Radioprotective and locomotor responses of mice treated with nimodipine alone and in combination with WR-151327.
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 <LD(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.
Landauer
M R
MR
Armed Forces Radiobiology Research Institute, Radiation Casualty Management Team, 8901 Wisconsin Avenue, Bethesda, MD 20889-5603, USA. landauer@mx.afrri.usuhs.mil
Castro
C A
CA
Benson
K A
KA
Hogan
J B
JB
Weiss
J F
JF
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects*; D009553:Nimodipine / Q000008:administration & dosage / Q000494:pharmacology*; D009946:Organothiophosphorus Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000401:mortality / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D015996:Survival Rate; D013997:Time Factors
D002121:Calcium Channel Blockers; D004338:Drug Combinations; D009946:Organothiophosphorus Compounds; D011837:Radiation-Protective Agents; D009553:Nimodipine; C048392:WR 151327