EP4346859A1 - Use of hispidulin combination in the treatment of proliferative vitreoretinopathy - Google Patents

Use of hispidulin combination in the treatment of proliferative vitreoretinopathy

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Publication number
EP4346859A1
EP4346859A1 EP23824891.8A EP23824891A EP4346859A1 EP 4346859 A1 EP4346859 A1 EP 4346859A1 EP 23824891 A EP23824891 A EP 23824891A EP 4346859 A1 EP4346859 A1 EP 4346859A1
Authority
EP
European Patent Office
Prior art keywords
hispidulin
pvr
treatment
cells
rpe
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.)
Pending
Application number
EP23824891.8A
Other languages
German (de)
French (fr)
Inventor
Suat ERDOGAN
Ruveyda GARIP
Sultan KAYA
Riza SERTTAS
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Trakya Ueniversitesi
Original Assignee
Trakya Ueniversitesi
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Trakya Ueniversitesi filed Critical Trakya Ueniversitesi
Priority claimed from PCT/TR2023/050752 external-priority patent/WO2024039330A1/en
Publication of EP4346859A1 publication Critical patent/EP4346859A1/en
Pending legal-status Critical Current

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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine

Definitions

  • the present invention relates to the formation of therapeutic combinations of the natural hispidulin molecule for use in the treatment of proliferative vitreoretinopathy (PVR) by formulating it with single and/or 5 -fluorouracil (5-FU) or taxol group chemotherapeutic agents.
  • PVR proliferative vitreoretinopathy
  • hispidulin is applicable in the pharmaceutical industry. Due to the potential of hispidulin to be used as a single or in combination with a low dose of 5-FU or docetaxel in the treatment of PVR, hispidulin has the property of being made into a single or combined preparation by pharmaceutical companies.
  • Proliferative vitreoretinopathy a common cause of severe vision loss or blindness, is an important eye health problem that develops in the failure of a ruptured retinal detachment (RD) repair.
  • Defects in the retina cause the migration of retinal pigment epithelium (RPE) and glial cells with proliferative potential to the vitreous cavity. It is a clinical syndrome associated with retinal traction and detachment in which cells proliferate and contract on the retinal surfaces and vitreous. Exposure of RPE and glial cells to growth factors and cytokines activates the pathogenic mechanisms of PVR. Cells migrate, multiply, and produce extracellular matrix proteins that suppress retinal traction.
  • PVR The critical step in the development of PVR is RPE metaplasia to fibroblast-like cells in the process known as mesenchymal transition from the epithelial. Severe PVR can complicate about 10% of cases of retinal detachment surgery, resulting in failure or requiring reoperation.
  • 5-FU in the posterior segment of the eye damages the photoreceptor cells.
  • 5-FU transforms into 5- fluorouridine, which is its active metabolite in the cell, creating an antiproliferative and anticontractile effect by inhibiting timidylate synthetase.
  • intraocular 5-FU combined with vitrectomy resulted in only 60% anatomical success in eyes with PVR.
  • VEGF Vascular endothelial growth factor
  • anti-VEGF drugs involved in the pathogenesis of PVR are well tolerated and are widely used in the treatment of disorders such as age-related macular degeneration and diabetic macular edema, among others.
  • VEGF Vascular endothelial growth factor
  • retinoic acid a vitamin A derivative that regulates cellular differentiation, has been reported to increase the reconnection rate of the retina in the treatment of PVR-complicated RD.
  • hispidulin (5,7-Dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-l-benzopyran-4-one, 4',5,7- Trihydroxy-6-methoxyflavone, 6-Methoxyapigenin, Salvitin, 6-Methylscutellarein, Dinatin, Scutellarein 6-methyl ether) in natural flavone structure applied at low concentration can completely block the RPE cell proliferation and migration prominent in this disease.
  • TGF-P2 Transforming growth factor beta 2
  • the natural hispidulin molecule contained in the invention has not been previously used and reported in the treatment of PVR disease by being formulated with single and/or 5-FU or taxol group chemotherapeutic agents. There are also no patents covering the results obtained according to the scans. Therefore, the results obtained for PVR therapy within the scope of the invention are unique.
  • Figure 1 (A) % effect of hispidulin on concentration and time-dependent RPE cell survival. Molecular structure of hispidulin, (B) 24 hours, (C) 48 hours, and (D) 72 hours of treatment efficacy. *P ⁇ 0.005 control group (0).
  • Figure 2 The efficacy of hispidulin in combination with single, 5-FU or docetaxel in the TGF-P2 induced PVR model; (A) hispidulin single or combined treatment with 5-FU in the RPE cell series, (B) apoptosis efficacy of treatment in the RPE cell series, (C) hispidulin single or combined treatment with 5-FU in bovine primary RPE cells, (D) hispidulin single or combined treatment with docetaxel in the RPE cell series. *p ⁇ 0.005 compared to the control group (0), **p ⁇ 0.001 TGF-P2 group. (His: hispidulin; 5-FU: 5-fluorouracil; Doc: docetaxel; RPE: retinal pigment epithelial cells; TGF-P2: transforming growth factor beta 2).
  • Figure 3 Single administration of hispidulin or its combination with 5-FU blocks RPE migration.
  • Combined therapy of RPE cells with 3 pM hispidulin and 50 nM 5-FU in the TGF- P2-induced PVR model inhibits cell migration (A, B).
  • Low-dose therapy significantly inhibited mRNA expression of the transcription factors Snail (C), Twist (D) and ZEB1 (E) involved in cell migration.
  • His hispidulin
  • 5-FU 5-fluorouracil
  • Doc docetaxel
  • RPE retinal pigment epithelial cells
  • TGF-P2 transforming growth factor beta 2.
  • Figure 4 The combination modality regulates the expression of several genes involved in cell migration.
  • the combination of low concentration hispidulin and 5-FU downregulates MMP1, MMP2, MMP7, MMP9 ( Figure A-D) and fibronectin (F) mRNA expression induced by TGF-P2.
  • the treatment modality upregulates mRNA expression of occludin (E) and N- cadherin (G)*p ⁇ 0.001 compared to the control group (untreated), **p ⁇ 0.05 compared to the TGF-P2 group, # p ⁇ 0.01 compared to the TGF-P2 group.
  • His hispidulin
  • 5-FU 5- fluorouracil
  • Doc docetaxel
  • RPE retinal pigment epithelial cells
  • TGF-P2 transforming growth factor beta 2.
  • TGF-P2 Transforming growth factor beta 2
  • the commercially obtained hispidulin was dissolved in dimethyl sulfoxide (DMSO) to obtain the doses of 0.78 pM, 1.56 pM, 3.12 pM, 6.25 pM, 12.5 pM, 25 pM, 50 pM and 100 pM. By testing these concentrations, it was observed that the strongest PVR inhibitory effect was 3 pM with the least toxic effect.
  • 5-FU solution which is sold as a ready-made preparation, is diluted with DMSO solution and doses of different concentrations were obtained. Among the doses obtained, the least toxic effect and the most PVR inhibitory effect were observed with 1 pM hispidulin + 50 nM 5-FU.
  • the natural hispidulin molecule contained in the invention has not been previously used and reported in the treatment of PVR disease by being formulated with single and/or 5-FU or taxol group chemotherapeutic agents.

