title: Single oral administration of the novel CXCR4 antagonist, KRH-3955, induces an efficient and long-lasting increase of white blood cell count in normal macaques, and prevents CD4 depletion in SHIV-infected macaques: a preliminary study.
abstract: We evaluated the long-term effects of the single oral administration of a new CXCR4 antagonist, KRH-3955, on elevation of white blood cell (WBC), neutrophil and lymphocyte counts in normal cynomolgus monkeys. In the monkeys treated with 0, 2, 20, 200 mg/kg of the compound, WBC, neutrophil and lymphocyte counts increased dramatically at 2 days after treatment. This effect was dose-dependent, and these cell counts remained elevated 15 days after drug treatment. Since neutrophils are the most abundant WBCs in circulation and bone marrow neutrophil exhaustion impairs the response to bacterial infections, it is intriguing to exploit this pharmacological increase of neutrophils as a tool to address its influence on viral infections in vivo. The SHIV infection studies using the SHIV-KS661c/cynomolgus monkey model showed that a single oral administration of KRH-3955 (100 mg/kg) approximately 24 h before virus exposure did not prevent infection, although it did prevent CD4 cell depletion in 3/3 monkeys. Furthermore, single oral administration of the drug 2 weeks before viral exposure rescued CD4 cells in 1/3 monkeys. This prevention of CD4 cell depletion was observed in both blood and lymphoid tissues. These results show that natural course of the SHIV infection is modulated by artificial increase of neutrophils and lymphocytes caused by KRH-3955 in the cynomolgus monkey model.
authors: AIDS Research Center, National Institute of Infectious Diseases, Tokyo, Japan. nakabone@nih.go.jp
authors: Tadashi
authors: T
authors: Nakasone
authors: Sei
authors: S
authors: Kumakura
authors: Michiko
authors: M
authors: Yamamoto
authors: Tsutomu
authors: T
authors: Murakami
authors: Naoki
authors: N
authors: Yamamoto
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007958:Leukocyte Count; D008212:Lymphocyte Depletion; D008251:Macaca; D008297:Male; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000097:blood* / Q000188:drug therapy / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D014018:Tissue Distribution; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001596:Benzylamines; D007093:Imidazoles; C541387:N,N-dipropyl-N'-(4-((((1H-imidazol-2-yl)methyl)((1-methyl-1H-imidazol-2-yl) methyl)amino)methyl)benzyl)-N'-methylbutane-1,4-diamine; D019718:Receptors, CXCR4