Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
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 • • • • 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 • • • • • • 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 • 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 Implications • To be effective treatment must start before virus invades CNS • Best to prevent virus from reaching CNS • Most effective drugs are also toxic • Use of less effective drugs may be bad • • • • 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? • 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 Neurological Score Trial Topical Drug Treatment 0 0 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 2 3 4 5 0 1 1 2 2 3 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?