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Glaucoma Therapy: The Glaucoma Therapy: The “Art” of Medical “Art” of Medical Management Management
J. James J. James Thimons,O.D.,FAAOThimons,O.D.,FAAO
Medical Director, Medical Director, Ophthalmic Consultants Ophthalmic Consultants
of CTof CT
The Role of IOP The Role of IOP Management in Management in
GlaucomaGlaucoma
PEAK Effect with Evening DosePEAK Effect with Evening DoseOnce daily drug:Once daily drug:• Peak effectPeak effect (8 mm Hg) at 12-14 hrs (8 mm Hg) at 12-14 hrs
post dosepost dose• Trough effectTrough effect (2 mm Hg) at 22-24 (2 mm Hg) at 22-24
hrs hrs post dosepost dose
3
Courtesy of David B. Yan, M.D., F.R.C.S.(C)
0
1
2
3
4
5
6
7
8
9
0 200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400
IOP
Re
du
ctio
n (
mm
Hg)
Time of Day (hr)
Office hours
Trough
2:00
am
4:00
am
6:00
am
12:00
pm
8:00
am
10:00
am
2:00
pm
4:00
pm
6:00
pm
8:00
pm
12:00
am
10:00
pm
Time of Day (hr) Dose
IOP VariabilityIOP Variability
Highest (peak) IOP may commonly occur Highest (peak) IOP may commonly occur outside of usual clinic office hoursoutside of usual clinic office hours1,21,2
In spite of achieving target IOP during In spite of achieving target IOP during office hours patients may experience:office hours patients may experience:– ““damaging”/above target IOPs at other times damaging”/above target IOPs at other times
of the dayof the day– disease progressiondisease progression
Are we missing IOP spikes, peak, Are we missing IOP spikes, peak, damaging IOP, IOPs at other times of damaging IOP, IOPs at other times of dayday33??
1. Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.2. Mosaed S, et al. Am J Ophthalmol. 2005; 139(2): 320–324.3. Hughes E, et al. J of Glaucoma 2003; 12: 232-236.
4
PURPOSE:PURPOSE: To determine the relationship between office To determine the relationship between office IOP and peak IOPIOP and peak IOP
METHODS (Study One)METHODS (Study One)11:: 42 patients with OAG42 patients with OAG Treated with 3 different IOP lowering eye drops Treated with 3 different IOP lowering eye drops 24 hr IOP values obtained in sitting position with 24 hr IOP values obtained in sitting position with
Goldmann applanation tomography at 3 hr intervalsGoldmann applanation tomography at 3 hr intervalsMETHODS (Study Two)METHODS (Study Two)22:: 103 patients with OAG (including 35 untreated)103 patients with OAG (including 35 untreated) 24 hr IOP values obtained at 2 hr intervals using a 24 hr IOP values obtained at 2 hr intervals using a
pneumatometer, in sitting and supine positions during pneumatometer, in sitting and supine positions during the diurnal/wake period and in the supine position the diurnal/wake period and in the supine position during the nocturnal/sleep periodduring the nocturnal/sleep period
5
Peak IOP Outside Office Hours
1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324.
Peak IOP Outside Office Peak IOP Outside Office HoursHours
• 67% of peak 67% of peak IOP occurs IOP occurs outside office outside office hourshours22
6
Times at which maximum and Times at which maximum and minimum IOP occurred in a 24-hr minimum IOP occurred in a 24-hr
periodperiod11::
Time of maximum IOP in 24-hourTime of minimum IOP in 24-hour
8
Num
ber o
f eye
s
2819
10
40
30
20
10
03am-6am
9am-12pm
3pm-6pm
9pm-12am
2010 12
23
1.Nakakura S, et al. J Glaucoma 2007; 16(2): 201-204.2.Mosaed S, et al. Am J Ophthalmol. 2005; 139: 320-324.
Study 1Study 2
IOP is Higher at NightIOP is Higher at Night Higher nocturnal supine IOP than diurnal sitting IOP Higher nocturnal supine IOP than diurnal sitting IOP
(healthy and OAG)(healthy and OAG) Supine IOP higher than sitting IOP, regardless of time of daySupine IOP higher than sitting IOP, regardless of time of day
7
Habitual IOP of healthy eyes
IOP
(m
m H
g)
Habitual IOP of glaucomatous eyes
3:3
0 A
M
3:3
0 P
M
5:3
0 P
M7
:30
PM
9:3
0 P
M1
1:3
0 P
M1
:30
AM
5:3
0 A
M7
:30
AM
9:3
0 A
M
11
:30
AM
1:3
0 P
M
252423222120191817161514
26
Clock Time
n=24
Nocturnal
Supine
Nocturnal
Supine
Diurnal SittingDiurnal Sitting
Diurnal SittingDiurnal SittingNocturnal
Supine
Nocturnal
Supine
Diurnal SittingDiurnal Sitting
Diurnal SittingDiurnal Sitting
Clock Time
1:3
0 P
M
IOP
(m
m
Hg
)
252423222120191817161514
26
3:3
0 A
M
3:3
0 P
M
5:3
0 P
M
7:3
0 P
M
9:3
0 P
M1
1:3
0 P
M
1:3
0 A
M
5:3
0 A
M7
:30
AM
9:3
0 A
M
11
:30
AM
n=24
Liu JH et al. Invest Ophthalmol Vis Sci. 2003; 44: 1586-1590.
*Error bars = SEM*Error bars = SEM
Diurnal Fluctuations in IOP: Diurnal Fluctuations in IOP: Independent Risk Factor?Independent Risk Factor?
8
Asrani S, et al. J Glaucoma 2000; 9: 134-142.