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

Abstract

The present invention relates to the formation of therapeutic combinations of the natural hispidulin molecule for use in the treatment of proliferative vitreoretinopathy (PVR) by formulating it with single and/or 5-fluorouracil (5-FU) or taxol group chemotherapeutic agents.

Description

USE OF HISPIDULIN COMBINATION IN THE TREATMENT OF PROLIFERATIVE VITREORETINOPATHY
Technical Field
The present invention relates to the formation of therapeutic combinations of the natural hispidulin molecule for use in the treatment of proliferative vitreoretinopathy (PVR) by formulating it with single and/or 5 -fluorouracil (5-FU) or taxol group chemotherapeutic agents.
The invention is applicable in the pharmaceutical industry. Due to the potential of hispidulin to be used as a single or in combination with a low dose of 5-FU or docetaxel in the treatment of PVR, hispidulin has the property of being made into a single or combined preparation by pharmaceutical companies.
State of the Art (Background)
Proliferative vitreoretinopathy (PVR), a common cause of severe vision loss or blindness, is an important eye health problem that develops in the failure of a ruptured retinal detachment (RD) repair. Defects in the retina cause the migration of retinal pigment epithelium (RPE) and glial cells with proliferative potential to the vitreous cavity. It is a clinical syndrome associated with retinal traction and detachment in which cells proliferate and contract on the retinal surfaces and vitreous. Exposure of RPE and glial cells to growth factors and cytokines activates the pathogenic mechanisms of PVR. Cells migrate, multiply, and produce extracellular matrix proteins that suppress retinal traction. The critical step in the development of PVR is RPE metaplasia to fibroblast-like cells in the process known as mesenchymal transition from the epithelial. Severe PVR can complicate about 10% of cases of retinal detachment surgery, resulting in failure or requiring reoperation.
Although a number of molecular targets have been investigated for the prevention and treatment of PVR, none have yet shown evidence of systematic benefit in humans. PVR remains a challenging clinical condition that can limit the success of RD repair, especially in sedentary and severe cases. Although surgical innovations have greatly improved PVR outcomes in recent years, resistant cases remain. Therefore, there is a need for effective pharmacological agents that can be used in the treatment of PVR.
Currently, there is no proven pharmacological agent for the treatment or prevention of PVR. The ability to manage this disease has been significantly improved by modem surgical methods, especially vitrectomy. However, permanent limitations to surgical success lead to the investigation of molecular targets. The most commonly studied and clinically used molecules in the medical treatment of PVR are anti-proliferative agents that inhibit cell proliferation and reduce experimental tractional retinal detachment, especially compounds such as 5 -fluorouracil (5-fluorouracil, 5-FU), daunorubicin, taxol, vincristine, cisplatin, mitomycin, colchicine, retinoic acid, and daptomycin. However, the clinical value of these substances is limited due to toxic undesirable side effects. For example, the use of 5-FU in the posterior segment of the eye damages the photoreceptor cells. 5-FU transforms into 5- fluorouridine, which is its active metabolite in the cell, creating an antiproliferative and anticontractile effect by inhibiting timidylate synthetase. In human studies, it was reported that intraocular 5-FU combined with vitrectomy resulted in only 60% anatomical success in eyes with PVR.
The intraocular inflammatory environment developing in PVR is an important aspect of PVR pathophysiology, so steroids have been explored as a potential therapeutic option. Although corticosteroids have the potential to greatly reduce the production of growth factors that contribute to mechanisms of action and membrane formation, in a randomized, controlled clinical study of patients at high risk of developing PVR, treatment with systemic corticosteroids was shown not to improve visual acuity while causing a decrease in epiretinal membrane formation. Combination therapies of low molecular weight heparin (LMWH) or steroids, an anticoagulant that binds many growth factors with 5-FU, reduce fibrin after vitrectomy, inhibit RPE proliferation, bind fibrogenic growth factors, and reduce experimental tractional retinal detachment. However, further clinical research on these combinations has proven that they do not show a beneficial effect on established PVR or unselected primary retinal detachments, but rather worsen visual acuity. According to the results of a different clinical study, the combination of 5-FU and LMWH does not improve the primary or final anatomical success rate of primary vitrectomy surgery for retinal detachment, nor does it make a statistical difference in the incidence of PVR in the treatment and placebo groups.
