S'c' Infusion of Apomorphine in PD

1
Apomorphine
Autoscoring Protocol On-Off Symptomatology
dysc
"on"
"off"
6 7 8 9 10 11 12 13 14 15 16 17
18 19 20 21 22
Time
L-dopa
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Apomorphine Pharmacology
Synthesis Morphine is reduced with HCl
Structure Tertiary amine
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Apomorphine Pharmacology
OH
OH
HO
HO
H
N
N
CH3
H
Dopamine
Dihydro-aporphine
- The R-enantiomer is the active form - To
inhibit oxidation Antioxidants and acid
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S.c. Apomorphine Injec- tions Pharmacology
OH
HO
N
CH3
Distribution T1/2 5 min Elimination T1/2 33 min
(syst. oxidation) Mean response latency 5-10 min
(1.5-32) Mean effect duration 58 min
(12-120) Mean optimal dose 2.8 mg (0.2-7)
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Subcutaneous Apomorphine Injections
Effect on UPDRS motor Score
Change from baseline
100
50
10
20
Time (min)
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Apomorphine History

• 1869 first synthesized
• Shortly after
• - emetic, anti-manic and anti-spasmodic
  effects were first described

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Apomorphine History

• First used as emetic drug, also as
• Sedative
• Against alcohol abuse
• Against homosexual/perverse behaviour
• Expectorative
• Muscle relaxation
• Against dystonia, against chorea
• Aphrodisiacum, at erectile dysfunction
• Because of side effects otherwise limited
  attention

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Apomorphine History

• Effect in Parkinsons disease
• Suggested 1884 (Mechanism unknown)
• 1951, Robert Schwab et al., Boston Effect
  against tremor and rigidity in Parkinsons
  disease
• Limited use because of
• short halflife, no system for administration,
  side effects (nausea, vomiting, postural
  hypotension, vertigo, sedation, bradycardia)

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Apomorphine History
Effect of apomorphine and domperidone in 4
patients with Parkinsons disease Corsini
G.U. et al., Lancet 1979
Case 1 2 3 4
Sex M M F F
Age 59y 64y 61y 61y
NaClApomorphine SE Improvement Nausea 27.
5 Sedation Hypotonia Nausea 40.3 Tiredness Yawn
ing Tiredness 35.6 Hypotonia Yawning Nausea 30.4
Tiredness
DomperidoneApo SE Improvement No 36.7
Yawning 49.2 Yawning 41.9 Yawning 43.3
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S.c. Apomorphine injec- tions Pharmacology
OH
HO
N
CH3

• Effect Degree and quality identical to that of
  L-dopa
• High inter-, low intra-individual variation
  because of absorption (Dose failure differing
  absorption rates, influenced e.g. by skin
  temperature and blood flow)
• No clinically relevant tolerance
• Higher doses Faster effect, longer effect,
  unchanged degree of effect

11
Apomorphine Test

• Method
• Domperidone (3 x 10-20 mg), 24-72 hours
• No Parkinson medication gt12 hours
• Injection of 1.5, 3....10 mg (or 1, 2, 3...10
  mg, or single dose 3 mg) Apomorphine s.c. each
  30-90 min. until effect (UPDRS III (gt18
  improvement), Hand-Arm Movements (gt15
  improvement) or walking (gt20 improvement) before
  and 20 min after injection) or severe SE

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Apomorphine Test

• Aim of apomorphine test
• Diagnosis Establish dopaminergic effect
• Prognosis for effect of chronic therapy
• Research purposes

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Apomorphine Test Studies Publication
year Number of patients Oertel 1989 42 Hughes 1
990 100 DCosta 1991 28 Hughes 1991 45 Bonuc
elli 1992 25 Gasser 1992 62 Schelosky 1993 4
1 Bonucelli 1993 37 Linazasoro 1993 43 Schwarz
1993 83 Roth 1994 39 Miranda 1995 32
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Metaanalysis/Apomorphine Test Hughes, 1999 340
Patients, 8 Publ

• Prognosis for L-dopa effect in idiopathic
  Parkinsons disease
• Positive predictive value 97
• Negative predictive value 63

• Diagnosis of idiopathic PD among Parkinson
  syndroms
• Positive predictive value 93
• Negative predictive value 73

Investigations Oertel et al., 1989, Hughes et
al., 1990, DCosta et al., 1991, Hughes et al.,
1991, Bonucelli et al., 1992, Gasser et al.,
1992, Bonucelli et al., 1993, Schelosky et al.,
1993
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Metaanalysis/Apomorphine Test Hughes, 1999 340
Patients, 8 Publ

