Clinical tolerance and profile of cytokine induction in healthy volunteers following the simultaneous administration of ifn-alpha and the synthetic immunomodulator murabutide.
As the therapeutic use of interferon-alpha (IFN-alpha) is limited by a dose-dependent toxicity and variable efficacy, ways of improving the therapeutic index of the cytokine are being sought. Murabutide (N-acetyl muramyl-L-alanyl-D-glutamine-O-n-butyl-ester) (ISTAC Biotechnology, Lille, France) is a safe synthetic and clinically acceptable immunomodulator that enhances the biologic activities of IFN-alpha in different experimental models. We evaluated in healthy human volunteers tolerance of the coadministration of Murabutide with increasing doses of IFN-alpha. The simultaneous administration of the two drugs was well tolerated without any increased or prohibiting toxicity, and all recipients experienced side effects that were similar to those observed after the administration of IFN-alpha alone. We also profiled the serum levels of cytokines induced following coinjection of the two drugs. We mostly detected an induction of anti-inflammatory cytokines and of human immunodeficiency virus type 1 (HIV-1)-suppressive beta-chemokines, in the absence of release of key proinflammatory cytokines. Therefore, the simultaneous administration of Murabutide and IFN-alpha is well tolerated and does not lead to increased toxicity. In addition, the selectivity in the profile of cytokines and chemokines induced following the coadministration of Murabutide and IFN-alpha points to the potential use of this combination in the treatment of inflammatory diseases and chronic viral infections.
Darcissac
E C
EC
ISTAC Biotechnology, Lille, France.
Vidal
V
V
Guillaume
M
M
Thebault
J J
JJ
Bahr
G M
GM
D000119:Acetylmuramyl-Alanyl-Isoglutamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000009:adverse effects; D000293:Adolescent; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000819:agonists / Q000097:blood; D018771:Arthralgia / Q000139:chemically induced; D018946:Chemokine CCL5 / Q000097:blood; D019742:Chemokines, CC / Q000819:agonists* / Q000097:blood; D016207:Cytokines / Q000097:blood / Q000187:drug effects*; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D019040:E-Selectin / Q000097:blood; D006261:Headache / Q000139:chemically induced; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood; D016898:Interferon-alpha / Q000008:administration & dosage* / Q000009:adverse effects; D016753:Interleukin-10 / Q000097:blood; D008231:Lymphopenia / Q000139:chemically induced; D008297:Male
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D018946:Chemokine CCL5; D019742:Chemokines, CC; D016207:Cytokines; D019040:E-Selectin; D016898:Interferon-alpha; D018799:Intercellular Adhesion Molecule-1; D016753:Interleukin-10; D000119:Acetylmuramyl-Alanyl-Isoglutamine; C033575:murabutide