PURPOSE: To study the risk associated with diurnal IOP variations in patients with OAG
METHODS:• 64 patients with OAG and IOP below 25 mm Hg (over 5 year
follow-up)• Patients successfully performed tonometry with a self-tonometer
5 times a day for 5 days• Baseline status and time to progression of visual field loss
identified from clinical charts• Level and variability of diurnal IOP characterized and risk of
progression analyzed using a nonparametric time-to-event model
9
0
1
2
3
4
5
6
Diurnal IOP range
3.1 mm Hg
Diurnal IOP range
5.4 mm Hg
1.0
5.76
Rela
tive
risk
of d
isea
se
prog
ress
ion
with
in 5
yea
rs
Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7
Hazard ratio between higher quartile and lower quartile for “Range in Home IOP” was 5.7
Diurnal Fluctuations Correlate with Visual Field Progression
Asrani S, et al. J Glaucoma 2000; 9: 134-142.
Patients on More ThanPatients on More ThanOne IOP-Lowering MedicationOne IOP-Lowering Medication
Source: Verispan’s PDDA, MAT Nov 2006.Source: Verispan’s PDDA, MAT Nov 2006.
69.8%
24.4%
5.6%
0.2%
1 Medication
2 Medications
3 Medications
4 Medications
Pathways to lower Intraocular Pathways to lower Intraocular PressurePressure
InflowInflow– Alpha 2- Alpha 2-
agonistsagonists– B1 blockersB1 blockers– CAICAI
Outflow Outflow – Alpha 2–Alpha 2–
agonistsagonists– CholinergicsCholinergics– Prostaglandins/ Prostaglandins/
ProstamindesProstamindes
Beta-blockersBeta-blockers 30 year history of successfully lowering 30 year history of successfully lowering
IOPIOP
Reduces aqueous humor formationReduces aqueous humor formation
Adrenergic agonistsAdrenergic agonists
Lowers IOP 22-28%Lowers IOP 22-28%
Ocularly well toleratedOcularly well tolerated
Beta BlockersBeta Blockers
Beta receptor in the ciliary body epitheliumBeta receptor in the ciliary body epithelium
Beta 1 receptors >> Beta 2 receptors in the Beta 1 receptors >> Beta 2 receptors in the eyeeye
Beta receptors stimulate productions of Beta receptors stimulate productions of aqueous.aqueous.
Beta blockers suppress aqueous productionBeta blockers suppress aqueous production
Beta-blockersBeta-blockers Timolol maleate – Timoptic, Timoptic Timolol maleate – Timoptic, Timoptic
XE (1/2, 1/4 %)XE (1/2, 1/4 %) Carteolol – Ocupress 1% (Intrinsic Carteolol – Ocupress 1% (Intrinsic
sympathomimetic activity)sympathomimetic activity) Levobunolol – Betagan ½%Levobunolol – Betagan ½% Timolol hemihydrate – Betimol ¼, ½%Timolol hemihydrate – Betimol ¼, ½% Istalol ¼,1/2% - QD dosing indicationIstalol ¼,1/2% - QD dosing indication Betaxolol ¼% - cardioselective, safer?Betaxolol ¼% - cardioselective, safer?
SystemicSystemic
BradycardiaBradycardia Congestive heart failureCongestive heart failure Exacerbation of heart blockExacerbation of heart block BronchospasmBronchospasm Mood changeMood change Impotence Impotence Lipid profileLipid profile
ContraindicationsContraindications
AsthmaAsthma Severs COPDSevers COPD CHFCHF Heart blockHeart block Myasthenia gravisMyasthenia gravis Diabetes Diabetes
Lama study (AJO 11/02)Lama study (AJO 11/02) Conclusions:Conclusions:
– ...identifies no scientific studies ...identifies no scientific studies supporting the development of supporting the development of worsening claudication, depression, worsening claudication, depression, hypoglycemia,sexual dysfunction or hypoglycemia,sexual dysfunction or impaired neuromuscular transmissionimpaired neuromuscular transmission
– Recommends careful medical history Recommends careful medical history and checking pulse rate and rhythmand checking pulse rate and rhythm
So?So?
TimololTimolol
Equally effective in Equally effective in AA’s and WhitesAA’s and Whites
IOP decrease 30-60 IOP decrease 30-60 minmin
Long term drift Long term drift – 47% decrease at 1 47% decrease at 1
wk wk – 25% at 1 yr 25% at 1 yr
Carteolol (ocupress)Carteolol (ocupress)
Intrinsic Intrinsic sympathomimetic sympathomimetic activityactivity
Less likely to Less likely to
increase systemic increase systemic lipid profilelipid profile
Ocular Side EffectsOcular Side Effects
Punctate keratopathyPunctate keratopathy
Corneal anesthesia ( Watch for DESx)Corneal anesthesia ( Watch for DESx)
BlepharoconjunctititisBlepharoconjunctititis
Brimonidine 0.1% AlphaganBrimonidine 0.1% Alphaganalpha-2 alpha-2
Decrease aqueous productionDecrease aqueous production Also increase uveoscleral outflow Also increase uveoscleral outflow
(small amount)(small amount) Not as effective as timolol but Not as effective as timolol but
closeclose May be neuroprotectiveMay be neuroprotective More effective than or More effective than or
dorzolamide?dorzolamide? Can cause mild mydriasisCan cause mild mydriasis Comes in 0.1%, 0.15%, 0.2%Comes in 0.1%, 0.15%, 0.2%
Brimonidine:Brimonidine:Dual Mechanism of IOP LoweringDual Mechanism of IOP Lowering
Enhances Enhances uveoscleral uveoscleral outflowoutflow
Suppresses Suppresses aqueous aqueous humor humor production production (inflow)(inflow)
Toris et al. 1995 and 1999. Toris et al. 1995 and 1999.
Brimonidine Formulation Brimonidine Formulation ComparisonComparison
ALPHAGANALPHAGAN®® P P ALPHAGANALPHAGAN®®
ConcentratioConcentration of n of BrimonidineBrimonidine
0.1%0.1% 0.15%0.15% 0.2%0.2%
pHpH 7.77.7 7.27.2 6.3-6.56.3-6.5
PreservativePreservative PURITEPURITE®® BAKBAK
Viscosity Viscosity agentagent
CarboxymethylcellulCarboxymethylcelluloseose Polyvinyl alcoholPolyvinyl alcohol
ElectrolytesElectrolytes
Potassium chloride, Potassium chloride, calcium chloride calcium chloride
dihydrate, dihydrate, magnesium chloride magnesium chloride
hexahydratehexahydrate
––
Side effectsSide effects
10-30% dry mouth10-30% dry mouth 10% allergy rate10% allergy rate Avoid with MAO Avoid with MAO
inhibitorsinhibitors Alphagan P 0.1%Alphagan P 0.1%
– Better toleratedBetter tolerated
Mean IOP at Peak (10 Mean IOP at Peak (10 amam))
Katz.Katz. J Glaucoma J Glaucoma. 2002.. 2002.