• Prognosis for L-dopa effect in de novo idiopathic
  Parkinsons disease
• Positive predictive value 96
• Negative predictive value 60

• Diagnosis of idiopathic Parkinsons disease among
  
• de novo patients
• Positive predictive value 98
• Negative predictive value 29

Investigations Oertel et al., 1989, Hughes et
al., 1990, DCosta et al., 1991, Hughes et al.,
1991, Bonucelli et al., 1992, Gasser et al.,
1992, Bonucelli et al., 1993, Schelosky et al.,
1993
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Mean UPDRS III improvementin PD, non-PD, MSA und
PSPRossi et al., 2000 (134 Patienten)
PD, Non-PD, MSA, PSP,
NC, ------------------------------------------
--------------------------------------------------
---------------- Apomorphine 1.5 mg 27.1
10.5 11.9 12.4 9.6 Apomorphine 3
mg 27.7 9.7 14.3 5.8 7.6 Apomorphine
4.5 mg 28.8 11.8 13.3
6.9 11.4 Levodopa 250 mg 29.8 12.2 12.8
13.4 13.1
Supports diagnosis IPD UPDRS III-improvement
gt18 (closest to 80 sensitivity and 80
specificity). Speaks for effect of chronic
L-dopa therapy UPDRS III-improvement gt14.5.
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L-dopa/Apomorphine Test Summary

• Consensus Albanese et al., 2001 Challange
  tests are useful in diagnosis and treatment of
  PD
• Important Many patients with typical IPD have
  negative tests (negative test must be interpreted
  carefully)
• Some people with for example MSA might have
  positive tests for years
• L-dopa/Apomorphine test is rather to be seen as a
  marker for L-dopa effect than for IPD diagnosis.

Neurology
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Subcutaneous Apomorphine Injections
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S.c. Apomorphine Injections

• Procedure (in ward!)
• Domperidone (3 x 10-20 mg), 24-72 hours
• Oral parkinson medications unchanged
• Injection of 50 of the titrated dose
  (Apomorphine test) or 1 mg at the onset of an
  off episode
• Increase the dose in 0.5-1.0 mg intervals until
  optimal effect

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Subcutaneous Apomorphine Injections

• Method
• 5. Optimal dosis at beginning of off. Injection
  repeated after 15 minutes, if no effect
• Evaluate effect. Discharge patient
• Stop domperidone

Apo
Apo
Apo
Apo
8
9
10
12
13
14
15
16
17
18
19
20
11
21
Subcutaneous Apomorphine Injections
off-time per day Without Apo 50.0
(25-70) With Apo (10.2 mo) 26.5 (14-45) With
Apo (42.2 mo) 29.5 (10-50)
Without Apo
10 mo Apo
42 mo Apo
No tachyphylactic effect
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Subcutaneous Apomorphine Injections
No of "off-periods Without Apo 4.0
(1-8) With Apo 5.0 (3-8)
Without Apo
With Apo
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Subcutaneous Apomorphine Injections
Dyskinesia/Intensity
Dyskinesia/Duration
No of Patients
No of Patients
Shorter
Better
Un- changed
Un- changed
Longer
Worse
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Östergaard et al

• Method
• Double blind placebo controlled study with
  apomorphine injection pen
• Placebo controlled apomorphine test
• Screening period (gt2 days)
• Dose-finding (lt 8 days)
• Double blind placebo controlled cross-over period
  (2x4 days)

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Östergaard et al
Method Double blind placebo controlled study
with apomorphine injection pen Open Therapy (8
weeks) Number of patients 22 included, 14
performed the complete study
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Östergaard et al
Apomorphine test 1/21 maximal effect of
placebo 20/21 maximal effect of apomorphine Mean
dosis 3.4 mg
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Östergaard et al
Time in Off per day (minutes), Cross-over


plt0.002
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Östergaard et al

Apomorphine
Off degree, Cross-over
Placebo
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Kontrollierte Studien Dewey et al., 2001

• Methode
• Randomisierte, doppel-blinde, placebo-kontrolliert
  e Studie mit Apomorphin
• 29 Patienten, gt 2 Stunden off pro Tag
• Apomorphin/Placebo, stationär 1 Monat ambulant
• UPDRS III-Veränderung und wirkungsvolle
  Injektionen

