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Efficacy of Topical Drug Therapy for Monkey B Virus Exposure R Eberle Center for Veterinary Health Sciences Oklahoma State University Stillwater, OK.

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Presentation on theme: "Efficacy of Topical Drug Therapy for Monkey B Virus Exposure R Eberle Center for Veterinary Health Sciences Oklahoma State University Stillwater, OK."— Presentation transcript:

1 Efficacy of Topical Drug Therapy for Monkey B Virus Exposure R Eberle Center for Veterinary Health Sciences Oklahoma State University Stillwater, OK

2 Macacine herpesvirus 1 Naturally occurring in genus Macaca Symptoms similar to HSV in humans Serious disease is rare in natural host Monkey B Virus

3 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)

4 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 Current Treatment for Zoonotic BV Infections

5 Comparative Drug Efficacy – In vitro Drug EC 50 ACV 23.3 ± 4.3 AraA (Tox) 5.7 ± 1.6 BUdR >200 BVDU >200 CDV 12.4 ± 2.1 EDU 14.2 ± 5.8 HBPG >200 GCV 18.4 ± 3.6 IUdR (Tox) 1.3 ± 0.5 PCV 11.3 ± 1.4 PFA >100 TFT (Tox) 1.3 ± 0.2

6 BV Mouse Model gm female Balb/c Shave flank Scarify skin Apply 10 5 PFU BV (~10 LD 50 ) Observe 2x/day, days Drugs given over 7 day course Systemic = inject i,p. Topical = transdermal PLO gel

7 BV Mouse Model: Neurological Scoring & Clinical Signs of Infection Score Clinical Neurological Signs 1Abnormal tail-lift reflex (curling of ipsilateral foot/leg) 2Paresis of ipsilateral hind leg, still alert & active 3Paralysis of ipsilateral hind leg, still alert & active 4Bilateral hind limb paralysis, scruffy coat, not very active 5Immobile, tremors, dead or requiring euthanasia Normal Abnormal

8 Systemic Efficacy ACV, PCV & EDU Start drugs day -1 for 7 days; i.p. injection 2x/day

9 Percent Survival Days Post-Infection CDV (mg/kg/day) 100, 50, 25, 12.5, 6.2, 3.1, GCV (mg/kg/day) 200, 100, 50, Systemic Efficacy GCV & CDV Start drugs day -1, i.p. injection 2x/day

10 Neurological Symptoms GCV & CDV Start drugs day -1 for 7 days; i.p. injection 2x/day

11 Effect of Delaying Start of Drug Therapy Percent Survival CDV (25 mg/kg/day) GCV (100 mg/kg/day) Virus in DRG Virus in Spinal Cord Start of Drug Regimen (DPI )

12 ACV, EDU & PCV not effective GCV & CDV effective Only when treatment started before virus gets into CNS CDV more effective than GCV CDV effective dose ~10 fold lower than GCV High CDV doses can prevents development of clinical neurological signs Conclusions

13 Implications To be effective treatment must start before virus invades CNS Best to prevent virus from reaching CNS Most effective drugs are also toxic Cannot use drugs most effective against BV GCV & CDV are also toxic, so treatments are in-patient Use of less effective drugs may be bad Ineffective inhibition may allow virus to replicate & invade nervous system Infection becomes harder to treat effectively once neurological symptoms become evident

14 Possible Alternative Approach: Topical Drug Treatment? Some toxic drugs can be used topically Patients can self-medicate Lower cost (out-patient) Easy to administer, likely high patient compliance Can initiate treatment soon after exposure Early peripheral treatment may stop virus from accessing the nervous system

15 5% GCV5% CDV Neurological Score Days PI Days PI 3 hr PI 6 hr PI 24 hr PI Treatment started at: Trial Topical Drug Treatment

16 Veh ACV PCV GCV CDV TFT RRI IUdR EDU Abrv % Survival All drugs at 3% Start treatment at 4 hr PI 3x/day for 7 days Screening of Drugs for Topical Efficacy

17 Days Post-Infection Days Post-Infection Days Post-Infection 5% 3% 1% 0.3% 0.1% Vehicle RRI CDVGCV Comparative Drug Efficacy: Survival Start drug treatments at 24 hr PI 3x/day for 7 days

18 Days Post-Infection Days Post-Infection Days Post-Infection 5% 3% 1% 0.3% 0.1% Vehicle RRI CDVGCV Comparative Drug Efficacy: Neurological Signs Start drug treatments at 24 hr PI 3x/day for 7 days

19 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

20 Acknowledgements Funding: Dolphin Fdn, ACLAM Fdn Collaborators/Personnel: Dr Lara Maxwell Dr George Wright Darla Black Vet Pharmacol CEO GLSynthesis Lab Manager

21 Questions?


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