Brimonidine-PURITE® 0.15% (N = 372)
Brimonidine 0.2%* (N = 376)
16
18
20
22
24
26
28
30
0 2 4 6 8 10 12Months of treatment
*Original ALPHAGAN*Original ALPHAGAN®®
Me
an
IOP
(m
m H
g)
Mean IOP at Trough (8 Mean IOP at Trough (8 amam))
Katz.Katz. J Glaucoma J Glaucoma. 2002.. 2002.
16
18
20
22
24
26
28
30
0 2 4 6 8 10 12
Months of treatment
Brimonidine-PURITE® 0.15% (N = 372)
Brimonidine 0.2%* (N = 376)
*Original ALPHAGAN*Original ALPHAGAN®®
Me
an
IOP
(m
m H
g)
Alpha Agonists-side effectsAlpha Agonists-side effects
Ocular-Ocular-– dermatitis, dermatitis, – lid retraction, lid retraction, – conjunctival conjunctival
blanching, blanching, – allergic reactionsallergic reactions
Systemic Systemic – dry mouth, dry mouth, – dry eyedry eye– lethargy, lethargy, – apnea in apnea in
children,children,– hypotensionhypotension
ContraindicationContraindication
ChildrenChildren
MAO inhibitorsMAO inhibitors
Nocturnal Efficacy: Nocturnal Efficacy: Brimonidine MonotherapyBrimonidine Monotherapy
Liu JH, et al. Ophthalmology 2010; 117: 2075–2079.
29
PURPOSE: To investigate the effect of brimonidine monotherapy on IOP during the nocturnal/sleep period
DESIGN: Prospective, open-label studyMETHODS: • Baseline data of 24 hr IOP in untreated patients collected in a
sleep laboratory• Measurements of IOP taken using a pneumatonometer every 2 hrs
in sitting and supine positions during the 16 hr diurnal period and in supine position during the 8 hr nocturnal period
• Patients treated afterward with brimonidine 0.1% 3 times per day for 4 weeks, and 24 hr IOP data were collected under the same laboratory conditions
PURPOSE: To investigate the effect of brimonidine monotherapy on IOP during the nocturnal/sleep period
DESIGN: Prospective, open-label studyMETHODS: • Baseline data of 24 hr IOP in untreated patients collected in a
sleep laboratory• Measurements of IOP taken using a pneumatonometer every 2 hrs
in sitting and supine positions during the 16 hr diurnal period and in supine position during the 8 hr nocturnal period
• Patients treated afterward with brimonidine 0.1% 3 times per day for 4 weeks, and 24 hr IOP data were collected under the same laboratory conditions
02468
101214161820222426283.
30PM
5.30
PM
7.30
PM
9.30
PM
11.3
0PM
1.30
AM
3.30
AM
5.30
AM
7.30
AM
9.30
AM
11.3
0AM
1.30
PM
BaselineBrimonidine
30
NOCTURNAL/SLEEP
DIURNAL/WAKE
DIURNAL/WAKE
Hab
itual
IOP
(mm
Hg)
Clock Time
brimonidine
brimonidine
brimonidine
Brimonidine Efficacy During Nocturnal Period
Liu JH, et al. Ophthalmology 2010; 117: 2075–2079.
Error bars = SEMN = 15Error bars = SEMN = 15
Glaucoma & PregnancyGlaucoma & Pregnancy
BJO 2009; JD Ho: BJO 2009; JD Ho: 244 pregnant women treated for 244 pregnant women treated for
glaucoma analyzed for birth weightglaucoma analyzed for birth weight 1,952 age matched controls1,952 age matched controls No significant difference between No significant difference between
women on BB’s vs: no Txwomen on BB’s vs: no Tx Herndon, L: D/C Brimonodine several Herndon, L: D/C Brimonodine several
weeks before d/t risk of apnea weeks before d/t risk of apnea
COMBIGAN™COMBIGAN™(Brimonidine Tartrate/Timolol (Brimonidine Tartrate/Timolol Maleate Ophthalmic Solution) Maleate Ophthalmic Solution)
0.2%/0.5%0.2%/0.5%
Diurnal Mean IOP at Month 12Diurnal Mean IOP at Month 12
0
4
8
12
16
20
Brimonidine (n = 382)***
Timolol (n = 392)***
Fixed brimonidine/timolol (n = 385)
*P < .001 vs timolol
Mea
n I
OP
(m
m H
g)
8 AM 10 AM 3 PM 5 PM
**P < .001 vs brimonidine
Dose all treatments
Dose brimonidine
Sherwood et al. Sherwood et al. Arch OphthalmolArch Ophthalmol. 2006.. 2006.
*****
**
***
Statistical significance does not necessarily correlate to clinical significance. ***Brimonidine and timolol monotherapies are approved for first line therapy.
Treatment-Related Adverse EventsTreatment-Related Adverse Events
***
* ****
***
*
0
5
10
15
20
25
30
35
40Fixed Brimonidine/Timolol BID (n = 385)
Brimonidine 0.2% TID (n = 382)***
Timolol 0.5% BID (n = 392)***
* P ≤ .03 vs brimonidine 0.2% TID** P ≤ .02 vs timolol 0.5% BID
Sherwood et al. Sherwood et al. Arch OphthalmolArch Ophthalmol. 2006.. 2006.
