Transcript Slide 1

Efficacy of Topical Drug Therapy for
Monkey B Virus Exposure
R Eberle
Center for Veterinary Health Sciences
Oklahoma State University
Stillwater, OK
Monkey B Virus
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Macacine herpesvirus 1
Naturally occurring in genus Macaca
Symptoms similar to HSV in humans
Serious disease is rare in natural host
Monkey B Virus:
Zoonotic Infections
• First isolation from human case in 1932
• About 50 documented human cases total
• Infection usually acquired from macaques
via bites or scratches
• ~80% fatal if untreated, ~20% with
immediate drug therapy
• Was a “Select Agent” – govt controlled
research (now removed from list)
Current Treatment for
Zoonotic BV Infections
• All drugs were developed to treat HSV, not BV
• Immediate post-exposure prophylactic treatment is
oral ACV or oral ValACV
• If any clinical symptoms are evident treatment is
i.v. ACV or i.v. GCV
• If CNS signs evident treatment is i.v. GCV
• There is no scientific evidence that these represent
optimal treatment regimens
Comparative Drug Efficacy – In vitro
Drug
ACV
AraA (Tox)
BUdR
BVDU
CDV
EDU
HBPG
GCV
IUdR (Tox)
PCV
PFA
TFT (Tox)
EC50
23.3 ± 4.3
5.7 ± 1.6
>200
>200
12.4 ± 2.1
14.2 ± 5.8
>200
18.4 ± 3.6
1.3 ± 0.5
11.3 ± 1.4
>100
1.3 ± 0.2
BV Mouse Model
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10-12 gm female Balb/c
Shave flank
Scarify skin
Apply 105 PFU BV (~10 LD50)
Observe 2x/day, 14-21 days
Drugs given over 7 day course
Systemic = inject i,p.
Topical = transdermal PLO gel
BV Mouse Model: Neurological
Scoring & Clinical Signs of Infection
Score
1
2
3
4
5
Clinical Neurological Signs
Abnormal tail-lift reflex (curling of ipsilateral foot/leg)
Paresis of ipsilateral hind leg, still alert & active
Paralysis of ipsilateral hind leg, still alert & active
Bilateral hind limb paralysis, scruffy coat, not very active
Immobile, tremors, dead or requiring euthanasia
Normal
Abnormal
Systemic Efficacy
ACV, PCV & EDU
Start drugs day -1 for 7 days; i.p. injection 2x/day
Systemic Efficacy
GCV & CDV
Start drugs day -1, i.p. injection 2x/day
100
100
90
90
CDV (mg/kg/day)
100, 50, 25,
12.5, 6.2, 3.1,
1.6
Percent Survival
80
70
60
80
70
60
50
50
40
40
30
30
20
20
10
10
0
0
0
7
14
GCV (mg/kg/day)
200, 100, 50, 25
0
Days Post-Infection
7
14
Neurological Symptoms
GCV & CDV
Start drugs day -1 for 7 days; i.p. injection 2x/day
Effect of Delaying Start of
Drug Therapy
Virus in DRG
Virus in Spinal
Cord
Percent Survival
100
80
60
CDV
(25 mg/kg/day)
GCV
(100 mg/kg/day)
40
20
0
-1
0
1
2
3
Start of Drug Regimen (DPI)
4
5
Conclusions
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ACV, EDU & PCV not effective
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GCV & CDV effective
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Only when treatment started before virus gets into CNS
CDV more effective than GCV
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CDV effective dose ~10 fold lower than GCV
• High CDV doses can prevents development of clinical
neurological signs
Implications
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To be effective treatment must start before
virus invades CNS
• Best to prevent virus from reaching CNS
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Most effective drugs are also toxic
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Use of less effective drugs may be bad
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Cannot use drugs most effective against BV
GCV & CDV are also toxic, so treatments are in-patient
Ineffective inhibition may allow virus to replicate
& invade nervous system
Infection becomes harder to treat effectively once
neurological symptoms become evident
Possible Alternative Approach:
Topical Drug Treatment?
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Some toxic drugs can be used topically
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Patients can self-medicate
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• Lower cost (out-patient)
• Easy to administer, likely
high patient compliance
Can initiate treatment soon after exposure
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Early peripheral treatment may stop virus from
accessing the nervous system
Neurological Score
Trial Topical Drug Treatment
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1
1
2
2
5% GCV
3
5% CDV
3
0
7
Days PI
Treatment started at:
14
21
3 hr PI
0
7
Days PI
6 hr PI
14
21
24 hr PI
Screening of Drugs for
Topical Efficacy
100
% Survival
80
60
40
All drugs at 3%
Start treatment
at 4 hr PI
3x/day for 7 days
20
0
Veh ACV PCV GCV CDV TFT RRI IUdR EDU Abrv
Comparative Drug
Efficacy: Survival
Start drug treatments
at 24 hr PI
3x/day for 7 days
5%
3%
1%
0.3%
0.1%
Vehicle
100
80
60
40
20
0
100
80
80
60
60
40
40
20
20
0
0
7
Days Post-Infection
14
0
7
14
Days Post-Infection
100
CDV
RRI
0
GCV
0
7
Days Post-Infection
14
Comparative Drug
Efficacy:
Neurological Signs
Start drug treatments
at 24 hr PI
3x/day for 7 days
5%
3%
1%
0.3%
0.1%
Vehicle
0
1
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4
5
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1
1
2
2
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3
4
4
5
0
7
Days Post-Infection
14
0
7
14
Days Post-Infection
0
CDV
RRI
5
GCV
0
7
Days Post-Infection
14
Future Experiments
• Dual drug regimens:
GCV + RRI
CDV + RRI
• Dual drug efficacy once BV is in CNS
• Temporal efficacy of CDV suppression
of BV replication in the skin
Acknowledgements
Collaborators/Personnel:
Dr Lara Maxwell
Vet Pharmacol
Dr George Wright
CEO GLSynthesis
Funding: Dolphin Fdn, ACLAM Fdn
Darla Black
Lab Manager
Questions?