Vascular endothelial growth factor (VEGF), anti-VEGF drugs involved in the pathogenesis of PVR are well tolerated and are widely used in the treatment of disorders such as age-related macular degeneration and diabetic macular edema, among others. However, according to the results of the study, there was no decrease in the rate of retinal detachment in the subjects who received 1.25 mg intravitreal bevacizumab at the end of vitrectomy surgery for RD with grade C PVR. In addition, according to the results of a prospective study conducted for treatment purposes, retinoic acid, a vitamin A derivative that regulates cellular differentiation, has been reported to increase the reconnection rate of the retina in the treatment of PVR-complicated RD.
According to several clinical trials, it wasobserved that the administration of vitamin A derivative oral 13-cis-retinoic acid or microtubule inhibitor colchicine after the operation reduces PVR and increases the retinal attachment rate after surgical repair. In recent years, substances obtained from foods with pharmaceutical potential have attracted increasing attention in various clinical disciplines and diseases. Flavonoid applications have been demonstrated to have different therapeutic potentials by reversing anti-inflammatory, antiproliferative, antioxidant effects and epithelial-mesenchymal transition. However, according to the results of all experimental and clinical research, PVR therapy does not yet have an effective treatment option. Therefore, there is a need to develop new approaches in the treatment of PVR.
Brief Description and Objects of the Invention
According to the experimental results for the treatment of proliferative vitreoretinopathy, hispidulin (5,7-Dihydroxy-2-(4-hydroxyphenyl)-6-methoxy-4H-l-benzopyran-4-one, 4',5,7- Trihydroxy-6-methoxyflavone, 6-Methoxyapigenin, Salvitin, 6-Methylscutellarein, Dinatin, Scutellarein 6-methyl ether) in natural flavone structure applied at low concentration can completely block the RPE cell proliferation and migration prominent in this disease. Demonstration of anti -PVR effect in commercial human RPE cell series (ARPE-19) and primary RPE cells obtained from bovine eyes in an in vitro experimental environment proved that hispidulin can be a potential candidate molecule. Transforming growth factor beta 2 (TGF-P2) is one of the peptides responsible for PVR development and is often used in modeling. According to the results obtained within the scope of the invention, proliferation increases by 30% in cells exposed to 10 ng/ml TGF-P2 for 48 hours, while the migration of cells is also encouraged. However, treatment of these TGF-P2 treated cells with 3 pM hispidulin inhibits cell proliferation by 100% while greatly suppressing cell migration. Moreover, the concentration of hispidulin used for control purposes does not cause toxicity to cells.
As a second alternative, it was also tested in the model created with 5-FU or taxol derivative docetaxel, which is most commonly used for treatment in PVR disease that develops in humans. Accordingly, 150 nM 5-FU or 3 nM docetaxel treatment to RPE cells exposed to 10 ng/ml TGF-P2 strongly suppresses cell proliferation and migration. However, the fact that these pharmacological agents are chemotherapy drugs causes the development of side effects. Therefore, 100% suppression of cell proliferation in PVR by reducing these chemotherapeutics by 2/3 at a dose of 50 nM 5-FU or 1 nM docetaxel and in combinations with 1 pM hispidulin indicates that hispidulin can be used as a single in the treatment of PVR or reduced by 2/3 with the specified chemotherapeutics. Reducing the use of 5-FU or docetaxel together with the non-toxic hispidulin molecule in its natural structure by 2/3 in treatment will also reduce or terminate its side effects.
The natural hispidulin molecule contained in the invention has not been previously used and reported in the treatment of PVR disease by being formulated with single and/or 5-FU or taxol group chemotherapeutic agents. There are also no patents covering the results obtained according to the scans. Therefore, the results obtained for PVR therapy within the scope of the invention are unique.
Definitions of Figures Describing the Invention
The figures and related descriptions required to better understand the subject of the invention are as follows. Figure 1: (A) % effect of hispidulin on concentration and time-dependent RPE cell survival. Molecular structure of hispidulin, (B) 24 hours, (C) 48 hours, and (D) 72 hours of treatment efficacy. *P<0.005 control group (0).