Conjunctivalhyperemia
Ocularstinging
Eyepruritus
Allergicconjunctivitis
Conjunctivalfollicles
Oraldryness
Per
cen
tag
e o
f p
atie
nts
***Brimonidine and timolol monotherapies are approved for first line therapy.
15.2 15.3
21.9
0
4
8
12
16
20
24
0 1 2 3
COMBIGAN™ in Adjunctive Therapy COMBIGAN™ in Adjunctive Therapy With a PGA: Mean IOPWith a PGA: Mean IOPM
ean
IO
P (
mm
Hg
)
Month
-6.9 mm Hg(29%)
Added to a PGA baseline
* *
*P < .0001 vs baseline
COMBIGAN™(brimonidine tartrate/timolol maleate
ophthalmic solution) 0.2%/0.5% + PGA (n = 37)
11Nixon and Hollander. Nixon and Hollander. 22AAO, 2007. Data on file, Allergan, Inc.AAO, 2007. Data on file, Allergan, Inc.
COMBIGAN™ and COMBIGAN™ and CosoptCosopt®®
Randomized, investigator-masked, 3-month, parallel Randomized, investigator-masked, 3-month, parallel comparison comparison
Pooled data from 2 studies at 10 sites with identical Pooled data from 2 studies at 10 sites with identical protocols (Canada)protocols (Canada)
Patients with OAG/OHT requiring additional IOP Patients with OAG/OHT requiring additional IOP lowering lowering
Two subgroups Two subgroups – Monotherapy: COMBIGAN™(brimonidine tartrate/timolol maleate Monotherapy: COMBIGAN™(brimonidine tartrate/timolol maleate
ophthalmic solution) 0.2%/0.5% (n = 54) and ophthalmic solution) 0.2%/0.5% (n = 54) and CosoptCosopt®® (dorzolamide (dorzolamide hydrochloride-timolol maleate ophthalmic solution) (n = 47) hydrochloride-timolol maleate ophthalmic solution) (n = 47)
– Adjunctive: COMBIGAN™ added to PGA (n = 37) and Adjunctive: COMBIGAN™ added to PGA (n = 37) and CosoptCosopt®® added to PGA (n = 42) added to PGA (n = 42)
IOP 2 hours after morning doseIOP 2 hours after morning dose Visits at baseline, 1 month, and 3 monthsVisits at baseline, 1 month, and 3 months
PGA = prostaglandin analoguePGA = prostaglandin analogue 11Nixon and Hollander. AAO. 2007; Nixon and Hollander. AAO. 2007; 22Data on file, Allergan, Inc.Data on file, Allergan, Inc.
COMBIGAN™ and COMBIGAN™ and CosoptCosopt®® as as Monotherapy: Mean IOPMonotherapy: Mean IOP
Mean IOP reductions from baseline at month 3 were 7.7 mm Hg Mean IOP reductions from baseline at month 3 were 7.7 mm Hg with COMBIGAN™ and 6.7 mm Hg with with COMBIGAN™ and 6.7 mm Hg with CosoptCosopt®® ( (PP = .040) = .040)
Mea
n I
OP
(m
m H
g)
23.6
16.3 17.223.0
15.8 15.6
0
4
8
12
16
20
24
0 1 2 3Month
*
*P = 0.04 (mean change from baseline)Cosopt® (dorzolamide hydrochloride-timolol maleate
ophthalmic solution) (n = 47)
COMBIGAN™ (brimonidine tartrate/timolol maleate ophthalmic solution) 0.2%/0.5% (n = 54)
11Nixon and Hollander. AAO. 2007; Nixon and Hollander. AAO. 2007; 22Data on file, Allergan, Inc.Data on file, Allergan, Inc.
COMBIGAN™ and COMBIGAN™ and CosoptCosopt ®®
Tolerability and ComfortTolerability and Comfort
Per
cen
tag
e o
f p
atie
nts
wit
h
rati
ng
of
mo
der
ate
or
seve
re
0%
10%
20%
30%
40%
Stinging Burning Unusual taste
COMBIGAN™(brimonidine tartrate/timolol
maleate ophthalmic solution) 0.2%/0.5% (n = 85)
Cosopt® (dorzolamide hydrochloride-timolol
maleate ophthalmic solution) (n = 86)
P = .0001 P = .0149 P = .0047
11Nixon and Hollander. Nixon and Hollander. 22AAO, 2007. Data on file, Allergan, Inc.AAO, 2007. Data on file, Allergan, Inc.
Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors
4 types of isoenzymes4 types of isoenzymes I erythrocytes and corneal epitheliumI erythrocytes and corneal epithelium II non pigmented ciliary body II non pigmented ciliary body
epithelium , iris retinas lensepithelium , iris retinas lens III skeletal muscleIII skeletal muscle IV kidneyIV kidney
Carbonic Anhydrase InhibitorsCarbonic Anhydrase Inhibitors
Aqueous humor formation depends Aqueous humor formation depends on secretion of bicarbonate from the on secretion of bicarbonate from the ciliary processes when bicarbonate is ciliary processes when bicarbonate is formed, it tied with sodium and water formed, it tied with sodium and water followsfollows
Similar process in CSF production Similar process in CSF production and in kidney and in kidney
CAICAI
DorzolamideDorzolamide 2%2% BrinzolamideBrinzolamide 1%1% AcetazolamideAcetazolamide 125, 250, 125, 250,
500mg sequels500mg sequels Methazolamide Methazolamide 25, 50 mg25, 50 mg
Systemic Side Effects Oral UseSystemic Side Effects Oral Use Malaise and fatigue Malaise and fatigue Weight lossWeight loss AnorexiaAnorexia Loss of libidoLoss of libido Depression Depression Sulfa allergiesSulfa allergies Sickle cellSickle cell Marked kidney/liver Marked kidney/liver Low potassiumLow potassium Low sodium levelLow sodium level Transient myopiaTransient myopia
– Swelling of CBSwelling of CB
Pregnancy Category CPregnancy Category C ParesthesiaParesthesia TinitusTinitus NauseaNausea Taste alterationsTaste alterations Metabolic acidosisMetabolic acidosis
Contraindications to Oral Therapy Contraindications to Oral Therapy
Sulfa allergiesSulfa allergies Sickle cellSickle cell Marked kidney/liver Marked kidney/liver Low potassiumLow potassium Low sodium levelLow sodium level Pregnancy Category CPregnancy Category C Metabolic acidosisMetabolic acidosis
CAIs make wonderful partnersCAIs make wonderful partners Feldman, et al 2006 –Feldman, et al 2006 – 1.5-1.8 mm lower IOP as compared 1.5-1.8 mm lower IOP as compared
to brimonidine 0.15% when added to to brimonidine 0.15% when added to travaprosttravaprost
This significance was present at all This significance was present at all time pointstime points
BID dosingBID dosing
Companion study #2Companion study #2 When compared to brimonidine 2% When compared to brimonidine 2%
adding them to Travaprost...adding them to Travaprost... IOP lowered by 13% w/ brimonidineIOP lowered by 13% w/ brimonidine IOP lowered by 23% w/ brinzolamideIOP lowered by 23% w/ brinzolamide
Brinzolamide as an Brinzolamide as an Adjunct to LatanoprostAdjunct to Latanoprost
Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507.
