Blood concentration and toxicity of the antimetastasis agent NAMI-A following repeated intravenous treatment in mice.
NAMI-A is a new generation antitumour ruthenium-based agent and characterised by strong efficacy against lung metastases of experimental solid tumours in mice. The effects of intravenous administration of 15, 35 and 50 mg/kg/day of NAMI-A for 5 consecutive days on blood concentration and host toxicity were tested on Swiss CD1 male and female mice. The blood concentration of NAMI-A, both after the first injection and at the end of the 5-day treatment fell rapidly and 5 min. after the last injection it was always below 10% of the administered dose. Kinetic parameters, calculated at the end of the 5-day treatment cycle according to a mono-compartment model (fitting with R2=0.9), indicate a t 1/2 of about 18 hr. Toxicity i) was observed only at the highest dose used (50 mg/kg/day), ii) was greater in females than in males, iii) in mice which survived treatment was completely reversed within 3-weeks of the end of the treatment. Haematological examinations, clinical chemistry data and histopathologic studies were consistent in terms of the effect on host lymphoid tissues, consisting in spleen and lymph node depletion and in a general increase of circulating leukocytes. Data on ruthenium organ retention confirm lack of brain penetration and a relatively high lung concentration which might account for the remarkable effect on lung metastases.
Cocchietto
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Institutes of Biological Research, Callerio Foundation, Trieste, Italy.
Sava
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D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D001772:Blood Cell Count; D001835:Body Weight / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000187:drug effects; D005260:Female; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000633:toxicity*; D012428:Ruthenium / Q000032:analysis / Q000493:pharmacokinetics; D017975:Ruthenium Compounds; D013054:Spectrophotometry, Atomic; D015996:Survival Rate; D014018:Tissue Distribution; D018675:Toxicity Tests
D000970:Antineoplastic Agents; D009942:Organometallic Compounds; D017975:Ruthenium Compounds; C113661:imidazolium-bis(imidazole)dimethylsulfoxideimidazotetrachlororuthenate(III); D012428:Ruthenium; D004121:Dimethyl Sulfoxide