PMID- 14683653
OWN - NLM
STAT- MEDLINE
DCOM- 20040213
LR  - 20220310
IS  - 1474-547X (Electronic)
IS  - 0140-6736 (Linking)
VI  - 362
IP  - 9400
DP  - 2003 Dec 13
TI  - Treatment of Ebola virus infection with a recombinant inhibitor of factor 
      VIIa/tissue factor: a study in rhesus monkeys.
PG  - 1953-8
AB  - BACKGROUND: Infection with the Ebola virus induces overexpression of the 
      procoagulant tissue factor in primate monocytes and macrophages, suggesting that 
      inhibition of the tissue-factor pathway could ameliorate the effects of Ebola 
      haemorrhagic fever. Here, we tested the notion that blockade of fVIIa/tissue 
      factor is beneficial after infection with Ebola virus. METHODS: We used a rhesus 
      macaque model of Ebola haemorrhagic fever, which produces near 100% mortality. We 
      administered recombinant nematode anticoagulant protein c2 (rNAPc2), a potent 
      inhibitor of tissue factor-initiated blood coagulation, to the macaques either 10 
      min (n=6) or 24 h (n=3) after a high-dose lethal injection of Ebola virus. Three 
      animals served as untreated Ebola virus-positive controls. Historical controls 
      were also used in some analyses. FINDINGS: Both treatment regimens prolonged 
      survival time, with a 33% survival rate in each treatment group. Survivors are 
      still alive and healthy after 9 months. All but one of the 17 controls died. The 
      mean survival for the six rNAPc2-treated macaques that died was 11.7 days 
      compared with 8.3 days for untreated controls (p=0.0184). rNAPc2 attenuated the 
      coagulation response as evidenced by modulation of various important coagulation 
      factors, including plasma D dimers, which were reduced in nearly all treated 
      animals; less prominent fibrin deposits and intravascular thromboemboli were 
      observed in tissues of some animals that succumbed to Ebola virus. Furthermore, 
      rNAPc2 attenuated the proinflammatory response with lower plasma concentrations 
      of interleukin 6 and monocyte chemoattractant protein-1 (MCP-1) noted in the 
      treated than in the untreated macaques. INTERPRETATION: Post-exposure protection 
      with rNAPc2 against Ebola virus in primates provides a new foundation for 
      therapeutic regimens that target the disease process rather than viral 
      replication.
FAU - Geisbert, Thomas W
AU  - Geisbert TW
AD  - Virology Division, US Army Medical Research Institute of Infectious Diseases, 
      Fort Detrick, MD 21702, USA. tom.geisbert@amedd.army.mil
FAU - Hensley, Lisa E
AU  - Hensley LE
FAU - Jahrling, Peter B
AU  - Jahrling PB
FAU - Larsen, Tom
AU  - Larsen T
FAU - Geisbert, Joan B
AU  - Geisbert JB
FAU - Paragas, Jason
AU  - Paragas J
FAU - Young, Howard A
AU  - Young HA
FAU - Fredeking, Terry M
AU  - Fredeking TM
FAU - Rote, William E
AU  - Rote WE
FAU - Vlasuk, George P
AU  - Vlasuk GP
LA  - eng
PT  - Journal Article
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - England
TA  - Lancet
JT  - Lancet (London, England)
JID - 2985213R
RN  - 0 (Helminth Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 0 (anti-coagulant protein C2, Ancylostoma caninum)
RN  - 9035-58-9 (Thromboplastin)
RN  - EC 3.4.21.21 (Factor VIIa)
SB  - IM
MH  - Animals
MH  - Blood Coagulation/drug effects/immunology
MH  - Disease Models, Animal
MH  - Ebolavirus/drug effects/immunology
MH  - Factor VIIa/*antagonists & inhibitors
MH  - Helminth Proteins/immunology/*pharmacology/therapeutic use
MH  - Hemorrhagic Fever, Ebola/*drug therapy/immunology/mortality
MH  - Macaca mulatta
MH  - Recombinant Proteins/*pharmacology/therapeutic use
MH  - Survival Rate
MH  - Thromboplastin/*antagonists & inhibitors
MH  - Virus Replication/drug effects/immunology
EDAT- 2003/12/20 05:00
MHDA- 2004/02/14 05:00
CRDT- 2003/12/20 05:00
PHST- 2003/12/20 05:00 [pubmed]
PHST- 2004/02/14 05:00 [medline]
PHST- 2003/12/20 05:00 [entrez]
AID - S0140-6736(03)15012-X [pii]
AID - 10.1016/S0140-6736(03)15012-X [doi]
PST - ppublish
SO  - Lancet. 2003 Dec 13;362(9400):1953-8. doi: 10.1016/S0140-6736(03)15012-X.