Radioprotectant Activity of Dicopper(II) Tetrakis(3,5- Diisopropylsalicylate) and Manganese(II) bis(3,5- Diisopropylsalicylate) Alone and in Combination.

Dicopper(ll) tetrakis(3,5-diisopropylsalicylate), (Cu(II)(2)(3,5-DIPS)(4), manganese(II) bis(3,5-diisopropylsalicylate), Mn(II)3,5-DIPS)(2) or combinations of them were used to treat gamma-irradIated mice in examining the possibility that combination treatments might be more effective in increasing survival than treatment with either complex alone. Doses of 0, 10, 20, or 40 mumol of each complex per kilogram of body mass were administered subcutaneously in a factorial design before 9 Gy gamna irradiation, an LD(90) dose of irradiation. Doses of 0, 10, 20, or 40 mumol Cu(II)(2)(3, 5-DIPS)(4) per kg of body mass produced 12, 28, 28, or 36 % survival, respectively, while doses of 0, 10, 20, or 40 mumol (II)(3), 5-DIPS)(2) per kg of body mass prduced 12, 36, 20, or 24 % survival, respectively. However, the combination of 20 mumol Cu(II)(2)(3, 5-DIPS)(4) and 10 mumol Mn(II)(3, 5-DIPS)(2) produced the greatest survival, 48 %, which was 300 % greater than vehicle-treated mice (P=0.01). It is concluded that specific combination treatments can be used to maximize survival of lethally irradiated mice.

Radioprotectant Activity of 5-Diethylsulfonamoylsalicylatocopper(II) in Gamma Irradiated Mice.

Survival and changes in mean body mass of whole-body irradiated mice were determined to examine the radioprotectant activity of 5-diethylsulfonamoylsalicylatocopper(II) [Cu(II) (5-DESS)]. One of four groups of 25 female C57BL/6 mice were treated subcutaneously (sc)with 0, 10, 20, 40, 60, 80, 100, or 120 mumol Cu(II)(5- DESS)/kg of body mass 3 hours before exposure to 8.0 Gy, gamma irradiation. In this paradigm, doses of Cu(II)(5- DESS) increased survival up to 92% above vehicle-treated control mice (P = 0.008). Mean body mass determinations revealed that mice treated with 80 to 120 mumol Cu(II)(5-DESS)/kg of body mass exhibited a smaller decrease in body mass than other complex-treated groups. These results support the hypothesis that Cu(II)(5-DESS) is an effective radioprotectant.

Radiorecovery activity of manganese(III)2(II)(mu 3-O)-(mu-3,5-diisopropylsalicylate)6.

Manganese(III)2(II)(mu 3-O)(mu-3,5-diisopropylsalicylate)6 [Mn3(O)(3,5-DIPS)6] was used to treat female C57BL/6 mice irradiated with LD50/30 doses of gamma rays and examine the possibility that treatment after irradiation increases survival. Female C57BL/6 mice were treated with 0, 10, 20, or 40 mumol Mn3(O)(3,5-DIPS)6/kg of body mass 1 or 3 h after irradiation. Treatment with 40 mumol/kg 1 or 3 h after irradiation produced survivals of 72 or 92%, respectively, increases of 29 or 130% in comparison with 56 or 40% survivals in the respective vehicle-treated groups. These data support the hypothesis that Mn3(O)(3,5-DIPS)6 is an effective radiorecovery agent.

Copper(II)ethylenediaminetetraacetate does disproportionate superoxide.

The superoxide dismutase (SOD) mimetic reactivity of Cu(II)EDTA was studied in the pH range of 6.0 to 8.0. Cu(II)EDTA disproportionated superoxide without inhibiting superoxide production by xanthine oxidase, as a result of bonding sites becoming available on the copper complex with increasing acidity. This disproportionation by Cu(II)EDTA is offered as evidence that the addition of EDTA to biological preparations for the purpose of complexing copper and thereby inhibiting copper-dependent superoxide disproportionation and promoting superoxide-dependent reactions is not a valid practice.

Copper complexes of non-steroidal antiinflammatory agents: analgesic activity and possible opioid receptor activation.

Cu(II)2(acetylsalicylate)4, Cu(II)(anthranilate)2, Cu(II)2[1-(p-chlorobenzoyl)-5-methoxy-2-methyl-3-indolylacetate]4, Cu(II)(3,5-diisopropylsalicylate)2, Cu(II)(salicylate)2, Cu(II)2(2-[3-(trifluoromethyl)-phenyl]aminonicotinate)4, Cu(II)(L-alaninate)2, Cu(II)(L-cystinate)2, and Cu(II)(glycinate)2 were generally found to be more effective analgesics than their parent ligands, Cu(II)(chloride)2, and Cu(II)2(acetate)4 in the Writhing Mouse and Adjuvant Arthritic Rat pain models following subcutaneous and oral administration. Comparison of the time course of analgesia for salicylic acid and Cu(II)(salicylate)2 in the adjuvant arthritis pain model revealed that this complex had more sustained activity in addition to being more potent than salicylic acid. Cu(II)2(indomethacin)4 was also found to be as effective as morphine in both pain models. These data and pertinent literature are discussed in support of the hypothesis that copper complexes activate copper-dependent opioid receptors.