Download F In the Treatment of Glaucoma

Roles of Ginexin – F
In the
Treatment of Glaucoma
By
Professor Kamal Eldin Hussien ElTahir
Department of Pharmacology
College of Pharmacy
King Saud University
Riyadh
March - 2006
1
Description of the Eye •
2
Formation of the Aqueous Humour •
* The Anterior chamber is filled with an aqueous fluid •
called The Aqueous Humour
* It is synthesized in the ciliary Bodies in the Posterior •
Chamber via the enzyme carbonic anhydrase.
H2CO
H2 + CO2
–
* It flows to the Anterior chamber via the Pupil. •
* It provides Nutrition to the Iris, Lens and Cornea. •
* It drains out (Passes out the eye) via: •
a) The Trabecular meshwork.
b) Schlemm’s Canal.
c) Uveosclera.
into the venous circulation
3
Intraocular Pressure (IOP) •
* The Presence of the Aqueous Humour in the •
Anterior Chamber creates a pressure known as
the Intraocular Pressure (IOP).
* Its normal value is 18 - 20 mmHg. •
* It is regulated by the rate of synthesis and •
drainage outside the eye.
* Blockage of draining systems leads to •
elevation of the pressure. The fluid will be forced
backward into the Posterior Chamber and the
back of the eye – the site of the optic nerve and
the optic disk.
4
Differences between Ocular Hypertension and •
Glaucoma
* Ocular Hypertension: •
This is an increase of (IOP) without optic nerve or •
optic disk damage. There is no loss of the visual field.
* Glaucoma is a disease with or without clear rises in the
IOP above the normal range but it is definitely
accompanied by a progressive optic neuropathy leading
to a slow progressive degeneration of the Retinal
Ganglion Cells and Axons resulting in loss of Vision
(Blindness). It affects 66 million Subjects in the world.
* The degeneration of neurons may extend to the Lateral
Geniculate Nucleus and the Visual Cortex.
•
•
5
Causes of Glaucoma •
A) Blockage of the Drainage system for the •
Aqueous Humour leads to rises in the (IOP). The
fluid forces its way backward and thus the
pressure increases on the Retinal ganglion cells
and axons. This causes compressions and
deformations of these structures. As a result
there is decrease in the transport of proteins
nutrients and trophic factors across the retinal
nerves leading to degeneration and death of the
cells.
6
Non – IOP – Factors •
B) Besides the increase in the (IOP) other factors •
Contribute to the Retinal Nerves damage and loss of
vision:
(1) Deficiency of Ocular Blood flow to the Retinal •
Nerves. May be due to pressure of blood clots or
decreases in release of prostacyclin and [NO], the major
vasodilators. The resulting ischaemia and Hypoxia
damage the nerves.
(2) Excessive Release of the excitatory amino acid- •
glutamic acid which is a neurotransmitter in the Retinal
ganglionic cell and neurons. Indeed the level of
glutamate increases in the Posterior Chamber in
subjects with Glaucoma. Glutamate induces damage of
the retinal neurons via stimulation of Release of
Intracellular Ca2+.
7
Non – IOP – Factors (Contin.) •
(3)Increase in formation of free radicals e.g. •
(-. O2), -. OH, -. O-O-H •
These are highly damaging to the neurons. The -. OH
•
radicals are highly damaging to the Neuronal DNA.
(4) Increase in release of Inflammatory Mediators e.g.
•
TNF, PAF, PGE2, 5-HETE, 12-HETE, LTB4 from the
Glial cells and Astrocytes.
(5) Presence of auto antibodies against the optic nerve. •
(6) Decrease in activity of cellular Pumps. N.B. Once
•
Neurons are damaged they release free radicals and
neurotrans mitters to damage nearby unaffected
neurons.
8
Risk Factors in Glaucoma •
(1) Increase in Age ( in IOP) •
(2) High Myopia ( in IOP) •
(3) Increase in thickness of cornea above 555 μm ( in IOP). •
(4) Genetical heredity. In 3 – 4 % of glaucoma Patients there are
mutations in the Glaucoma Gene at the GLCIA locus known as
(Myocilin).
(5) Systemic Hypotension. •
(6) Defective vascular autoregulations. •
(7) Retinal Haemorrhages. •
(8) Cerebral Microvascular ischaemia. •
(9) Hypertension. •
(10) Migraine. (11) Retinal vessels vasospasms. •
(12) Smoking ( IOP) + Retinal vein occlusion. •
(13) Alcohol ( IOP). •
•
9
Types of Glaucoma •
(1) Primary open Angle Glaucoma. In this Type: •
* The Entrance to the Drainage System is open but there •
is Blockage inside the drainage canals.