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Dewey et al., 2001
UPDRS III Change/Optimal Dosis
Apomorphine Placebo off on Di
ff off on Diff L-dopa 41.8 15.2 -26.6 -6
5 39.9 17.3 22.6 -58 Apo/Placebo 39.7 15.8 -23.
9 -62 36.3 36.2 -0.1 -1 plt.001 (Apo
vs. Placebo)
L-dopa Dosis/Apo group 225 mg L-dopa
Dosis/Placebo group 208 mg Apomorphine dosis
5.4 mg
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Dewey et al., 2001
Autoscoring/at home
Apomorphine Placebo p No of
injections 2.5 2.3 0.16 off
interrupted 95 23 lt.001 First dosis of
the day 96.5 Last dosis of the
day 95.3 Change/off time -2 h 0
h 0.02
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Published clinical studies with Apomorphine
Injections
1 2 3 4 5 6 7 8 9 x Patients 12 5
6 49 16 22 11 24 20 Age (y) 57 57 59 62 60 59 57
59 66 61 Disease (y) 11 10 15 15 14 10 14 11 9 12
.3 Apo (Mo) 6 11 6 27 12 2 23 22 1 13.7 Dose/inj(m
g) 4 2.1 2.8 nr 3.7 3.4 3 1.9 5.4 3.4 Dose/day 8.6
8.9 11.6 18.6 17.9 nr 9 9.7 13.5 12.2
Criterias 1. Poewe et al., 1989, 2. Pollak et
al., 1990, 3. Kempster et al., 1991, 4. Hughes
et al., 1993, 5. Merello et al., 1995, 6.
Östergaard et al., 1998, 7. Esteban-Munoz et al.,
1995, 8. Pietz et al., 1998, 9. Dewey et al.,
2001
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Published clinical studies with Apomorphine
Injections
1 2 3 4 5 6 7 8 9 x off
() -56 -63 -41 -42 -53 -43 -45 -41 -34 -49 on
Dysk nr nr nr nr nr nr nr 7.7 nr 7.7 Dysk
Intens nr nr nr nr nr nr nr -5.8 nr -5.8 L-dopa
() 0 -14 nr -7 0 nr 15 27 nr 4.0
Criterias 1. Poewe et al., 1989, 2. Pollak et
al., 1990, 3. Kempster et al., 1991, 4. Hughes
et al., 1993, 5. Merello et al., 1995, 6.
Östergaard et al., 1998, 7. Esteban-Munoz et al.,
1995, 8. Pietz et al., 1998, 9. Dewey et al.,
2001
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Subcutaneous Apomorphine Injection
Systemic side effects (n165) Nodules, itching,
bruises 69 Nausea 25 Yawning 9 Ortostatic
hypotension 6 Vertigo, dizziness 6 Rhinorrhea
6 Chest pain 3 Oedema of extremity 2 Eosinop
hilia 2 Diarrhea 1 Headache 1 Mostly
effectively counteracted with domperidone,
patients on low frequency injection (lt4 inj./day)
might need this for a long time
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Subcutaneous Apomorphine Injection
Neuropsychiatric side effects (n165) Sedation
21 Non-defined 7 Hallucinations 7 Sleep
disturbance 2 Confusion 1

Sleep attacks Reported by Homann et al., 2
pat. at first exposure, 2 mg Apomorphine Risk
seems related to total amount and frequency of
exposure Effects on libido and erectile function
Less well monitored. Inform about this!

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Effects regarding non-motor off-Symptoms

• Painful dystonia
• Pain without dystonia
• Panic attacks
• Dysphagia
• Anorectal dysfunction
• Obstructive bladder dysfunction

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Subcutaneous Apomorphine Injections What happens
if Entacapone is added?

• Apomorphins pharmakokinetic properties unchanged
• Clinical symptomatology (tapping, AIMS) unchanged
• Duration of clinical effect unchanged
• Theoretically Increased bioavailability through
  reduction of COMT methabolism in liver possible
  (shown for tolcapone in rat)

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S.c. Apomorphine Injections

• The suitable patient
• Repeated (lt 10 per day) short off-periods in
  spite of optimized oral therapy (wearing-off,
  early on-off)
• Good L-dopa effect in on
• Good cognitive functions must recognize off
  and on and understand treatment principles
• Ability to inject
• - Young and active

