NE-58095: a diphosphonate which prevents bone erosion and preserves joint architecture in experimental arthritis.
The rat adjuvant arthritis model, like human rheumatoid arthritis, is characterized by fulminating intra- and periarticular inflammation and bone lysis. This model was used to determine the effectiveness of a potent antiresorptive diphosphonate (NE-58095: monosodium [2-(3-pyridinyl) ethylidene] hydroxy diphosphonate) prophylactically in Lewis rats and therapeutically in Sprague-Dawley rats. Modified Freund's adjuvant (MFA) was injected into the tail of Lewis and Sprague-Dawley rats. Prophylactic treatment in Lewis rats [oral (PO): 14.8 mg/kg/day); subcutaneous (SC): 0.148 mg/kg/day] was begun on the day of MFA injection. A significant reduction in paw swelling was seen as early as day 12 after MFA injection with both oral and parenteral treatment. NE-58095 produced a reduction in paw swelling of 28, 39 and 61% on days 12, 17 and 24 respectively, as compared to the saline-treated MFA control. Bone lysis in the saline-treated MFA group was 85% of total possible incidence for 6 joint regions in the hind paws and 4 regions in the front paws at day 24. This resorption was reduced by 70% in the rats administered NE-58095 PO and SC at 24 days after MFA. In the therapeutic experiments with Sprague-Dawley rats, treatment with NE-58095 (SC: 0.148 mg/kg/day) was begun on day 14 after MFA injection, at which time significant paw swelling (greater than 0.5cc) had occurred. On day 25 (12 days of treatment), paw swelling was reduced 70% by NE-58095 treatment as compared to the saline-treated MFA controls. Histologically, the architecture of the tibio-tarsal joints in the saline-treated MFA rats was affected, in contrast to the NE-58095-treated MFA rats where the architecture of the joint was preserved. This new potent diphosphonate is not an anti-inflammatory compound by any of the classical tests and is effective both orally and parenterally. The mechanism by which this diphosphonate protects joint integrity is not clear but appears to be related to its ability to block bone resorption and the consequent inhibition of the diffusion into the joint space of calcium, chemotactic factors and cytokinas released from bone matrix, resulting in a quenching of the arthritic process.
Francis
M D
MD
Woods Corners Laboratories, Norwich Eaton Pharmaceuticals Inc., Procter and Gamble Company, Norwich, New York 45239-8707.
Hovancik
K
K
Boyce
R W
RW
D000818:Animals; D001168:Arthritis / Q000473:pathology*; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D001862:Bone Resorption / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D007596:Joints / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011919:Rats, Inbred Strains
C060493:NE 58095; D012968:Etidronic Acid