active compounds may be used.
  • the photosensitive agents or anti-angiogenic compounds may be administered as an aqueous composition, as a transmucosal or transdermal composition, as a subtenons or intraocuclar injection or in an oral formulation.
  • the formulation may also include liposomes. Liposomal compositions are particularly preferred especially where the photoactive agent is a green porphyrin.
  • the anti-angiogenic drug is preferably administered via an aqueous carrier.
  • the above mentioned compounds can be administered in any of a wide variety of ways, for example, orally, parenterally, or rectally, or the compound may be placed directly in or on the eye.
  • Parenteral administration such as intravenous, intramuscular, or subcutaneous, is preferred for the photosensitizer.
  • Intravenous injection is especially preferred.
  • Oral administration or ocular administration is preferred for administration of the anti-angiogenic agent.
  • the dose of the above compounds can vary widely depending upon the mode of administration; the formulation in which it is carried, such as in the form of liposomes, or whether it is coupled to a target-specific ligand, such as an antibody or an immunologically active fragment.
  • a target-specific ligand such as an antibody or an immunologically active fragment.
  • the anti-antigenic drug is administered in a manner and amount sufficient to effect drug interaction with the unwanted neovasculature.
  • the photosensitive agent is administered in an amount effective to provide closure to the unwanted neovasculature.
  • a typical dosage is of the range of 0.1-50 mg/m 2 of body surface area, preferably from about 1-10 mg/m 2 and even more preferably about 2-8 mg/m 2 .
  • a typical dosage is of the range of 1-500 mg/kg (of body weight) preferably from about 10-250 mg.
  • the irradiation (laser power, irradiation duration) is carried out in accordance to the prior art mentioned above, for example in accordance to the light treatment protocol of the disclosure of WO 97/33619.

Abstract

The present invention describes an improved photodynamic treatment to treat subfoveal choroidal neovascularization (CNV).