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OH
HO
N
CH3
Quick Rescue from disabling off
Increased freedom and confidence
Improved possibilities to continue work and a
normal social life
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Apomorphine Applications
Typical single doses Time to
on off red. S.c. Injections 0.2-11.5
mg 5-10 min -50 S.c. Infusions 0.02-0.15
mg/kg/h 5-10 min -65 I.v. Infusions 0.02-0.3
mg/kg/h -90 Sublingual 20-60 mg 10-40
min -50 Intranasal 2-8 mg 10
min -50 Rectal 200 mg 32 min - Transdermal
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Subcutaneous Apomorphine Infusion
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Subcutaneous Apomorphine Infusion
Method 1. Apo-Infusion started at 1 mg/h, then
up-titrated in 0.5 mg/h intervals until optimal
effect is reached 2. L-dopa may be reduced in
30- 50 of the patients? 3. Adjustment of
L-dopa doses
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Subcutaneous Apomorphine Infusion
Method 4. Infusion over 2 days 5. Bolus doses
added 6. Patient education on the hospital ward
over 1-2 weeks
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Change in Medication during Apomorphine Infusion
8 patients with monotherapy
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Subcutaneous Apomorphine Infusion
Time in Off per day Without Apo 57.0
(21-74) With Apo (20 mo) 20.0 (10-45) With
Apo (54 mo) 22.0 (10-50)
Without Apo
20 mo Apo
54 mo Apo
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Subcutaneous Apomorphine Infusion
Number of off periods Without Apo 4.0
(1.5-10) With Apo 5.0 (2-20)
Without Apo
With Apo
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Published clinical investigations with
Apomorphine Infusion
1 2 3 4 5 6 7 8 9 10 11 X Patients
7 9 14 10 22 7 25 34 11 12 12 Duration 11 10 26
12 36 3 44 10 13 14 10 20 mo Dosis
(mg/h) n.r. 5.4 6.8 3.2 n.r. 4.2 4.0 nr nr nr nr 4
.7mg/h Off () -85 -67 -77 -57 -59 -58 -50 -42 -
40 -80 -60 -61 Dysk.() -45 -20 n.r. -40 n.r. n.
r. -14 nr nr nr -48 -33 L-dopa
() -39 -53 -81 -48 16 -50 -50 -18 -30 -23 -55 -3
9
Ref. 1. Chaudhuri et al., 1988. 2. Pollak et
al., 1990. 3. Kreczy-Kleedorfer et al., 1993. 4.
Stocchi et al., 1993. 5. Hughes et al., 1993. 6.
Gancher et al., 1995. 7. Pietz et al., 1998. 8.
Chaudhuri et al., 1999. 9. Vanderheyden et al.,
1999. 10. Kanovsky et al., 2002. 11. DiRosa et
al., 2003.
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24 Hours or 12/16 Hours
of Subcutaneous Apomorphine Infusion?
12/16 hours 24 hours Studies 4 3
Total daily dose (mg) 47 119 Part of day in
Off () -65 -65 L-dopa reduction
() -30 -61 Psychiatric side
effects are probably less common with the 16
hour infusion protocol.
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Apomorphine Infusion as Monotherapy?
Colzi et al., 1998 19 Patients (originally
on L-dopa Apomorphine) Given Monotherapy
Apomorphine Infusion 16 hours/day Part of
day in Off - 71.6 Time with
dyskinesias - 85 Dyskinesia intensity -
65 Mechanism More exact dose?
More physiologic? Neuroprotective?
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Apomorphine infusion and dyskinesias
Kanovsky et al., 2002 12 patients, 16 hour
protocol Part of day in off - 80
Part of day w. peak dose dyskinesias - 61
End of dose dyskinesias - 100 Biphasic
dyskinesias -72 Effect stabile over 9
years
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Apomorphine infusion and dyskinesias
Katzenschlager et al., 2005 Objective
dyskineisa measure during L-dopa and apomorphine
tests (12 patients two blinded
raters) Baseline 6 mo Change p L-dopa
test AIMS 8.9 (4.6) 4.9 (2.8) -44 lt0.01 Goetz
2.2 (0.7) 1.3 (0.8) -40 lt0.01 Apomorphine AIMS
9.7 (4.9) 5.9 (2.9) -39 lt0.01 Goetz 2.2
(0.8) 1.4 (0.8) -36 lt0.01
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Subcutaneous Apomorphine Infusion
Neuropsychiatric side effects (n118) Sedation
15 Non-defined 9 Hallucinations 8 Psychosis
5 Increased libido 3 Confusion 2 Agitation
2 Euphoria 1 Illusions 1 Nightmares 1
Emotional lability 1
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Change of medication during Apomorphine infusion
Who develops psychiatric SE?
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Characteristics of Patients who Develop
Psychiatric Side Effects Patients
with Patients without Psychiatric
Psychiatric side effects side effects Age
(y) 66.5 (7.4) 63.0 (6.8) Disease (y) 17.8
(11-32) 20.1 (12-20) L-dopa (y) 16.1
(7-24) 18.5 (12-25) On-Off (y) 11.9
(7-24) 11.7 (4-16) Cognitive Problems Start of
study 4 Pts. (36) 1 (7) End of study 7
(64) 2 (14)
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Subcutaneous Apomorphine Infusion