* There is an elevation in IOP (Gradual). •
* Optic Disk and Nerve Damage. •
* The most common type in 90% of patients. •
(2) Closed Angle Glaucoma. In this type: •
* The openning of the Drainage System is narrowed. •
* When the Pupil enlarges the iris branches up over the •
drainage canal.
* The IOP rises quickly → Acute type or Gradual → •
Chronic closed or narrow Angle Glaucoma.
10
Types of Glaucoma (Contin.) •
Symptoms of closed-Angle Glaucoma: •
Headache, Eye Pain, Nausea Rainbows •
around lights at night and Blurred vision.
(3) Normal Tension Glaucoma: •
* Results from decrease in blood flow •
through the tiny arteries in the optic nerve.
11
Types of Glaucoma (Contin.) •
(4) Secondary glaucoma •
* Results following: •
Eye injury, Inflammation, Tumors, •
Cataract, Diabetes mellitus Chronic use of
steroids.
* May be of the open-or closed-type. •
12
Types of Glaucoma (contin.) •
(5) Pigmentary Glaucoma •
* This is a secondary open-angle glaucoma. •
* Results following the blockage of the drainage canals •
of the trabecular meshwork with small granules that
break from the back of the iris and flow with the aqueous
humour to close the canals and induce rise in the IOP.
(6) Pseudo-exfoliative Glaucoma •
* This is a Secondary open-angle glaucoma. •
* It Results when a flaky material peels off the outer layer •
of the lens and blocks the space between the angle of
the iris and the cornea of the eye resulting in inhibition of
flow of aqueous humour to the trabeculator meshwork.
Thus, No drainage of fluid.
* Observed in Scandinavian. •
13
Types of Glaucoma (contin.) •
(7) Neovascular Glaucoma: •
(Rubeotic Glaucoma) •
* It is a type of Secondary open-glaucoma. •
* It occurs in severe diabetes mellitus. •
A retinal vein may block in one eye leading to •
leakage of blood which activates the Retinal
cells leading to their damage and release of
Vascular Endothelial Growth Factor (VEGF).
* VEGF reaches the trabecular meshwork to •
stimulate growth of new blood vessels that also
spread to the iris. As a result the drainage
network is blocked leading to rise in IOP.
14
Diagnosis of Glaucoma via: •
(1) Measurement of the (IOP) using a •
Tonometer.
(2) Performance of Gonioscopy to check the •
openning or closure of the angle where the iris
meets the cornea.
(3) Performance of Ophthalmoscopy to examine •
the optic disk and Retinal nerves using an
Ophthalmoscope or preferably using Slit lamp
Biomicroscope with an indirect lens or a contact
lens to obtain an steroscopic view. This allows
observation of optic disk curving (cupping),
haemorrhages and retinal nerve fibre layer loss.
15
Diagnosis (Contin.) •
(4) Performance of automated Perimetry to •
assess the patient’s visual field.
The peripheral field vision is affected earlier than •
the central visual acuity. In this test, the patient
may be asked to look straight a head, then a
moving light is passed and he will be asked
when does the moving light pass his side vision.
Alternatively, white stimuli on white background
or blue stimuli against yellow backgrounds may
be used.
(5) Measure the cornea thickness using a •
Pachymeter.
16
Diagnosis (Contin.) •
(6) Performance of optic nerve and optic disk •
computer imaging using Optical Cohernce
Tomography (OCT).
This gives a contour map of the optic nerve, •
optic cup (disk) and Retinal Nerve Fibre
Thickness.
Or (7) Assess the thickness of the Retinal Nerve •
Fibre using Scanning Laser Polarimetry using a
GDX machine.
Or (8) Assess the Topography of the optic disk •
and the retinal surface to obtain Heidelberg
Retinal Tomography [HRT II] using a cofocal
Scanning Laser Opthalmoscope.
17
Treatment Strategy •
A) In glaucomas with elevated IOP, treatment should be directed to •
initially lower the IOP to 20 – 50% its initial level via drugs, laser
therapy or surgery.
B) In non-IOP- dependent glaucomas, treatment should be directed •
to enhance the retinal blood flow. A decrease in the IOP will also
benefit the patient indirectly by enhancing blood flow to the retinal
neurones.
C) In all types of glaucomas attempts should be made to administer •
neuroprotectors to prevent secondary degeneration of the
unaffected neurones. The neuroprotectors will act to prevent the
spread of degeneration from the affected retinal ganglion cells and
neurones to the yet undamaged ones. This can be obtained via
administration of drugs that are: Vasodilators, antioxidants,
antiglutaminergic at the N-methyl-D-Asparate receptor (NMDA), antiinflammatory and antiplatelets.
