Chemokines, nitric oxide and antiarthritic effects of 9-(2-phosphonomethoxyethyl)adenine (Adefovir).

Abstract

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.

• Authors: Z Zídek, D Franková, A Holý
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 376 Issue 1-2 Pg. 91-100 (Jul 02 1999) ISSN: 0014-2999 [Print] Netherlands
• PMID: 10440094 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Chemokine CCL5
• Organophosphonates
• Organophosphorus Compounds
• Prodrugs
• bis(isopropyloxymethylcarbonyl) 9-(2-phosphonomethoxypropyl)adenine
• bis(pivaloyloxymethyl)-9-(2-phosphonylmethoxyethyl)adenine
• Nitric Oxide
• adefovir
• Tenofovir
• Adenine

Topics

• Adenine (analogs & derivatives, pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arthritis, Experimental (drug therapy, metabolism, pathology)
• Chemokine CCL5 (biosynthesis, blood)
• Female
• Fibrosis
• Macrophages, Peritoneal (drug effects, metabolism)
• Nitric Oxide (biosynthesis, blood, urine)
• Organ Size (drug effects)
• Organophosphonates
• Organophosphorus Compounds (pharmacology)
• Prodrugs (pharmacology)
• Rats
• Rats, Inbred Lew
• Spleen (pathology)
• Tenofovir