Abstract
The effect of combining a radiation‐protective phosphorothioate with another agent was investigated in an attempt to increase radioprotection and reduce toxicity. The calcium channel blocker nimodipine (NIMO) was administered alone (1 or 10 mg kg^−1^) or in combination with 200 mg kg^−1^ of the phosphorothioate radioprotector WR‐151327 (WR) (S‐3‐(3‐methylaminopropylamino)propylphosphorothioic acid). Radioprotection as measured (30‐day survival) of mice treated i.p. 30 min before ^60^Co irradiation at a dose rate of 1 Gy min^−1^) was evaluated in CD2F1 male mice. The effects of nimodipine and WR‐151327 on locomotor activity were investigated also in a separate group of non‐irradiated mice. The LD~50/30~ for the Emulphor vehicle control group was 8.56. For nimodipine alone (1 or 10 mg kg^−1^) the LD~50/30~was 8.39 and 10.21 Gy, respectively, yielding dose modification factors (DMFs) of 0.98 and 1.19, respectively. When WR‐151327 was given alone, the 50/30 was 12.48 Gy (DMF = 1.46; P < 0.05 from vehicle). WR‐151327 combined with 1 or 10 mg kg^−1^ nimodipine resulted in an LD~50/30~ of 12.73 Gy (DMF 1.49, P < 0.05 from vehicle), and when WR‐151327 was combined with 10 mg kg^−1^ nimodipine the LD~50/30~ was 14.29 Gy (DMF = 1.67, P < 0.001 from WR‐151327). For either dose of nimodipine, locomotor activity did not differ from vehicle. WR‐151327 and WR‐151327 + 1 mg kg^−1^ nimodipine resulted in locomotor decrements for up to 4 h post‐administration (P < 0.05 from vehicle), and WR‐151327 + 10 mg kg^−1^ nimodipine for up to 6 h (P < 0.05 from WR‐151327). Therefore, although there was an additive radioprotective effect when the higher dose of nimodipine was combined with WR‐151327, the locomotor decrement was also enhanced. These results demonstrate that a combination of nimodipine and a phosphorothioate such as WR‐151327 may be useful as a clinical setting where behavioral and physiological side‐effects can be monitored. Published in 2001 by John Wiley & Sons, Ltd.