18
Treatment with Drugs
•
A) Drugs used to lower (IOP): •
Group A: Prostaglandins Analogues •
Eye Drops of: (1)Latanoprost [xalatan]. •
(2)Travoprost [Travatan] •
(3)Bimatoprost[Lumigan] •
(4)Unoprostone •
Mechanism of Action: •
a) They increase aqueous humour outflow through the •
uveoscleral pathway.
b) Activate the enzymatic activity of matrix metaloproteinases •
leading to remodeling of the extra cellular matrix and decrease of
resistance to outflow.
Side effects: Ocular irritation and redness, darkening of iris, macular
Oedema and lengthening and darkness of eye lashes.
•
19
Drugs (Contin.)
•
Group (B): β-Adrenoceptor Blockers. •
Eye Drops:(1)Timolol [Timpotic]0.25&0.5% •
(2)Betaxolol[Betopic]0.25&0.5% •
(3) Cartelol. •
Mechanism of Action: They inhibit production of the Aqueous humour.
Side effects: Eye dryness & irritation. •
•
Group (C): Carbonic Anhydrase Inhibitors: •
Eye Drops: (1) Brinzolamide [Azopt] 1%. •
(2) Dorzolamide. •
Tablets: (1) Acetazolamide [Diamox] 500mg. •
(2) Menthazolamide. •
Mechnism of Action: Inhibition of the enzyme cabonic anhydrase that is •
involved in the production of the Aqueous humour.
Side effects: For Drops: Eye Redness & irritation. •
For Tablets: Sedation, Parethesia, Anorexia, renal calculi, diarrhoea, fever. •
20
Drugs (Contin.) •
Group (D): Cholinergic Drugs: •
Eye Drops: (1) Pilocarpine [Isoptocarpine] 0.5-4%. •
(2) Carbachol. •
Mechanism of Action: They increase Aqueous humour
outflow.
Side effects: Miosis leading to blurred vision, •
Myopia and Headache (due to ciliaryspasm). •
Group (E): α2 –Adrenergic Agonists: •
Eye Drops: (1) Apraclonidine. •
(2) Primonidine. •
Mechanism of Action: Reduction in secretion of Aqueous
humour and increase in its outflow.
Side effects: Sedation, Redness and irritation of the eye,
conjuntivitis.
•
•
•
21
•
Introduction
Ginkgo biloba (Family):
•
Common Name: Maidenhair tree. •
Height
: 30 – 40 meters. •
Circumference : 4 meters. •
The Leaves
: Fan – shaped •
Green to Golden Yellow
Indigenous to : Korea, China & Japan. •
Known in China for: Over 5000 Years. •
Old Chinese uses : Circulation disorders •
Memory Disturbance
Asthma, Bronchitis
Introduction in Europe: 1730 •
in America : 1784 •
Start of Interest in it : 1965 •
In Germany •
•
•
•
22
Part of the Plant used: Leaves •
Constituents: •
a) Flavonoidal Glycosides •
(Mono –, bio – and tri – osides of:) •
Quercetin, Kaempferol, Isorhamnetin and 3´-O
methyl Myristicin.
b) Bioflavonoids: •
Bilobetin, Amentoflavone, Ginkgetin, 5-Methyl
Bilobtin and Isoginkgetin.
c) Tri Lactonic diterpenes: •
Ginkgolides A, B and C •
d) Tri Lactonic Sesquiterpene: •
Bilabolide •
e) Anthocyanin •
•
•
23
Cinkgo Extraction: Acetone: Water and Spray Drying. •
Standardization of Extraction: •
Standardized to Contain: •
24% Flavonoid glycosides •
6% Lactonic di- and sesqui-Terpenes •
Less than 0.6 mg Ginkgolic Acid per 100gm •
1Kg Extract = 70 Kg dried Leaves •
Pharmaceutical Forms: Capsules & Tablets, 40; 60; and
120 mg.
Trade Names: Ginexin – F; EGB 761;
Ginkgold; Ginkoba; GBE 24; Tebonin •
Status Classification: •
In USA: Dietry Supplement •
In Canada: Food Additive •
In France and Germany:As over–the Counter Drugs •
(No Prescription)
•
Availability : In more than 50 Countries •
24
Reported Pharmacological Actions •
1) Blockade of Platelets-Activiting Factor
(PAF) Receptors due to the Ginkgolides
and bilabolides.
2) Stimulation of Release of Nitric oxide [NO]
from the endothelia due to the anthocyanin.
3) As Anti-oxidant to scavenge oxygen free radicals
due to the flavonoids: Quercetin, Kaempferol and
isorhamntin.
4) Vasodilator to Blood vessels. •
It increases blood flow to tissues. •
5) Inhibition of Cyclic Guanosine monophospho
Diesterase (cGMPD).
•
•
•
•
25
Actions (Contin.) •
6) Release of prostacyclin from blood vessels (PGI2).
7) Decrease in blood triglycerides. •
8) Membrane Stabiliser. •
9) Stimulation of choline uptake by the Hippocampus
Increase in Ach.