46
PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%) as an adjunctive therapy to latanoprost (0.005%) in patients with open-angle glaucoma or ocular hypertension
METHODS: • 14 patients with open-angle glaucoma or ocular hypertension who
had been using latanoprost for more than 6 months were initiated on adjunctive brinzolamide therapy
• IOP values at 1, 2 and 3 months compared with baseline (beginning of adjunctive therapy)
• Incidence of adverse events examined
PURPOSE: To evaluate the IOP lowering effect of brinzolamide (1.0%) as an adjunctive therapy to latanoprost (0.005%) in patients with open-angle glaucoma or ocular hypertension
METHODS: • 14 patients with open-angle glaucoma or ocular hypertension who
had been using latanoprost for more than 6 months were initiated on adjunctive brinzolamide therapy
• IOP values at 1, 2 and 3 months compared with baseline (beginning of adjunctive therapy)
• Incidence of adverse events examined
47
Brinzolamide as an Adjunct to Latanoprost
Shoji N, et al. Cur Med Res Opin 2005; 21: 503-507.
21.1 ± 4.816.9 ± 4.5 16.6 ± 4.0 15.9 ± 3.1
0
5
10
15
20
25
30
Baseline 1 Month 2 Months 3 Months
IOP
(mm
Hg)
** P < 0.01 (Wilcoxon signed ranked test)
** ****
Adjunctive therapy lowered IOP by an additional Adjunctive therapy lowered IOP by an additional 5.2 mm Hg after 3 months5.2 mm Hg after 3 months
02468
101214161820222426
3.30
PM
5.30
PM
7.30
PM
9.30
PM
11.3
0PM
1.30
AM
3.30
AM
5.30
AM
7.30
AM
9.30
AM
11.3
0AM
1.30
PM
latanoprostlatanoprost + brinzolamidelatanoprost + timolol
48
Brinzolamide or Timolol: Adjunct to Latanoprost in an Open-Label Study
Liu JH, et al. Ophthalmology 2009; 116(3): 449-54.
N=26Error bars = SEMN=26Error bars = SEM
Clock Time
Hab
itual
IOP
(mm
Hg)
DIURNAL/WAKEDIURNAL/WAKE DIURNAL/WAKEDIURNAL/WAKENOCTURNAL/SLEEPNOCTURNAL/SLEEP
ProstaglandinsProstaglandins/Prostamides/Prostamides
Uveal seleral outflowUveal seleral outflow Affects many properties with the Affects many properties with the 1955-Ambache described irin which 1955-Ambache described irin which
medicated ocular response to medicated ocular response to inflammationinflammation
Naturally synthesized by trabecular Naturally synthesized by trabecular endothelial cells/ciliary muscle cellsendothelial cells/ciliary muscle cells
May have only minor inflammatoryMay have only minor inflammatory Regulatory effects Regulatory effects
ProstaglandinsProstaglandins/Prostamides/Prostamides
Different receptor sites DP,EP,IPDifferent receptor sites DP,EP,IP Prostaglandins E and F most effective Prostaglandins E and F most effective
in lowering IOPin lowering IOP They seem to facilitate aqueous They seem to facilitate aqueous
outflow via the uvealscleral pathwayoutflow via the uvealscleral pathway
Latanoprost 0.005%Latanoprost 0.005% XalatanXalatan– Prostaglandin F 2a analogueProstaglandin F 2a analogue– Prodrug Prodrug
Travoprost 0.004% Travoprost 0.004% TravatanTravatan– Prostaglandin F 2a analogueProstaglandin F 2a analogue– ProdrugProdrug
Brimatoprost 0.03%Brimatoprost 0.03% LumiganLumigan– Synthetic prostamide analogSynthetic prostamide analog– Not a prodrugNot a prodrug
Tafluprost ZioptanTafluprost Zioptan
- Non-preserved unit dose- Non-preserved unit dose
XLT Study – Parrish, Palmberg, et al.XLT Study – Parrish, Palmberg, et al.(AJO, May 2003, Vol. 135, No.5)(AJO, May 2003, Vol. 135, No.5)
Multicenter study to compare IOP Multicenter study to compare IOP lowering efficacy of Bimatoprost vs lowering efficacy of Bimatoprost vs Latanoprost vs TravaprostLatanoprost vs Travaprost
Also compared safety profiles of the 3 Also compared safety profiles of the 3 drugsdrugs
Conclusions: All 3 drugs were Conclusions: All 3 drugs were comparable in their ability to lower IOP at comparable in their ability to lower IOP at all time periods.all time periods.– Latanoprost exhibited greater ocular Latanoprost exhibited greater ocular
tolerabilitytolerability
PGAs: IOP-Lowering EffectsPGAs: IOP-Lowering EffectsPURPOSE:PURPOSE: To compare the IOP-lowering effect and safety of To compare the IOP-lowering effect and safety of
latanoprost, bimatoprost, and travoprostlatanoprost, bimatoprost, and travoprostMETHODS:METHODS: 12-week, randomized, parallel-group study conducted at 12-week, randomized, parallel-group study conducted at
45 45 US sites US sites
Previously treated patients with OAG or OH and an IOP ≥ Previously treated patients with OAG or OH and an IOP ≥ 23 mm Hg in one or both eyes after washout23 mm Hg in one or both eyes after washout
Received either latanoprost (0.005%), bimatoprost Received either latanoprost (0.005%), bimatoprost (0.03%), or travoprost (0.004%) once daily in the evening (0.03%), or travoprost (0.004%) once daily in the evening
At baseline and after 6 and 12 weeks of therapy, masked At baseline and after 6 and 12 weeks of therapy, masked evaluators measured IOP in triplicate at 8:00 AM, noon, evaluators measured IOP in triplicate at 8:00 AM, noon, 4:00 PM, and 8:00 PM. The primary efficacy outcome 4:00 PM, and 8:00 PM. The primary efficacy outcome measure was change between baseline and week 12 in measure was change between baseline and week 12 in the 8:00 AM IOPthe 8:00 AM IOP
57Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.