Figure 2: The efficacy of hispidulin in combination with single, 5-FU or docetaxel in the TGF-P2 induced PVR model; (A) hispidulin single or combined treatment with 5-FU in the RPE cell series, (B) apoptosis efficacy of treatment in the RPE cell series, (C) hispidulin single or combined treatment with 5-FU in bovine primary RPE cells, (D) hispidulin single or combined treatment with docetaxel in the RPE cell series. *p<0.005 compared to the control group (0), **p<0.001 TGF-P2 group. (His: hispidulin; 5-FU: 5-fluorouracil; Doc: docetaxel; RPE: retinal pigment epithelial cells; TGF-P2: transforming growth factor beta 2).
Figure 3: Single administration of hispidulin or its combination with 5-FU blocks RPE migration. Combined therapy of RPE cells with 3 pM hispidulin and 50 nM 5-FU in the TGF- P2-induced PVR model inhibits cell migration (A, B). Low-dose therapy significantly inhibited mRNA expression of the transcription factors Snail (C), Twist (D) and ZEB1 (E) involved in cell migration. *p<0.001 compared to the control (untreated), **p<0.001 compared to the TGF-P2 group. (His: hispidulin; 5-FU: 5-fluorouracil; Doc: docetaxel; RPE: retinal pigment epithelial cells; TGF-P2: transforming growth factor beta 2).
Figure 4: The combination modality regulates the expression of several genes involved in cell migration. The combination of low concentration hispidulin and 5-FU downregulates MMP1, MMP2, MMP7, MMP9 (Figure A-D) and fibronectin (F) mRNA expression induced by TGF-P2. The treatment modality upregulates mRNA expression of occludin (E) and N- cadherin (G)*p<0.001 compared to the control group (untreated), **p<0.05 compared to the TGF-P2 group, #p<0.01 compared to the TGF-P2 group. (His: hispidulin; 5-FU: 5- fluorouracil; Doc: docetaxel; RPE: retinal pigment epithelial cells; TGF-P2: transforming growth factor beta 2).
Detailed Description of the Invention
Demonstration of anti -PVR effect in commercial human RPE cell series (ARPE-19) and primary RPE cells obtained from bovine eyes in an in vitro experimental environment proved that hispidulin can be a potential candidate molecule. Transforming growth factor beta 2 (TGF-P2) is one of the peptides responsible for PVR development and is often used in modeling. According to the results obtained within the scope of the invention, proliferation increases by 30% in cells exposed to 10 ng/ml TGF-P2 for 48 hours, while the migration of cells is also encouraged. However, treatment of these TGF-P2 treated cells with 3 pM hispidulin inhibits cell proliferation by 100% while greatly suppressing cell migration. Moreover, the concentration of hispidulin used for control purposes does not cause toxicity to cells.
As a second alternative, it was also tested in the model created with 5-FU or taxol derivative docetaxel, which is most commonly used for treatment in PVR disease that develops in humans. Accordingly, 150 nM 5-FU or 3 nM docetaxel treatment to RPE cells exposed to 10 ng/ml TGF-P2 strongly suppresses cell proliferation and migration. However, the fact that these pharmacological agents are chemotherapy drugs causes the development of side effects. Therefore, 100% suppression of cell proliferation in PVR by reducing these chemotherapeutics by 2/3 at a dose of 50 nM 5-FU or 1 nM docetaxel and in combinations with 1 pM hispidulin indicates that hispidulin can be used as a single in the treatment of PVR or reduced by 2/3 with the specified chemotherapeutics. Studies have shown that 5-FU suppresses PVR pathogenesis. However, it shows certain toxic effects on photoreceptor cells in the retina at doses where it is effective. It is known that the expected visual levels may not be achieved in the postoperative period due to these toxic effects. For this reason, the doses at which the strongest effect could be achieved were tried by minimizing the toxic effect of 5- FU and docetaxel. In the dose studies, these chemotherapeutics were reduced in various doses and their combination with hispidulin was examined. In line with the data obtained, reducing the use of 5-FU and docetaxel together with the non-toxic hispidulin molecule in the natural structure by 2/3 in treatment may also reduce or terminate the toxic side effects on the retina.
In the experimental study, the commercially obtained hispidulin was dissolved in dimethyl sulfoxide (DMSO) to obtain the doses of 0.78 pM, 1.56 pM, 3.12 pM, 6.25 pM, 12.5 pM, 25 pM, 50 pM and 100 pM. By testing these concentrations, it was observed that the strongest PVR inhibitory effect was 3 pM with the least toxic effect. In combination treatments, 5-FU solution, which is sold as a ready-made preparation, is diluted with DMSO solution and doses of different concentrations were obtained. Among the doses obtained, the least toxic effect and the most PVR inhibitory effect were observed with 1 pM hispidulin + 50 nM 5-FU.
The natural hispidulin molecule contained in the invention has not been previously used and reported in the treatment of PVR disease by being formulated with single and/or 5-FU or taxol group chemotherapeutic agents.

Claims

1. A pharmaceutical composition, characterized in that it comprises the following:
• hispidulin molecule and 5 -fluorouracil (5-FU) chemotherapeutic agent or
• hispidulin molecule and taxol group chemotherapeutic agent.
2. The pharmaceutical composition, characterized in that the taxol group chemotherapeutic agent is docetaxel.
3. The composition comprising hispidulin molecule for use in the treatment of proliferative vitreoretinopathy (PVR).
4. Use according to Claim 3, characterized in that 3 pM of the hispidulin molecule is used.
5. The pharmaceutical composition according to Claim 1, for use in the treatment of proliferative vitreoretinopathy (PVR).
6. Use according to Claim 5, characterized in that 1 pM hispidulin and 50 nM 5-FU are used.
7. Use according to Claim 5, characterized in that 1 pM hispidulin and 1 nM docetaxel are used.
EP23824891.8A 2022-08-17 2023-07-31 Use of hispidulin combination in the treatment of proliferative vitreoretinopathy Pending EP4346859A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR202213022 2022-08-17
PCT/TR2023/050752 WO2024039330A1 (en) 2022-08-17 2023-07-31 Use of hispidulin combination in the treatment of proliferative vitreoretinopathy

Publications (1)

Publication Number Publication Date
EP4346859A1 true EP4346859A1 (en) 2024-04-10

Family

ID=90124908

Family Applications (1)

Application Number Title Priority Date Filing Date
EP23824891.8A Pending EP4346859A1 (en) 2022-08-17 2023-07-31 Use of hispidulin combination in the treatment of proliferative vitreoretinopathy

Country Status (1)

Country Link
EP (1) EP4346859A1 (en)

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