10) Neurone protector. •
11) Inhibition of age-induced decrease in brain
muscarinic receptors.
12) Suppression of cerebral cortex and Retina
Oedemas.
13) It increases brain O2 and blood supply. •
14) It stimulates glucose influx and ATP production in
cells.
15) It helps the brain to record Information,
communicate ideas and recall concepts
•
༜
•
•
•
•
•
26
Ginexin – F As a Neuroprotector •
Properties that Qualify Ginexin – F to be as a Neuroprotector in •
Glaucomas:
(1) Ability to vasodilate peripheral and central blood vessels. Thus, •
it
a) enhances blood flow to various organs. •
(This is due to its non-flavone component) •
Via release of [NO] and [PGI2]. •
b) Antagonises ischaemia – induced inflammation and cellular •
damage.
c) Antagonises hypoxia – induced decrease in ATP and membranes •
break down.
d) Antagonises ichaemia-induced decrease in Plasminogen •
activating factor and increase in Plasmingen activator inhibition.
Thus, it enhance fibrinolytic activity.
e) Enhances glucose uptake by cells. •
f) Antagonises the retinal artery occlusion-induced oedema and •
necrosis.
27
Ginexin-F properties •
(2) Inhibits formation of O2 Radicals & scavenging them via its •
flavonoidal components: Quercetin, Kaempferol and isorhamnetin.
Furthermore, it
a)Stimulates production of reduced glutathione that protects cell •
membranes from the damaging action of lipid & other peroxides.
b)It increases the level of glutathione disulphide redctase (GDS) that
acts to regenerate reduced glutathione as follows:
4 -. O-O-H Reduced glutathione
2H2O + O2 •
+peroxidase
peroxides
+ •
Glutathione
disulphide(GDS)
GDS – Reductase
Reduced Glutathione
•
c) prevents conversion of low density lipoprotein cholestrol to the •
cytotoxic oxysterols.
•
•
28
Ginexin-F (properties) •
d) Inhibits oxidative stress-induced mitochondrial •
aging and damage leading to maintenance of
ATP production.
(3) Antagonises PAF-induced Platelets •
aggregation and enhances blood fluidity i.e. it
decreases its viscosity and thus helps in blood
flow to organs.
(4) Decreases glutamic acid-induced neuronal •
damage and elevation of the harmful
intracellular Ca2+ levels via antagonism of PAF
that enhaces glutamic acid actions.
29
Ginexin-F (properties) •
(5) Inhibits glutamate-induced elevation of •
intracellular Ca2+ ions that damage cells and
neurones. This is attributed to the flavonoids and
bilobalide components.
(6) Enhances regeneration of damaged nerves •
via its bilobalide component.
(7) Antagonises proteolytic enzymes-induced •
retinal cell damage.
(8) Inhibits PAF-induced inflammation due to its •
ginkogolides and bilabolide.
(9) Protects retinal ganglion cells from cautery- •
induced retinal degeneration.
30
Use of Ginexin-F in Glaucoma •
(1) Intake of 40 mg 3x daily for 4weeks by •
glaucoma patients produced significant
improvement in the visual field indices but
did not decrease (IOP).
(2) Treatment of glaucoma patients with •
Ginexin-F 40mg 3x daily for 2 days
significantly increased the velocity of blood
flow in the ophthalmic artery by 23% but
did not affect (IOP).
31
Treatment of Glaucoma (Contin.) •
B] Laser treatment: •
(1) In primary open Angle glaucoma, Laser •
Traberculoplasty Techniques are used. The Laser rays
are directed to the Trabecular meshwork to reduce their
resistance to the Aqueous humour outflow.
(2) In advanced cases of primary open Angle •
glaucoma, the laser rays are applied to the white sclera
to damage the ciliary bodies to reduce Aqueous humour
secretion.
(3) In closed Angle glaucoma, the cornea is •
anaesthetized, a contact lens is placed on the eye and a
laser shot is given to make a hole in the iris to allow
passage of fluid from the posterior chamber to the
anterior chamber & hence to outside the eye.
32
Concluding Remark •
Ginexin-F seemed to have a high potential in •
treating of glaucomas if combined with IOP
lowering drugs. It has a high potential to act as a
Neuroprotector to prevent the spread of the
damage that occurred in some retinal ganglion
cells & neurones to unaffected cells. Its benefit
will be high if it is started early as soon as the
neuronal damage is detected. It is hoped that
further clinical trials and studies will establish its
role as a neuroprotector.
33
Summary of Glaucoma’s Treatments •
Glaucoma Type
1) Closed Angle
Treatment
Initially Eye drops + a
few days later Laser
2) Pigmentry
Eye drops + Surgery
3) Neovascular
Eye drops + Laser.
Laser stops prodction
of VEGF in Retina
cells
Eye drops + Surgery
4) Pseudoexfoliative
34