Primary OutcomePrimary Outcome
58
8 A.M. IOP reduction (mm Hg) from baseline 8 A.M. IOP reduction (mm Hg) from baseline to week 12:to week 12:
Latanoprost: 8.6 ± 3.7Latanoprost: 8.6 ± 3.7 Travoprost: 7.9 ± 3.4Travoprost: 7.9 ± 3.4 Bimatoprost: 8.7 ± 3.8Bimatoprost: 8.7 ± 3.8
Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.
59
Parrish et al., Am J Ophthalmol. 2003; 135(5): 688-703.
Adverse EffectsLatanoprost Latanoprost
(n=136)(n=136)Bimatoprost Bimatoprost
(n=137)(n=137)Travoprost Travoprost (n=138)(n=138)
nn No. eventsNo. events nn No. eventsNo. events nn No. No. eventsevents
hyperemiahyperemia 6464 7171 9494 110110 8080 9090
Eye irritationEye irritation 99 1010 1515 1616 66 66
Vision blurredVision blurred 00 00 55 55 22 22
Eye painEye pain 22 22 11 11 44 44
Growth of Growth of lasheslashes
00 00 44 44 11 11
Skin Skin discolorationdiscoloration
22 22 44 44 44 44
Dry eyeDry eye 22 22 33 33 22 22
Visual acuity Visual acuity reducedreduced
22 22 22 33 33 33
PruritusPruritus 00 00 00 00 33 33
Look at their failure rate:Look at their failure rate: Percent of pxs who didn’t reach their Percent of pxs who didn’t reach their
target IOPtarget IOP– Latanoprost – 14%Latanoprost – 14%– Bimatoprost- 6%Bimatoprost- 6%– Travaprost – 8%Travaprost – 8%
Adverse EffectsAdverse Effects
Changes to pigmented tissuesChanges to pigmented tissues– Iris pigmentation starts at pupil and spreads Iris pigmentation starts at pupil and spreads
concentricallyconcentrically– Long thick lashesLong thick lashes– Periobital pigment changesPeriobital pigment changes
Caution with macular edema, iris/uveitis, Caution with macular edema, iris/uveitis, keratitiskeratitis
Caution with renal/hepatic dysfunctionCaution with renal/hepatic dysfunction Pregnancy category CPregnancy category C
Prostaglandin Side EffectsProstaglandin Side Effects Iris pigmentationIris pigmentation
– Is it reversible?Is it reversible?– Is it pre-cancerous?Is it pre-cancerous?
Xalatan – 6.7% @ 6mthsXalatan – 6.7% @ 6mths 16% @ 12mths 16% @ 12mths
Travatan – 3% @ 12 mthsTravatan – 3% @ 12 mths Lumigan – 1.9% @ 12mthsLumigan – 1.9% @ 12mths
Other Prostaglandin side effectsOther Prostaglandin side effects CMECME UveitisUveitis Reactivation of HSKReactivation of HSK HypertrichosisHypertrichosis Periorbital skin darkeningPeriorbital skin darkening
One must take into consideration the One must take into consideration the benefits of low IOP with the risks of the benefits of low IOP with the risks of the side effectsside effects
TravatanTravatan(Travoprost 0.004%)(Travoprost 0.004%)
Lowers IOP 30-33% Lowers IOP 30-33% Contraindicated in pregnant womanContraindicated in pregnant woman Excellent responder rated in black Excellent responder rated in black
ptspts No CMENo CME
Responder rates in all patientsResponder rates in all patients
56.3% for IOP 17 mm Hg for travatan56.3% for IOP 17 mm Hg for travatan 49% for xalatan49% for xalatan 39% for timolol39% for timolol
PGAs: Effects on Circadian PGAs: Effects on Circadian IOPIOP
66
PURPOSE: To compare 24 hr reduction in IOP with latanoprost, travoprost and bimatoprost in patients with OAG and ocular hypertension (OH)
DESIGN: Randomized, double-masked, crossover studyPARTICIPANTS: 24 OAG and 20 OH patientsMETHODS: • Patients treated with randomized cross-over sequence of
latanoprost, travoprost and bimatoprost for 1 month each, with 30 day washout in between
• 24 hr tonometric curves were recorded at baseline (prior to each treatment) and after each treatment period in seated and supine positions
• Baseline and post-treatment IOP measured at 3:00, 6:00, 9:00 AM and noon and 3:00, 6:00, 9:00 PM and midnight
Orzalesi N, et al. Ophthalmology 2006; 113: 239-246.
Bimatoprost and Travoprost:Bimatoprost and Travoprost:12-Week Study12-Week Study
Parrish et al. Am J Ophthalmol. 2003.