Description

IMPROVED TREATMENT OF NEOVASCULARIZATION
The invention relates to an improved method to treat subfoveal choroidal neovascularization (CNV) by use of an anti-angiogenic agent as an adjunct to photodynamic therapy (PDT) also called photodynamic treatment.
The present treatment of age related macular degeneration (AMD) with photodynamic therapy using an appropriate photosensitizer leads to excellent short-term results for treating CNV and is a significant improvement over laser photocoagulation. However, it has been demonstrated that in patients treated with PDT there is a recurrence of choroidal neovascularization within the treatment area and/or development of new lesions outside the original lesions (so called progression) such that repeated PDT is required. Therefore a pharmaceutical treatment which could be used in conduction with PDT, and which prevents the growth of new vessels would be a significant advancement and would be advantageous for the treatment of CNV. The prevention of new unwanted neovasculature could reduce the number of PDT treatments required in some subjects. The present techniques may also be useful for treating other types of ocular tissue as well, such as retinal neovascular lesions.
Accordingly, the present invention describes in a first aspect a method for an improved treatment of unwanted neovasculature due to CNV in a subject, which method comprises:
(a) administration of an effective amount of an anti-angiogenic drug to said subject;
(b) administration of an effective amount of a photosensitive agent to said subject; and
(c) irradiating said unwanted neovasculature with light having a wavelength absorbable said photosensitive agent.
The present invention relates in a further aspect to the use of an anti-angiogenic drug in conjunction with a photosensitive agent in the preparation of a medicament for the improved photodynamic treatment of unwanted neovasculature due to CNV in a subject, preferably a human subject.
The invention relates in a further aspect to the use of an anti-angibgenic drug in conjunction with a photosensitive agent in the preparation of a medicament for the improved photodynamic treatment of unwanted neovasculature due to CNV in a subject, preferably human subject, wherein said improved photodynamic treatment comprises the steps of:
(a) administration of an effective amount of an anti-angiogenic drug to said subject;
(b) administration of an effective amount of a photosensitive agent to said subject; and (c) irradiating said unwanted neovasculature with light having a wavelength absorbable said photosensitive agent.
It has now been found that administration of an anti-angiogenic can be used in conjunction with PDT for the treatment of a subject having unwanted ocular neovasculature as a result of CNV.
PDT as a treatment is well known in the art, and generally involves the use of a photosensitize agent activated by a laser. A preferred PDT treatment having a photosensitize agent and laser treatment protocol is disclosed in the issued European patent EP 680*365 B1 and in the International application WO 97/33619. In PDT, the photosensitive agent lodges in the ocular tissue affected by CNV (i.e., the target occular tissue) and is activated by a laser having a wavelength absorbable by the photosensitive agent. In the present invention, the anti- angiogenic drug is administered before, after and / or simultaneously with the photosensitizer used in the PDT treatment. The combination of PDT and anti-angiogenic drug is referred to as adjunctive PDT.
The anti-angiogenic may be administered either sequentially or simultaneously with the photosensitive agent, the preferred method being sequential. Therefore, the term "in conjunction with"shall be construed in accordance to the definitions as provided within this disclosure. As an example of sequential treatment, an anti-angiogenic drug may be administered for 1 to 4 weeks, more preferably 0.5 to 1.5 weeks before administration of the PDT photosensitizer. In an alternative sequential treatment, the anti-angiogenic may be administered 0 to 4 weeks, more preferably 0 to 1 weeks after administration of the PDT photosensitie agent. If necessary, the anti-angiogenic may be sequentially administered both before and after PDT according to the schedule described above. Alternatively, the treatment is considered simultaneous if the anti-angiogenic is co-administered with the photosensitizer. Particular subjects may require multiple adjunctive PDT treatments or adjunctive PDT treatments with the anti-angiogenic and particular adjunctive PDT treatments may require multiple administrations of the anti-angiogenic drug.
Anti-angiogenic drugs, as the term is used herein mean drugs that work by preventing, inhibiting or reversing the growth of new blood vessels via the process commonly known as angiogenesis. Examples of anti-angiogenic drugs useful in adjunctive PDT include staurosporins, for example N-benzoyl-staurosporine, somatostatins, such as octreotide
(D)Phe-Cys-Phe-(D)Trp-Lys-Thr-Cys-Thr-ol j and steroids, such as triamcinolone. Other anti- angiogenic drugs useful in the present invention are VEGF inhibitors, such as CGP 79987D, CGP 57 148B or CGP 53716,
CGP 79787D CGP 53716
Figure imgf000004_0002
and the like. These anti-angiogenic drugs are particularly useful to inhibit the recurrence, reopening, development and / or progression of blood vessel growth that occurs during choroidal neovascularization, and offer significant benefits in adjunctive PDT. A preferred anti-angiogenic drug is selected from inhibitors of protein kinase C (PKC) (e.g., N- benzoyl-staurosporine), inhibitors of growth hormone and IGF-1 (e.g., octreotide), inhibitors of vascular endothelial growth factor (VEGF) (e.g., CGP 79787, N-benzoyl-staurosporine, CAM 781 ), inhibitors of cyclooxgenase II (e.g., diclofenac, COX 189), inhibitors of angiotensin II (e.g., valsartan), inhibitors of NF-kappa B, and PLA2 antagonists, more preferably from PKC inhibitors, VEGF inhibitors and from inhibitors of growth hormone and IGF-1.
A highly preferred anti-angiogenic drug is selected from an inhibitor of PKC and VEGF, in particular from an inhibitor of PKC. A highly preferred anti-angiogenic drug is selected from N- benzoyl-staurosporine, CGP 79787 and octreotide and in particular from N-benzoyl- staurosporine.
The preferred photosensitizers are selected from the group of a chlorine, a bacteriochlorine, a phthalocyanine, a porphyrin, a purpurin, a merocyanine, a pheophorbide and a psoralen.
A highly preferred photosensitizer is selected from the porphyrins and is typically the so-called green porphyrin or BPD-MA.
Any of the photosensitive compounds described above can be used in the method of the invention. Of course, mixtures of two or more photosensitive compounds can also be used; however, the effectiveness of the treatment depends on the absorption of light by the photosensitive compound so that if mixtures are used, components with similar absorption maxima are preferred.
The nature of the formulation used to deliver the anti-angiogenic drug or photosensitive agent will depend in part on the mode of administration and on the nature of the anti-angiogenic drug and the photoactive agent selected. Any pharmaceutically acceptable excipient, or combination thereof, appropriate to the particular active compounds may be used. Thus, the photosensitive agents or anti-angiogenic compounds may be administered as an aqueous composition, as a transmucosal or transdermal composition, as a subtenons or intraocuclar injection or in an oral formulation. The formulation may also include liposomes. Liposomal compositions are particularly preferred especially where the photoactive agent is a green porphyrin. The anti-angiogenic drug is preferably administered via an aqueous carrier.
The above mentioned compounds can be administered in any of a wide variety of ways, for example, orally, parenterally, or rectally, or the compound may be placed directly in or on the eye. Parenteral administration, such as intravenous, intramuscular, or subcutaneous, is preferred for the photosensitizer. Intravenous injection is especially preferred. Oral administration or ocular administration is preferred for administration of the anti-angiogenic agent.
The dose of the above compounds can vary widely depending upon the mode of administration; the formulation in which it is carried, such as in the form of liposomes, or whether it is coupled to a target-specific ligand, such as an antibody or an immunologically active fragment. As is generally recognised, there is a nexus between the type of photoactive agent, the formulation, the mode of administration, and the dosage level. The anti-antigenic drug is administered in a manner and amount sufficient to effect drug interaction with the unwanted neovasculature. The photosensitive agent is administered in an amount effective to provide closure to the unwanted neovasculature.
While various photoactive compounds require different dosage ranges, if green porphyrins are used, a typical dosage is of the range of 0.1-50 mg/m2 of body surface area, preferably from about 1-10 mg/m2 and even more preferably about 2-8 mg/m2.
While various anti-angiogenic compounds require different dosage ranges, a typical dosage is of the range of 1-500 mg/kg (of body weight) preferably from about 10-250 mg.
The irradiation (laser power, irradiation duration) is carried out in accordance to the prior art mentioned above, for example in accordance to the light treatment protocol of the disclosure of WO 97/33619.

