The pharmacokinetic of 4'-deoxydoxorubicin, a new analog of doxorubicin, was compared with that of its parent compound in mice treated with equal and equiactive doses. The levels of total fluorescence due to the initial drugs and to metabolites were determined in tissue extracts by fluorometry. 4'-Deoxydoxorubicin reached the same tissue levels as doxorubicin in all the organs tested except in spleen and lung, where a higher peak was found in the animals treated with the new analog. The rate of elimination of 4'-deoxydoxorubicin from the organs tested was higher than that of doxorubicin.
The tissue distribution of 4-demethoxydaunorubicin and 4-demethoxydoxorubicin was studied in comparison with that of their patient compounds, daunorubicin and doxorubicin, in mice bearing transplanted tumors. The doses administered were equal or equitoxic to those of their parent compounds. The levels of total fluorescence due to initial drugs and metabolites were determined on tissue extracts by fluorometry. After administration of equal doses of daunorubicin and 4-demethoxydaunorubicin, the calculated Cxt values of 4-demethoxydaunorubicin equivalents were higher than those for daunorubicin in all the organs tested except the heart. In animals treated with equitoxic doses, lower 4-demethoxydaunorubicin levels were found in all the organs tested. In mice treated with equitoxic doses of doxorubicin and 4-demethoxydoxorubicin, 4-demethoxydoxorubicin reached higher drug concentrations than doxorubicin in spleen and liver, whereas in all the other organs tested lower drug levels were found. The rate of drug disappearance from organs was slower in animals treated with 4-demethoxyderivatives than in those treated with their parent drugs.
It has been reported that 4-demethoxy-4'-O-methyldoxorubicin (4-dm-4'-O-methylDX) is more potent than doxorubicin (DX), equally active in some murine leukemias and solid tumors, and almost devoid of cardiotoxicity. We used HPLC to investigate the metabolism and the disposition of this drug in comparison with DX in mice bearing colon 38 adenocarcinoma SC and treated with IV doses of the two drugs that were equiactive and equitoxic (4-dm-4'-O-methylDX 1 mg/kg; DX 10 mg/kg). 4-Dm-4'-O-methylDX was metabolized to a polar metabolite, presumably 4-demethoxyDX, which was eliminated more slowly than the parent drug from all the organs and accounted for 25%-50% of total fluorescence; traces of two metabolites less polar than the parent drug (2% of total fluorescence) were found only at early times in the liver. In DX-treated mice traces of doxorubicinol (1%-3% of total fluorescence) were found in tumor and organs, and two aglycones were detected only at early times in the liver. In plasma both drugs declined biexponentially and 4-dm-4'-O-methylDX was eliminated slightly faster than DX. The rate of elimination of the new analogue from lung, kidney, spleen, and small intestine was faster than that of DX; in heart and liver 4-dm-4'-O-methylDX was detectable for only up to 24 h, while DX was detectable for up to 7 days. In the tumor the kinetics and the elimination patterns of the two drugs were similar. The distribution of 4-dm-4'-O-methylDX, as a percentage of the administered dose, was 1.3-2 times higher than that of DX in the organs and 3 times higher in the tumor, which suggests an improved selectivity of the new analogue for the tumor compared with DX.
In a multi-centre double-blind cross-over trial using the double-placebo technique, 55 patients with rheumatoid arthritis were treated for 10 days for each trial drug with ketoprofen (200 mg/day) and ibuprofen (1200 mg/day). Both drugs induced a clinically and statistically significant improvement of all the symptoms studied, except for pain at night during ibuprofen administration. Ketoprofen displayed a therapeutic efficacy significantly superior to ibuprofen in five of the eight symptoms studied. Side-effects were recorded in 10 patients receiving ketoprofen (one patient withdrew because of heartburn) and in nine patients receiving ibuprofen.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.