Baseline mean IOP comparable between groupsBaseline mean IOP comparable between groups
Travoprost: 25.5, 23.8, 22.8, 22.0Travoprost: 25.5, 23.8, 22.8, 22.0 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg)Bimatoprost: 25.7, 23.8, 22.8, 22.3 Bimatoprost: 25.7, 23.8, 22.8, 22.3 (8 AM, 12 PM, 4 PM, 8 PM; mm Hg)
8 AM 12 PM 4 PM 8 PM
Time of Day
Mea
n I
OP
(m
m H
g)
0
4
8
12
16
20
24
Travoprost (n = 138)Bimatoprost (n = 136)
Mean IOP at Week 12
Travoprost AppearsTravoprost Appears Consistent Peak to Trough Consistent Peak to Trough
Peak-to-trough loss:Peak-to-trough loss:• Bimatoprost = 38%Bimatoprost = 38%• Latanoprost = 26%Latanoprost = 26%• Travoprost = 14%Travoprost = 14%
68
60%% o
f pea
k IO
P re
ducti
on(@
12
hr)
Time
65%
70%75%
80%
85%90%95%
100%
9:00am
3:00pm
9:00pm
12 hours post dose = peak IOP reduction 24 hours post dose = trough IOP reduction
TravoprostLatanoprostBimatoprost
Orzalesi N, et al. Ophthalmology 2006; 113: 239-246.
69
Effect of Travoprost on Diurnal and Nocturnal IOP
Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133.
PURPOSE: To assess the diurnal and nocturnal persistence of IOP reduction after omission of up to two doses of once-daily topical travoprost in patients with OAG or OH
DESIGN AND METHODS:• Prospective, open-label study• 20 patients underwent 24 hr IOP monitoring at baseline prior to
treatment and after 4 weeks or more of travoprost treatment
Effect of Travoprost on Diurnal Effect of Travoprost on Diurnal and Nocturnal IOPand Nocturnal IOP
Measured in the usual Measured in the usual “habitual position” of the “habitual position” of the patients during those time patients during those time periodsperiods
– Diurnal period – sittingDiurnal period – sitting– Nocturnal period – supineNocturnal period – supine
70
Sit AJ, et al. Am J Ophthalmol. 2006; 141(6): 1131-1133.
NOCTURNAL/SLEEP
DIURNAL/WAKEDIURNAL/WAKE28
26
24
22
20
18
16
14
3:30
PM
5:30
PM
7:30
PM
9:30
PM
11:3
0 PM
1:30
AM
3:30
AM
5:30
AM
7:30
AM
9:30
AM
11:3
0 AM
1:30
PM
Hab
itual
IOP
(mm
Hg)
Clock TimeBaseline “On Treatment”
Error bars = SEMError bars = SEM
Bimatoprost and Travoprost:Bimatoprost and Travoprost:6-Month Safety Results6-Month Safety Results
Both medications were well toleratedBoth medications were well tolerated Most common adverse event: ocular rednessMost common adverse event: ocular redness
– 16 patients (20.8%) in the bimatoprost group and 12 16 patients (20.8%) in the bimatoprost group and 12 patients (14.8%) in the travoprost group (patients (14.8%) in the travoprost group (PP = .326) = .326)
Ocular itching reported for 7.4% of travoprost Ocular itching reported for 7.4% of travoprost patients and 2.3% of bimatoprost patients (patients and 2.3% of bimatoprost patients (PP = .278)= .278)
Treatment-related adverse events leading to Treatment-related adverse events leading to patient discontinuations patient discontinuations – 8 patients in the travoprost group exited early: 4 for lack 8 patients in the travoprost group exited early: 4 for lack
of efficacy, 2 for ocular redness and lid erythema, 1 for of efficacy, 2 for ocular redness and lid erythema, 1 for ocular dryness and itching, and 1 for allergic symptoms ocular dryness and itching, and 1 for allergic symptoms
– 2 patients in the bimatoprost group exited early: 1 for 2 patients in the bimatoprost group exited early: 1 for blurry visionblurry visionand 1 for ocular redness and lid erythemaand 1 for ocular redness and lid erythema
Cantor et al. Br J Ophthalmol. In press.
Bimatoprost Bimatoprost (Lumigan 0.03%)(Lumigan 0.03%)
Lowers IOP 30-33%Lowers IOP 30-33% Favorable lowering of IOP with Favorable lowering of IOP with
lumigan vs xalatanlumigan vs xalatan Side effectsSide effects 15-45% hyperemia15-45% hyperemia 15% ocular pruritis15% ocular pruritis 45% Eyelash growth45% Eyelash growth CME rare CME rare
Bimatoprost and TimololBimatoprost and Timolol12-Month Study12-Month Study
Higginbotham et al. Arch Ophthalmol. 2002.
Bimatoprost QD (n = 474) Timolol BID (n = 241)
*P < .010 vs timolol
Target IOP (mm Hg)
Per
cen
tag
e o
f P
atie
nts
Rea
chin
g T
arg
et
IOP
at
10 A
M,
Mo
nth
12
≤
Target Pressures at Month 12
≤ ≤ ≤ ≤ ≤ ≤ ≤ ≤
**
*
*
*
*
**
*
25
9
16
26
37
47
61
69
712
21
31
47
58
69
77
85
0
10
20
30
40
50
60
70
80
90
12 13 14 15 16 17 18 19 20
Additional Intraocular Pressure Lowering (mm Hg)
-2
-2.5
-3.9-4.5
-4-3.5
-3-2.5
-2-1.5
-1-0.5
0
Alpha Agonist Beta-blocker TCAI
74
Additive IOP-Lowering Effect
O’Connor DJ, et al. Am J Ophthalmol. 2002; 133(6): 836-7.
N=25N=25
N=25N=25N=23N=23
Nocturnal Efficacy: Nocturnal Efficacy: Timolol vs. LatanoprostTimolol vs. Latanoprost
PURPOSE: PURPOSE: To compare the nocturnal effects of once-To compare the nocturnal effects of once-daily timolol and latanoprost on IOP daily timolol and latanoprost on IOP
DESIGN: DESIGN: Prospective, open-label, crossover studyProspective, open-label, crossover studyMETHODS: METHODS: 18 patients received topical treatments with timolol 18 patients received topical treatments with timolol
(0.5%), latanoprost (0.005%), and no IOP-lowering (0.5%), latanoprost (0.005%), and no IOP-lowering medication, for at least 4 weeksmedication, for at least 4 weeks
At the end of each treatment period, the patient was At the end of each treatment period, the patient was housed in a sleep laboratory for 24 hrs and IOP was housed in a sleep laboratory for 24 hrs and IOP was measured every 2 hrs using a pneumotonometermeasured every 2 hrs using a pneumotonometer
Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.