Claims

CLAIMS:
1. Use of an anti-angiogenic drug in conjunction with a photosensitive agent in the preparation of a medicament for the improved photodynamic treatment of unwanted neovasculature due to CNV in a subject.
2. Use of claim 1 , wherein said improved photodynamic treatment comprises the steps of:
(a) administration of an effective amount of an anti-angiogenic drug to said subject;
(b) administration of an effective amount of a photosensitive agent to said subject; and (c) irradiating said unwanted neovasculature with light having a wavelength absorbable said photosensitive agent.
3. Use of claim 1-2, wherein said anti-angiogenic drug is administered 1 to 4 weeks before the administration of said photosensitive agent.
4. Use of claim 1-2, wherein the administration of said anti-angiogenic drug and said photosensitize agent is carried out simultaneously.
5. Use of claim 1-2, wherein the administration of the anti-angiogenic drug is carried out for 1 to 4 weeks after the administration of said photosensitize agent.
6. Use of claim 1 , wherein said anti-angiogenic drug is selected from inhibitors of protein kinase C, inhibitors of growth hormone and IGF-1 inhibitors of vascular endothelial growth factor, inhibitors of cyclooxgenase II, inhibitors of angiotensin II, inhibitors of NF-kappa B, and PLA2 antagonists.
7. Use of claim 6, wherein said anti-angiogenic drug is selected from inhibitors of PKC and VEGF, in particular from an inhibitor of PKC.
8. Use of claim 7, wherein said anti-angiogenic drug is selected from N-benzoyl- staurosporine, CGP 79787 and octreotide and in particular from N-benzoyl-staurosporine.
9. Use of claim 1 , wherein said photosensitizer agent is selected from a porphyrin and a purpurin and more preferably from a porphyrin.
10. A method for an improved treatment of unwanted neovasculature due to CNV in a subject, which method comprises;
(a) administration of an effective amount of an anti-angiogenic drug to said subject;
(b) administration of an effective amount of a photosensitive agent to said subject; and
(c) irradiating said unwanted neovasculature with light having a wavelength absorbable by said photosensitive agent.
PCT/EP2001/003265 2000-03-24 2001-03-22 Improved treatment of neovascularization WO2001074389A2 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
PL01359027A PL359027A1 (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
CA002403612A CA2403612A1 (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
BR0109499-8A BR0109499A (en) 2000-03-24 2001-03-22 Enhanced neovascularization treatment
HU0300347A HUP0300347A3 (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
JP2001572131A JP2003528926A (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
NZ521360A NZ521360A (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
IL15183301A IL151833A0 (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
UA2002097520A UA75350C2 (en) 2000-03-24 2001-03-22 Method for photodynamic treatment of undesirable subfoveal choroidal neovascularization using antiangiogenic agent
KR1020027012287A KR20020082487A (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
AU2001250401A AU2001250401B2 (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
EP01923695A EP1265636A2 (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
AU5040101A AU5040101A (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
EEP200200547A EE200200547A (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization
MXPA02009351A MXPA02009351A (en) 2000-03-24 2001-03-22 Improved treatment of neovascularization.
NO20024486A NO20024486L (en) 2000-03-24 2002-09-19 Improved treatment of neovascularization

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US19180700P 2000-03-24 2000-03-24
US60/191,807 2000-03-24

Publications (2)

Publication Number Publication Date
WO2001074389A2 true WO2001074389A2 (en) 2001-10-11
WO2001074389A3 WO2001074389A3 (en) 2002-07-11