• How to avoid psychiatric side effects
• 16 instead of 24 hour infusion
• Avoid patients with dementia
• Special care in patients with psychiatric SE
  from other dopaminergic drugs

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Subcutaneous Apomorphine Infusion
Effect reg. cognition and depression Morgante et
al., 2004 2 years 12 patients with apo vs. 18
p.o. therapy BPRS Apomorphine L-dopa Baseline
28.0 26 Endpoint 26.5 26 BDI Baseline
22.0 20 Endpoint 10.0 21 off-Zeit Base
line 5.0 6.5 Endpoint 2.0 6.7 MMSE Base
line 27.6 27.5 Endpoint 27.4 27.2
BPRS Brief psychiatric rating scale
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Subcutaneous Apomorphine Infusion
Systemic SE (n118) Noduli 94 Orthostatic
hypotension 10 Eosinophilia 9 Nausea 7 Haem
olytic anemia 4 Vertigo 3 Rhinorrhea 2 Inc
reased appetite 2 Diarrhoea 2 Incontinentia
2 Hickups 1 Dysarthria 1
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Subcutaneous Apomorphine Infusion

• Hämolytic Anemia
• 3 so far only patients with L-dopa and
  apomorphine infusions reversible
• Therapy
• 1. Steroids (50 mg/day, slow reduction)
• 2. Apomorphine stopped (individual decision)

• Regular blood cell counts for patients with
  L-dopa and apomorphine infusion

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Comparison of outcomes following deep brain
stimulation of the subthalamic nucleus and
continuous apomorphine SC infusions.
Y-axis denote percentage favorable change from
baseline. APO-inf. (a), average outcomes from
Colzi et al. 1998 Di Rosa et al. 2003 Kanovsky
et al. 2002 and Stocchi et al. 2001 STN-DBS
(b), Krack et al. 2003 (5-year follow-up of
STN-DBS in 49 patients) STN-DBS (c) and Gpi-DBS
(c), The Deep-Brain Stimulation for Parkinsons
Disease Study Group 2001 (6 month double-blind
trial comparing STN- and Gpi-DBS in 96 and 38
patients, respectively).
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Cognitive Effects of Apo Inf and STN-DBS
Alegret et al., 2004 (9 patients with STN-DBS
and 7 patients with Apomorphine, 1y) Motor
effects Time in on 43 63 UPDRS in
worst off -58 -53
Dyskinesia severtiy 59 ns Dyskinesi
a duration -62 ns
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61
Cognitive Effects of Apo Inf and STN-DBS
Alegret et al., 2004 Neuropsychological
changes between pre- and posttreatment
Pretreatment 6 mo 1 year Declarative
memory RAVLT 38.43 (10.81) 36.00 (8.76) 36.57
(10.01) 39.00 (10.10) 42.71 (14.08) 40.57
(8.02) Frontal lobe Stroop interfer 90.02
(51.50) 69.76 (29.24) 74.96 (34.38) 100.85
(45.20) 75.26 (20.75) 71.25 (42.45) Trail
making 295.14 (101.24) 294.29(120.13)309.71(148.9)
119.50 (91.61) 194.00 (99.48) 210.50
(163.1) Phonetic verbal 22.86 (7.86) 17.00
(6.08) 19.00 (6.00) fluency 22.71
(10.80) 24.57 (14.93) 22.86 (13.31)
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Cognitive Effects of Apo Inf and STN-DBS
Alegret et al., 2004 Neuropsychological
changes between pre- and posttreatment
Pretreatment 6 mo 1 year Visuomotor
speed Stroop naming 46.14 (8.11) 36.14
(5.52) 36.43 (5.94) 53.00 (16.69) 50.33
(11.99) 50.00 (12.46) Visuospatial JLO 15.29
(6.52) 13.00 (4.90) 12.71 (6.47) 15.57
(7.98) 16.00 (7.44) 16.00 (7.26)
Mood BDI 24.29 (11.29) 20.29
(11.66) 22.29 (6.21) 20.57 (11.44) 21.43
(11.49) 21.86 (11.32)
plt0.05
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Cognitive Effects of Apo Inf and STN-DBS
Alegret et al., 2004 Neuropsychological
changes between pre- and posttreatment
Frontal lobe Visuomotor speed
Phonetic verbal fluency score
Stroop naming score



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Subcutaneous Apomorphine Infusion

• The ideal patient
• Repeated off-periods in spite of optimized
  peroral therapy
• Good L-dopa effect in on
• Good cognitive functions
• Motivated
• Pre- and post- operative
• costs 9 000-27 000 /year

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Important for success Patient
selection Intensive patient education and
frequent control visits
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