Chemokines, nitric oxide and antiarthritic effects of 9-(2-phosphonomethoxyethyl)adenine (Adefovir).
Antiarthritic effects of two acyclic nucleoside phosphonates, 9-(2-phosphonomethoxyethyl)adenine (PMEA; Adefovir) and 9-(2-phosphonomethoxypropyl)adenine (PMPA), as well as their more bioavailable prodrugs, bis(pivaloyloxymethyl)ester of PMEA [bis(POM)-PMEA; Adefovir Dipivoxil] and bis(isopropyloxycarbonyloxymethyl)ester of PMPA [bis(POC)-PMPA], were investigated in a model of adjuvant-induced arthritis in Lewis rats. The drugs were injected subcutaneously at doses of 5-50 mg/kg. PMEA and its prodrug inhibited by > 80% arthritic paw swelling, splenomegaly and fibroadhesive perisplenitis. Both prophylactic and therapeutic dosing regimens were effective. Neither PMPA nor bis(POC)-PMPA suppressed development of arthritic lesions. Substantially reduced nitrite + nitrate levels were detected in serum and urine of PMEA-treated animals as compared to those of untreated diseased controls. Also, complete suppression of the disease-associated, greatly enhanced systemic levels of the chemokine, RANTES (regulated upon activation, normal T cell expressed and secreted), was observed in rats injected with PMEA. Additional in vitro studies showed that PMEA does not change, PMPA enhances, and both prodrugs inhibit the immune-activated NO production. Under the same conditions PMEA inhibits, while PMPA slightly stimulates, secretion of RANTES. Collectively, these data suggest that the in vivo-inhibited production of nitric oxide (NO) is a consequence rather than a mechanism of antiarthritic action of PMEA. Possible mechanisms for the anti-RANTES activity of PMEA remains to be firmly established.
Zídek
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Z
Institute of Pharmacology, Academy of Sciences of the Czech Republic, Prague. zidekz@biomed.cas.cz
Franková
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Holý
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D000225:Adenine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018946:Chemokine CCL5 / Q000096:biosynthesis* / Q000097:blood; D005260:Female; D005355:Fibrosis; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism; D009569:Nitric Oxide / Q000096:biosynthesis* / Q000097:blood / Q000652:urine; D009929:Organ Size / Q000187:drug effects; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000473:pathology; D000068698:Tenofovir
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018946:Chemokine CCL5; D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C111774:bis(isopropyloxymethylcarbonyl) 9-(2-phosphonomethoxypropyl)adenine; C089823:bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine; D009569:Nitric Oxide; C053001:adefovir; D000068698:Tenofovir; D000225:Adenine