cicaprost and eptaloprost

Much attention has recently focused on the role of tumor cell-platelet interaction in the metastatic cascade. Prostacyclin and stable prostacyclin analogues have been shown to inhibit specifically the formation of metastases in experimental tumor models. This action is based on their ability to reduce the attachment of tumor cells to platelets and to inhibit adhesion of tumor cells-platelet aggregates to the endothelial lining. To investigate the antimetastatic potential of two prostacyclin analogues (Iloprost and Eptaloprost, Schering AG), we have tested these compounds in the spontaneously metastasizing R 3327 MAT Lu prostate carcinoma of the Cop rat in two types of experiments. Treatment was performed for 33 days, starting one day before s.c. implantation of the tumor. The primary s.c.-implanted tumor remained in situ throughout the experiment. In the first test, Iloprost (0.3 micrograms/kg/min) and Eptaloprost (0.1 micrograms/kg/min) were administered via Alzet mini pumps s.c.. There was a considerable reduction of the number of visible lung metastases by Eptaloprost. In the second test, Eptaloprost was administered p.o. in doses of 0.1 and 0.5 mg/kg daily. The number of lung metastases was significantly reduced. Both compounds had no effect on the growth of the primary tumor in the first as well as in the second test. These data show that the prostacyclin analogue Eptaloprost has a significant antimetastatic activity in a spontaneously metastasizing tumor model and thus merits further investigation.

Topics: Animals; Antineoplastic Agents; Epoprostenol; Iloprost; Molecular Structure; Neoplasms, Experimental; Platelet Aggregation Inhibitors; Prodrugs

Topics: Animals; Antineoplastic Agents; Epoprostenol; Iloprost; Immunocompetence; Melanoma, Experimental; Neoplasm Metastasis

Cica-, eptalo- and iloprost are chemically and metabolically stabilized derivatives of prostacyclin which maintain the pharmacodynamic profile of the endogenous precursor. While iloprost is still subject to beta-oxidative degradation of the upper side chain, cicaprost is highly metabolically stable. Eptaloprost was synthesized to realize the pro-drug concept in PGI2-mimetics and was designed to be activated to cicaprost by single beta-oxidation. All three prostacyclin-mimetics were studied in various animal species (mouse, rat, rabbit, monkey, dog and pig) and in man to determine their pharmacokinetic profiles. Based upon this data, it was of interest whether an inter-species extrapolation of pharmacokinetic parameters can be performed to show the predictive value of animal experimentation. Allometric inter-species extrapolation is performed by modelling pharmacokinetic data (Y) as exponential functions (x) of species characteristics (e.g. body weight, W) as: Y = .aWx. For total clearance and volumes of distribution at steady state, a clear-cut correlation with x-values of 0.6-0.8 and 1.0-1.1 could be shown for all three compounds. For cicaprost, which was excreted unchanged in several species, renal and non-renal clearance was also mathematically scalable. Due to the use of different compartment models to describe plasma disposition, different sets of half-life data were obtained and could not be extrapolated reasonably. However, mean residence time showed a dependency on body weight with 0.25 as power function. In case of cicaprost, only the dog, which extensively metabolizes the compound, could not be enrolled in inter-species extrapolation. Excretion half-lives or residence times did not show a significant correlation to body weight or maximum life time potential. The present inter-species extrapolation showed a dependency from species body weight for model-independent pharmacokinetic data, e.g. clearance, volume of distribution at steady state and correspondingly mean residence time. The disposition profile of these compounds can therefore be predicted. Preliminary information on bio-degradation is an additional prerequisite for extrapolation. These data demonstrate that basic physiologically determined processes, which show some evolutionary allometric dependency, also influence the disposition of prostacyclin-mimetics. An extrapolation of data from animal to man could easily be realized giving additional justification for animal studies in pharmaco

Topics: Animals; Dogs; Epoprostenol; Half-Life; Haplorhini; Humans; Iloprost; Mice; Molecular Mimicry; Rabbits; Rats; Species Specificity; Swine

Eptaloprost is a novel concept PGI2-mimetic, which is designed to be activated to the pharmacologically potent cicaprost via beta-oxidation. By pro-drug formation advantages in terms of sustained delivery of prostacyclin-mimetic activity were envisaged. The active metabolite is known to be metabolically stable and highly pharmacologically potent. In the present set of experiments the pharmacokinetics of eptaloprost was studied in rat, monkey and man by i.v. and ig administration of tritiated compound. Eptaloprost was completely and rapidly absorbed in all three species. Peak plasma levels of the parent compound were observed within 30 min postdose. Total clearance of the pro-drug accounted for 170, 62 and 66 ml/min/kg in rat, monkey and man. Disposition of eptaloprost exhibited half-lives of 0.1 to 0.5 h and mean residence times accounted for 0.15, 0.4 and 0.6 h in the three species. The active metabolite cicaprost was present in the central compartment with a slight delay as compared to eptaloprost. Its peak plasma levels were found within 0.25 to 0.5 h postdose. Disposition of radiolabel in plasma and 3H-excretion with the urine and feces was determined by the pharmacokinetic behaviour of cicaprost. In rats excretion was mainly biliary while monkeys and man excreted almost unchanged cicaprost in equal portions with urine and feces. Half-lives of renal excretion were in the range of terminal half-lives in the central compartment. Neither in animals nor in man eptaloprost administration resulted in an advantageous systemic profile of cicaprost. On the contrary the bioavailable dose fraction of cicaprost was lower as compared to cicaprost administration. A delay or an extension of cicaprost plasma levels was not observed. The present pharmacokinetic data of eptaloprost studied in three species demonstrated that a pro-drug concept based on simple beta-oxidative bioactivation could be successfully realized for a special PGI2-mimetic. An advantage resulting from oral pro-drug administration as compared to direct treatment with the active metabolite could not be shown. For long-lasting plasma levels of cicaprost a chemically determined retardation might require a more sophisticated pro-drug concept or alternatively pharmaceutical technology is required.

Topics: Absorption; Aged; Animals; Biotransformation; Epoprostenol; Feces; Female; Half-Life; Humans; Iloprost; Kinetics; Macaca fascicularis; Male; Middle Aged; Rats; Rats, Wistar; Species Specificity; Tritium

Topics: Animals; Antineoplastic Agents; Epoprostenol; Female; Iloprost; Mice; Neoplasm Metastasis; Platelet Aggregation