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WO2003024420A1 (en) * 2001-09-14 2003-03-27 Novartis Ag Ophthalmic depot formulations for periocular or subconjunctival administration
EP1441743A2 (en) * 2001-11-09 2004-08-04 Eyetech Pharmaceuticals Methods for treating ocular neovascular diseases
FR2867189A1 (en) * 2004-03-08 2005-09-09 Ludovic Bourre New compound comprising protein kinase regulator and photoactivatable molecule, useful for treating protein kinase-related diseases, e.g. tumors and inflammation
WO2006015016A2 (en) * 2004-07-30 2006-02-09 Massachusetts Eye And Ear Infirmary Photodynamic therapy and compositions for treating ocular glaucoma
US7288106B2 (en) 2002-10-03 2007-10-30 Light Sciences Oncology, Inc. System and method for excitation of photoreactive compounds in eye tissue
WO2011087066A1 (en) 2010-01-14 2011-07-21 株式会社三和化学研究所 Pharmaceutical for preventing or treating disorders accompanied by ocular angiogenesis and/or elevated ocular vascular permeability
US8753673B2 (en) * 2006-05-23 2014-06-17 Taiwan Liposome Co. Ltd. Liposome composition for delivery of a therapeutic agent to eyes
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EP1940440A4 (en) 2005-08-29 2009-11-11 Healor Ltd Methods and compositions for prevention and treatment of diabetic and aged skin
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Cited By (13)

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Publication number Priority date Publication date Assignee Title
WO2002058730A3 (en) * 2000-11-01 2003-05-15 Allergan Inc Compositions for treatment of ocular neovascularization
WO2002058730A2 (en) * 2000-11-01 2002-08-01 Allergan, Inc. Compositions for treatment of ocular neovascularization
WO2003024420A1 (en) * 2001-09-14 2003-03-27 Novartis Ag Ophthalmic depot formulations for periocular or subconjunctival administration
EP1441743A2 (en) * 2001-11-09 2004-08-04 Eyetech Pharmaceuticals Methods for treating ocular neovascular diseases
EP1441743A4 (en) * 2001-11-09 2009-02-25 Eyetech Pharmaceuticals Methods for treating ocular neovascular diseases
US7288106B2 (en) 2002-10-03 2007-10-30 Light Sciences Oncology, Inc. System and method for excitation of photoreactive compounds in eye tissue
FR2867189A1 (en) * 2004-03-08 2005-09-09 Ludovic Bourre New compound comprising protein kinase regulator and photoactivatable molecule, useful for treating protein kinase-related diseases, e.g. tumors and inflammation
WO2006015016A3 (en) * 2004-07-30 2007-02-01 Massachusetts Eye & Ear Infirm Photodynamic therapy and compositions for treating ocular glaucoma
WO2006015016A2 (en) * 2004-07-30 2006-02-09 Massachusetts Eye And Ear Infirmary Photodynamic therapy and compositions for treating ocular glaucoma
US10272261B2 (en) 2004-07-30 2019-04-30 Massachusetts Eye And Ear Infirmary Methods and compositions for treating ocular glaucoma
US8753673B2 (en) * 2006-05-23 2014-06-17 Taiwan Liposome Co. Ltd. Liposome composition for delivery of a therapeutic agent to eyes
US9241996B2 (en) 2008-06-30 2016-01-26 Pci Biotech As Photochemical internalisation of kinase inhibitors
WO2011087066A1 (en) 2010-01-14 2011-07-21 株式会社三和化学研究所 Pharmaceutical for preventing or treating disorders accompanied by ocular angiogenesis and/or elevated ocular vascular permeability

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US20120203162A1 (en) 2012-08-09
US20010039438A1 (en) 2001-11-08
AU5040101A (en) 2001-10-15
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KR20020082487A (en) 2002-10-31
CN1420788A (en) 2003-05-28
AU2001250401B2 (en) 2005-08-11
US8862224B2 (en) 2014-10-14
HUP0300347A2 (en) 2003-06-28
CA2403612A1 (en) 2001-10-11
CN100398153C (en) 2008-07-02
KR20070114856A (en) 2007-12-04
WO2001074389A3 (en) 2002-07-11
NZ521360A (en) 2004-07-30
NO20024486D0 (en) 2002-09-19
IL151833A0 (en) 2003-04-10
US20060263392A1 (en) 2006-11-23
EE200200547A (en) 2004-02-16
US20080096865A1 (en) 2008-04-24
UA75350C2 (en) 2006-04-17
US8158669B2 (en) 2012-04-17
HUP0300347A3 (en) 2005-03-29
AR032151A1 (en) 2003-10-29
CZ20023174A3 (en) 2003-01-15
ZA200207638B (en) 2003-10-16
JP2003528926A (en) 2003-09-30
EP1265636A2 (en) 2002-12-18
RU2271222C2 (en) 2006-03-10
NO20024486L (en) 2002-09-19
BR0109499A (en) 2002-12-10
PL359027A1 (en) 2004-08-23

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