mitoguazone and propylglyoxal-bis(guanylhydrazone)

Phenylglyoxal bis(guanylhydrazone) (PGBG) is a synthesized analogue of methylglyoxal bis(guanylhydrazone) (MGBG), which has demonstrated anti-parasitic activity in rabbits. The pharmacokinetic behaviour of PGBG after intravenous administration (10 mg/kg bodyweight) was studied in five rabbits. Plasma concentrations of PGBG were measured by high-performance liquid chromatography. Plasma PGBG concentrations decreased rapidly and were not detectable beyond 90 min after treatment. The mean [+/- standard deviation (SD)] volume of distribution at steady state (Vdss) was 2.19 +/- 0.47 l/kg and the mean plasma clearance value (Cl) was 29.99 +/- 3.98 ml/min kg. This drug is rapidly eliminated from the body in rabbits, having a short elimination half-life (0.93 h) and mean residence time (1.21 h).

Topics: Animals; Antiparasitic Agents; Enzyme Inhibitors; Half-Life; Injections, Intravenous; Metabolic Clearance Rate; Mitoguazone; Rabbits

Guanylhydrazones, methylglyoxal bis(guanylhydrazone) (MGBG) and a new compound, phenylglyoxal bis(guanylhydrazone) (PGBG), interfering with polyamine biosynthesis have considerable potential for the use as antiparasitic and antitumor agents. The effect of these drugs on the cellular viability of Chinese hamster ovary cells was examined by in vitro neutral red assay. The time exposure and metabolic influence was studied. These compounds have a dose- and time-dependent cytotoxicity. The IC50 values were of 597.22 micrograms/ml and 1.77 micrograms/ml for MGBG after 3 and 24 h of incubation, respectively, and 380.50 micrograms/ml for PGBG after 24 h of incubation. The PGBG treatment during 3 h had no cytotoxic effect when the concentrations were lower than 3000 micrograms/ml. With the cytotoxicity assay used, we observed that the presence of S9 in cultured medium did not influence the cytotoxicity of these compounds.

Topics: Adenosylmethionine Decarboxylase; Animals; Antineoplastic Agents; Cell Survival; Cells, Cultured; CHO Cells; Cricetinae; Dose-Response Relationship, Drug; Enzyme Inhibitors; Mitoguazone; Neutral Red

Topics: Absorption; Adenosylmethionine Decarboxylase; Administration, Oral; Animals; Biological Availability; Half-Life; Injections, Intravenous; Mitoguazone; Rabbits

1. Activity of S-adenosylmethionine decarboxylase, one of the rate-limiting enzymes of polyamine biosynthesis, was determined in oocysts of Eimeria stiedai, a coccidian parasite of the rabbit. 2. Several properties of the enzyme were compared to the mammalian enzyme. It showed considerably less substrate affinity than the analog enzyme from the rabbit. 3. The E. stiedai enzyme showed a low sensitivity to methylglyoxal bis(guanylhydrazone), a frequently used inhibitor of the enzyme in mammals, and two phenylated derivatives. 4. Results with the inhibitors are discussed in view of their potential use in chemotherapy.

Topics: Adenosylmethionine Decarboxylase; Animals; Carboxy-Lyases; Eimeria; Kidney; Kinetics; Liver; Mitoguazone; Rabbits; Rats; Species Specificity; Spleen

Two phenylated compounds of methylglyoxal bis(guanylhydrazone), potentially inhibitors of diamine oxidase activity, have been synthesized: phenylglyoxal bis(guanylhydrazone) and diphenylglyoxal bis(guanylhydrazone). Their inhibitory capacity was tested: while PGBG was able to reduce the enzyme activity by 50% at 1.3 microM, DPGBG was only able to reduce diamine oxidase activity by less than 2% at a concentration 1000-fold higher. The inhibition of PGBG was non-competitive and the Ki calculated by a Dixon plot was estimated as 1.7 microM.

Topics: Amine Oxidase (Copper-Containing); Animals; In Vitro Techniques; Intestine, Small; Kinetics; Mitoguazone; Proteins; Rats; Rats, Inbred Strains