The Laboratory Mouse (Handbook of Experimental Animals) - USP
Therapy of human rabies: lessons from experimental studies in a mouse model
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Transcript of Therapy of human rabies: lessons from experimental studies in a mouse model
Therapy of human rabies: lessons from experimental studies in a mouse model
Alan C. Jackson, MD Courtney A. Scott, BScJames Owen, BScSimon C. Weli, PhDJohn P. Rossiter, MB, PhD
Departments of Medicine (Neurology) Microbiology and ImmunologyCentre for Neuroscience StudiesQueen’s University, Kingston, ON, Canada
Medical complications of rabies
multisystem organ failure respiratory
failure, hyperventilation, aspiration pneumonia
cardiac failure, arrhythmias
gastrointestinal hemorrhage hyperthermia or hypothermia endocrine – SIADH, DI
Recovery from rabies 6-yr-old male from Ohio. Hattwick et al.
Ann Intern Med (1972)
45-yr-old female from Argentina. Porras et al. Ann Intern Med (1976)
32-yr-old male lab worker from New York. Tillotson et al. MMWR (1977)
9-yr-old male from Mexico. Alvarez et al. Pediatr Infect Dis (1994)
6-yr-old female from India. Madhusudana et al. Int J Infect Dis (2002)
Clinical Infectious Diseases 36:60-63, 2003
Specific therapies rabies vaccine
human rabies immune globulin (or mabs)
ribavirin
interferon-
ketamine
role of combination therapy?
Jackson et al.: Clinical Infectious Diseases 36:60-63, 2003
N Engl J Med 352:2508-14, 2005
Survival Case healthy 15-year-old in Wisconsin bitten by bat – probable bat rabies virus (no
virus isolated, no antigen or RNA identified) antibodies on presentation (RFFIT 1:102) midazolam infusion to produce burst
suppression pattern on EEG with supplemental phenobarbital
IV ketamine infusion 2 mg/kg/hr antiviral therapy with ribavirin (IV) and
amantadineN Engl J Med 352:2508-14, 2005
Survival Case Did specific therapy play important role in
recovery? therapeutic coma?? ketamine? antiviral therapy?
Attenuated bat rabies virus strain? Early antibody response Lack of detection of viral antigen and RNA,
suggests that effective viral clearance was in progress
Ketamine dissociative anesthetic agent ketamine (1-2 mM) inhibits in vitro replication of
rabies virus by inhibiting genome transcription with stereotaxic inoculation of fixed rabies virus
into neostriatum of rats, ketamine 60 mg/kg IP q12h reduced infection in multiple brain regions (hippocampus, cerebral cortex, and thalamus)
Lockhart et al. – Antiviral Chem Chemother 1991 and 1992
Antimicro Agents Chemother 1991
Journal of Virology 80:10270, 2006
Toluidine blue-stained plastic sectionscerebral cortex – 48 hrs
Mock-infected CVS-infected
J Virol 80:10270, 2006
Trypan blue exclusioncerebral cortex – 72 hrs
Mock-infected CVS-infected
J Virol 80:10270, 2006
Trypan Blue StainingCerebral Cortex Hippocampus
J Virol 80:10270, 2006
Effects of 125 μM ketamine on viability of cortical neurons in CVS infection
J Virol 80:10270, 2006
Cumulative mortalityketamine 60 mg IP q12h or vehicle
intracerebral footpad
log rank test p= 0.50 log rank test p= 0.53
J Virol 80:10270, 2006
Therapy with Ketamine
Ketamine did not:
• reduce mortality• attenuate the clinical neurologic illness or
prolong survival• reduce viral spread or the number of
infected neurons• reduce the amount of infectious virus• reduce neuronal apoptosis after
intracerebral inoculation
Lancet Neurology 3:744, 2004
multiple sclerosisspinal cord injuryParkinson’s diseaseHuntington’s diseaseamyotrophic lateral sclerosisviral diseases of CNS – reovirus, SIV, Sindbis v.
Journal of Virology 81:6248, 2007
log rank test p=0.003
J Virol 81:6248, 2007
Summary Therapy with minocycline (50 mg/kg/d) was
associated with more severe neurologic disease and higher mortality than with vehicle in rabies virus – infected mice.
The number of rabies virus-infected neurons was similar with vehicle and minocycline.
Neuronal apoptosis was more marked in infected mice that received vehicle than minocycline (minocycline was anti-apoptotic).
There were smaller numbers of CD3 positive cells in the brainstem of mice that received minocycline than vehicle, indicating an anti-inflammatory effect of the drug.
J Virol 81:6248, 2007
Conclusions Therapy of rabies with minocycline in an
experimental mouse model did not provide neuroprotection and aggravated the neurological disease.
Caution should be taken before using minocycline for empirical therapy of rabies or other viral encephalitis in humans before more experimental data become available.
Therapeutic approach similar to the Willoughby protocol has been unsuccessful in at least 8 cases:
• United States – 3 (TX, IN, CA)• Canada (Alberta)• Germany – 2 • India• Thailand
Conclusions: Ketamine Lack of efficacy of ketamine in about 8
human cases since the Milwaukee case
Lack of efficacy of ketamine in primary neuronal cultures and in vivo in mice at 120mg/kg/d
More experimental evidence is needed that supports the use of ketamine in rabies virus infection before recommending its use for the therapy of human rabies.
Therapeutic coma useful for therapy of status epilepticus efficacy in other neurologic disorders is unproven no experimental evidence of efficacy in rabies or
any other infectious disease potential serious adverse effects lack of effective neuroprotective agents even in
common acute neurologic disorders (e.g., stroke), despite numerous clinical trials
no scientific rationale for use in rabies does not work risks outweigh benefits should not be used for human rabies
Willoughby protocol• Multiple failures of the protocol in developed and
developing countries.• It is now highly questionable that therapy using
this protocol was directly responsible for the favorable outcome.
• This protocol should not be repeated indefinitely.• Experimental work should be performed in cell
culture and in animal models to identify promising therapeutic agents.
• New approaches should be taken for future rabies patients.
Acknowledgments
Queen’s University Violet E. Powell Fund