mitoguazone and Trypanosomiasis--African

A series of novel aromatic derivatives based on the structure of methylglyoxal bis(guanylhydrazone) (MGBG) was examined for trypanocidal activities in human and veterinary trypanosomes of African origin. One agent, CGP 40215A, a bicyclic analog of MGBG which also resembles the diamidines diminazene (Berenil) and pentamidine, was curative of infections by 19 isolates of Trypanosoma brucei subspecies as well as a Trypanosoma congolense isolate. Several of these isolates were resistant to standard trypanocides. Curative doses were < or = 25 mg/kg of body weight/day for 3 days in these acute laboratory model infections. In addition, CGP 40215A also cured a model central nervous system infection in combination with the ornithine decarboxylase inhibitor DL-alpha-difluoromethylornithine (DFMO; Ornidyl, eflornithine). Curative combinations were 14 days of oral 2% DFMO (approximately 5 g/kg/day) plus 5, 10, or 25 mg/kg/day for 3 or 7 days given by intraperitoneal injection or with a miniosmotic pump. Combinations were most effective if CGP 40215A was given in the second half or at the end of the DFMO regimen. MGBG has modest activity as an inhibitor of trypanosome S-adenosylmethionine decarboxylase (50% inhibitory concentration [IC50]. 130 microM), while CGP 40215A was a more active inhibitor (IC50, 20 microM). Preincubation of trypanosomes with CGP 40215A for 1 h caused a reduction in spermidine content (36%) and an increase in putrescine content (20%), indicating that one possible mechanism of its action may be inhibition of polyamine biosynthesis.

Topics: Adenosylmethionine Decarboxylase; Animals; Female; Mice; Mice, Inbred ICR; Mitoguazone; Random Allocation; Robenidine; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosoma brucei rhodesiense; Trypanosoma congolense; Trypanosomiasis, African

Trypanosoma brucei E164 and a dyskinetoplastic derivative, Dysk164, were injected into mice that were treated subsequently with methylglyoxal-bis-guanylhydrazone, berenil, ethidium bromide, and acriflavine. Additionally, parasites were photoaffinity labeled with ethidium monoazide to effect covalent drug attachment prior to injection into animals. In all cases, killing of animals with E164 was blocked by the drug treatment, whereas killing due to Dysk164 was not. These findings are consistent with the view that the intact kinetoplast plays an essential role in the action of these drugs.

Topics: Acriflavine; Animals; Azides; Diminazene; Dose-Response Relationship, Drug; Drug Resistance; Ethidium; Female; Light; Mice; Mitochondria; Mitoguazone; Mutation; Parasitemia; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

The efficacy of melarsoprol in the treatment of chronic T. b. brucei infections in mice can be increased approximately 5 times if DL-a-difluoromethylornithine (DFMO) is given in the drinking water at the same time. A more detailed study substantiated the concept that a reduction in both the size and the rate of replacement of the trypanothione pool are the key factors in the efficiency of melarsoprol chemotherapy. It was therefore best to give the melarsoprol towards the end of the DFMO regimen, and as a guanylhydrazone (TBG) also blocks trypanothione (polyamine) biosynthesis, if TBG/DFMO are given together the treatment period can be reduced to 8 days. The antimony compound, sodium stibogluconate (Pentostam), used in combination with DFMO can also cure these infections and demonstrates that arsenic could be substituted by antimony in the treatment of CNS infections.

Topics: Animals; Antimony Sodium Gluconate; Arsenicals; Drug Synergism; Drug Therapy, Combination; Eflornithine; Melarsoprol; Mice; Mitoguazone; Trypanosoma brucei brucei; Trypanosomiasis, African

This study reports the action of ten drugs on two strains of Trypanosoma brucei brucei (Antat 1.9 virulent in mice and Antat 1.1E more chronic) in vitro in acellular semi defined medium and in vivo in Swiss mice. Minimum efficient concentration of drugs is evaluated by means of an in vitro assay: melarsoprol (1 microgram/ml); DFMO (cytostatic effect from 50 micrograms/ml); suramin (1 microgram/ml); 2 nitroimidazole derivative Ro 15-0216 (1 microgram/ml); triacetylbenzene trisguanylhydrazone (TBG) (between 1 and 10 mg/ml). Fluconazole is not efficient in vitro on T. b. brucei. In vivo: TBG is efficient at 3 mg/kg, DFMO given orally and intraperitoneally is not efficient at 4 g/kg, but surviving time of mice is increased. Suramin (20 mg/kg/d X 4) alone or associated with ornidazole (50 and 500 mg/kg/d X 4) is efficient on bloodstream trypanosomes but no efficacy is revealed on brain forms. Cyclosporin (30 mg/kg/d X 3) lightly increases surviving time of mice. Fluconazole, pefloxacin and acyclovir are not efficient in vivo.

Topics: Acetanilides; Animals; Culture Media; Cyclosporins; Eflornithine; In Vitro Techniques; Melarsoprol; Mice; Mitoguazone; Nitroimidazoles; Suramin; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

The efficacy of 1,3,5-triacetylbenzene tris(guanylhydrazone) trihydrochloride i.e. [(TBG)] in the treatment of early and late stage infections of Trypanosoma brucei in mice was investigated. Successful treatment on day 3 after infection could be achieved by doses of 2 X 2.5 mg kg-1. If treatment was delayed to 21 days after infection then the mice had to be given either suramin (1 X 20 mg kg-1) or difluoromethyl-ornithine (DFMO) 2% solution for 14 days in addition to either 15 mg kg-1 (TBG) daily for 4 days or 10 mg kg-1 twice daily for 4 days to obtain permanent cures. Other guanylhydrazone compounds were investigated for the treatment of chronic T. brucei infections and, at the limited dose levels used, failed to give any permanent cures. The use of (TBG) in the treatment of early and late stage infections of T. congolense and T. evansi indicated that treatment on day 3 after infection could be successful but on day 21 after infection the results were disappointing.

Topics: Animals; Drug Therapy, Combination; