Vegf inhibitors for ophthalmic use
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Transcript of Vegf inhibitors for ophthalmic use
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PROCESS OF ANGIOGENESIS
• Induction– Vasodilation and increased
permeability of preexisting vessels
– Activated endothelial cells release proteases to degrade matrix
– Endothelial cells proliferate and migrate
– Proliferating cells adhere to one another
• Resolution– Differentiation and maturation
of blood vessels
CLASSIFICATION OF VEGF
• The archetypal member of the VEGF family is VEGF – A.
• Other members are 1. Placental growth factor (PGF), 2. VEGF – B, 3. VEGF – C, and 4. VEGF – D.
• A new member of VEGF – – Related family encoded by viruses (VEGF – E)– In the venom of some snakes (VEGF – F ) have also been
discovered.
TYPE OF VEGF FUNCTIONS
VEGF – A AngiogenesisIncreases migration of endothelial cellsIncreases mitosis of endothelial cellsIncreases matrix metalloproteinase activityCreation of blood vessel lumenCreates fenestrationChemotactic for macrophages and granulocytes Vasoilation ( Indirectly by NO release )
VEGF – B Embryonic angiogenesis (myocardial tissue to be specific )
FUNCTIONS
TYPE OF VEGF FUNCTIONS
VEGF – C Lymphangiogenesis
VEGF – D Development of lymphatic vasculature surrounding lung bronchioles.
Placental Growth Factor (PGF)
VasculogenesisAngiogenesis during ischemiaInflammationWound healing andCancer
FUNCTIONS
CLINICAL SIGNIFICANCE
VEGF in disease : VEGF – A has been implicated with poor prognosis in breast cancer.
Numerous studies show a decreased overall survival and disease free survival in those tumors overexpressing VEGF.
The overexpression of VEGF – A may be an early step in the process of metastasis.
•VEGF – A is also released in Rheumatoid arthritis in response to TNF – α , increasing endothelial permeability and swelling and also stimulating angiogenesis.
CLINICAL SIGNIFICANCE
• VEGF – A plays a role in the disease pathology of the wet form Age related macular degeneration,which is the leading cause of blindness for the elderly of the industrialized world.
• The vascular pathology is similar to diabetic retinopathy with some differences in neovascularization.
• VEGF – D levels are significantly elevated in patients with Angiosarcoma.
CLINICAL SIGNIFICANCE
• Patients suffering from pulmonary emphysema have decreased levels of VEGF in the pulmonary arteries.
• In kidneys, increased expression of VEGF – A in glomeruli directly causes the glomerular hypertrophy that is associated with proteinuria.
• VEGF alternatives can be predictive of early onset pre-eclampsia.
• The best studied of angiogenic factors is VEGF.• VEGF initiates endothelial cell proliferation when
it binds to a member of VEGF receptor (VEGFR) family, a group of highly homologous receptors with intracellular tyrosine kinase domain that includes
• - VEGFR1(FLT1)• - VEGFR2(KDR)• - VEGFR3(FLT4)
VEGF RECEPTORS
RECEPTOR BIOLOGY
• All members of the VEGF family stimulate cellular responses by binding to Tyrosine kinase receptors (the VEGFRs) on the cell surface
• Binding leads to dimerization and activation through transphosphorylation
The VEGF receptors have 1. An extracellular portion consisting of 7
immunoglobulin - like domains, 2. A single transmembrane spanning region and 3. An intracellular portion containing a split tyrosine-
kinase domain.
RECEPTOR BIOLOGY• VEGF-A binds to VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1)
• VEGFR-2 appears to mediate almost all of the known cellular responses to VEGF
• The function of VEGFR-1 is less well defined, although it is thought to modulate VEGFR-2 signaling
• Another function of VEGFR-1 is to act as a dummy/decoy receptor, sequestering VEGF from VEGFR-2 binding.
• VEGFR-3 mediates lymphangiogenesis in response to VEGF-C and VEGF-D
RECEPTORS AS TARGETS
• Antibodies directed at the primary angiogenic factor. VEGF decreases the interstitial pressure within the tumors and reverse the changes in oxygenation and blood flow.
• By “normalizing” interstitial pressure and improving blood flow, anti angiogenic agents enhance the ability of chemotherapeutic agents to reach the tumor.
• Hence, an additional benefit of antiangiogenic molecule may be their ability to increase the delivery of chemotherapy to the tumor.
Anti - VEGF THERAPIES
• Anti-VEGF therapies are important in the treatment of certain cancers and in age-related macular degeneration.
• can involve :• monoclonal antibodies eg. Bevacizumab• antibody derivatives eg. Ranibizumab• Oral Tyrosine kinase inhibitors
• Lapatinib• Sunitinib• Sorafenib • Axitinib • Pazopanib
Anti - VEGF THERAPIES
OTHERS : THC and Cannabidiol inhibit VEGF and slow Glioma growth in Brain.
• A 2014 Cochrane Systematic Review studied the effectiveness of ranibizumab and Pegaptanib, on patients suffering from macular edema caused by central retinal vein occlusion.– Participants on both treatment groups showed
improvement in visual acuity measures and a reduction in macular edema symptoms over six months.
Braithwaite T, Nanji AA, Greenberg PB (2010). "Anti-vascular endothelial growth factor for macular edema secondary to central retinal vein occlusion". Cochrane Database Syst Rev 10: CD007325
REPORTS FROM PRECLINICAL STUDIES
• Several animal models have demonstrated that tumor secretion of proangiogenic factors turns on an “angiogenic switch” a process essential to tumor growth and metastasis.
• In multiple experimental models, blockade of these proangiogenic molecules halts tumor growth and in human cancers antiangiogenic drugs also have inhibitory effects.
BEVACIZUMAB
• Recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting VEGF-A
• It received its first approval in 2004, for combination use with standard chemotherapy for metastatic colon cancer
• It has since been approved for use in – Certain lung cancers, – Renal cancers, – Ovarian cancers– Glioblastoma multiforme of the brain
USE IN EYE DISEASE
• Bevacizumab has been successfully used to inhibit VEGF and slow the progress of Age-related macular degeneration (AMD) & diabetic retinopathy
• Recently been used by ophthalmologists in an off-label use as an intravitreal agent in the treatment of proliferative (neovascular) eye diseases – particularly for Choroidal neovascular
membrane (CNV) in AMD.
ADMINISTRATION AND DOSING
• In ophthalmology, Bevacizumab is typically given by transconjunctival intravitreal injections into the posterior segment
• Intravitreal injections for retinal pathologies are typically administered at 4-6 week intervals, although this varies widely based on disease and response.
• DOSE: The typical dose is 1.25mg in 0.05ml in adults,and half that dose in babies.
PHARMACOKINETICS
Absorption• Time to reach steady state is predicted to be
100 days.
Elimination• Estimated half-life is approximately 20 days
DRUG INTERACTIONS
• Irinotecan/5–fluorouracil/leucovorin: The incidence of epistaxis and GI hemorrhage, minor gum bleeding, vaginal hemorrhage) .
• Live vaccines: Coadministration of live vaccines may result in a reduced immune response.
• Paclitaxel: Decreased paclitaxel exposure when given in combination with bevacizumab.
• Sunitinib: Coadministration of Bevacizumab and sunitinib has been reported to cause unexpected severe toxicity (eg, microangiopathic hemolytic anemia). – Coadministration of Sunitinib and Bevacizumab is not
recommended.
ADVERSE REACTIONS
• Cardiovascular: Hypertension, thromboembolism• CNS: headache, dizziness, sensory neuropathy• Dermatologic: Alopecia (32%)• GI:Abdominal pain, vomiting, anorexia• Genitourinary: Proteinuria, vaginal hemorrhage• Hematologic-Lymphatic:Bleeding/hemorrhage,
leukopenia, neutropenia• Respiratory: Upper respiratory tract infection, epistaxis
PEGAPTANIB
• Approved for the treatment of neovascular (wet) age-related macular degeneration(AMD)
• Pegaptanib is a pegylated anti-vascular endothelial growth factor (VEGF) aptamer, a single strand of nucleic acid
• Pegaptanib specifically binds to the 165 isoform of VEGF
MEANS OF ADMINISTRATION
• Administered in a 0.3 mg dose once every six weeks by intravitreal injection
• Marketed as a pre-filled syringe
Precautions: indicated for ophthalmic intravitreous injection.
• It is contraindicated in patients with ocular or periocular infections.
PHARMACOKINETICS
• Absorption• C max approximately 80 ng/mL and occurs within 1 to 4 days after 3 mg monocular dose
• Metabolism• Following a 3 mg monocular dose, plasma t ½ is about 10 days
RANIBIZUMAB
• Available as Injection, intravitreal 10 mg/mL• Binds to and inhibits the biologic activity of VEGF-A
Pharmacokinetics:• Absorption: – C max is below the concentration thought necessary to inhibit biological activity of VEGF-A by 50% (0.3 to 2.36 ng/mL).
– T max is 24 h.
• Elimination: Vitreous elimination half-life is approximately 9 days.
AFLIBERCEPT
• Recombinant fusion protein consisting of VEGF-binding portions from the extracellular domains of human VEGF receptors 1 and 2, that are fused to the Fc portion of the human IgG1 immunoglobulin
INDICATIONS & ADMINISTRATION
• Administered as an intravitreal injection for the treatment of wet macular degeneration
• Also indicated for the treatment of visual impairment due to diabetic macular oedema
CONTRAINDICATIONS:• Contraindicated in patients with infections or active inflammations of or near the eye
CONCLUSION
"New indication for Eylea". The Pharmaceutical Journal (7826) (Royal Pharmaceutical Society). 27 Aug 2014. Retrieved 20 September 2014