75
Clock Time
Hab
itual
IOP
(mm
Hg)
Sitting Supine Sitting
76
Timolol: Nocturnal IOP
Liu JH, et al. Am J Ophthalmol. 2004; 138: 389-395.
02468
10121416182022242628
3.30
PM
5.30
PM
7.30
PM
9.30
PM
11.3
0PM
1.30
AM
3.30
AM
5.30
AM
7.30
AM
9.30
AM
11.3
0AM
1.30
PM
No treatment
TimololN=18Error bars = SEMN=18Error bars = SEM
Can There be Too much Can There be Too much Prostaglandin?Prostaglandin?
Alverado, J; Oct 2009 UCSFAlverado, J; Oct 2009 UCSF Laboratory Analysis of Effect of SLT on Trabecular OutflowLaboratory Analysis of Effect of SLT on Trabecular Outflow SCE’s were exposed to six different IOP lowering drugs and SCE’s were exposed to six different IOP lowering drugs and
SLT/TME’sSLT/TME’s The junction assembly/dissassembly was monitored by The junction assembly/dissassembly was monitored by
confocal flourescent time lapse microscopyconfocal flourescent time lapse microscopy Latanaprost, bimatoprost & Travaprost shared a common Latanaprost, bimatoprost & Travaprost shared a common
mechanism of action with SLTmechanism of action with SLT– Widening of the paracellular pathwaysWidening of the paracellular pathways– Induction of intercellular junction dissassemblyInduction of intercellular junction dissassembly– Decreased transepithelial flow across SCE’sDecreased transepithelial flow across SCE’s
Clinical impact: TME’s play a critical role in regulating SCE’sClinical impact: TME’s play a critical role in regulating SCE’s Non-Competing IOP agents may improve IOP spot SLTNon-Competing IOP agents may improve IOP spot SLT
CholinergicsCholinergics
Cholinergics are bound by melanin and Cholinergics are bound by melanin and may need a high concentration to affect may need a high concentration to affect darker iridesdarker irides
Anticholinesterases have similar effects to Anticholinesterases have similar effects to cholinergicscholinergics
These medications facilitate outflow via These medications facilitate outflow via the trabecular meshworkthe trabecular meshwork
Echothiophate iodine may prolong the Echothiophate iodine may prolong the effects of succinylcholineeffects of succinylcholine
CholinergicsCholinergics
Generally contraindicated in Generally contraindicated in synechial angle closure, neovascular synechial angle closure, neovascular glaucomaglaucoma
Uveitic glaucoma, retinal detachment Uveitic glaucoma, retinal detachment of peripheral breaksof peripheral breaks
Pilocarpine pregnancy category CPilocarpine pregnancy category C Anticholinesterases contraindicated Anticholinesterases contraindicated
in pregnant womenin pregnant women
CholingegicsCholingegics
CholinergicsCholinergics– Pilocarpine HCLPilocarpine HCL 0.25%-10%0.25%-10%– Pilocarpine nitrated Pilocarpine nitrated 1%, 2%, 4%1%, 2%, 4%– Pilocarpine ocuserts Pilocarpine ocuserts 20%, 40%20%, 40%
Cholinesterase InhibitCholinesterase Inhibit– EchothiophateEchothiophate 0.03%, 0.06% 0.03%, 0.06%
0.125%0.125%– DemecariumDemecarium 0.125%, 0.25%0.125%, 0.25%
MixedMixed– CarbacholCarbachol 0.75%,1.5%, 2.25%, 0.75%,1.5%, 2.25%,
3.%3.%
PilocarpinePilocarpine
Low concentrations deepen chamberLow concentrations deepen chamber High concentrations may cause High concentrations may cause
pupillary blockpupillary block Increase axial length of the lens, Increase axial length of the lens,
shallows ACshallows AC Induce myopiaInduce myopia Decrease uveosclearl outflowDecrease uveosclearl outflow
Pilocarpine Pilocarpine
Cilary block (malignant) glaucoma is Cilary block (malignant) glaucoma is worsened with miotisworsened with miotis
Increase permeability of blood aqueous Increase permeability of blood aqueous barrierbarrier
Increase post-op inflammationIncrease post-op inflammation Need higher concentration in pigmented Need higher concentration in pigmented
iridesirides Max effect occurs in 2 hours last 8 hours; Max effect occurs in 2 hours last 8 hours;
12-15 hr still 14-15% reduction in IOP12-15 hr still 14-15% reduction in IOP
Pilo toxicity-WetPilo toxicity-Wet
SalivationSalivation LacrimationLacrimation SweatingSweating Vomiting/diarrheaVomiting/diarrhea Pulmonary edema/deathPulmonary edema/death Makes Parkinsons disease worse Makes Parkinsons disease worse
– (more acetylcholine than dopamine)(more acetylcholine than dopamine) 10 ml 1% pilocarpine, 100mg is dangerous10 ml 1% pilocarpine, 100mg is dangerous
Ocular Side EffectsOcular Side Effects
Conj Conj hyperemia/folliclehyperemia/follicle
MiosisMiosis Brow achesBrow aches EpitheliopathyEpitheliopathy MyopiaMyopia Shallowing of the Shallowing of the
ACAC IritisIritis
Pupillary cystsPupillary cysts
Lens opacitiesLens opacities
Retinal detachmentRetinal detachment
Pemphigoid type Pemphigoid type reactionreaction
Systemic side effectsSystemic side effects
DiarrheaDiarrhea BradycardiaBradycardia TearingTearing SalivationSalivation NauseaNausea DiaphoresisDiaphoresis Cramps Cramps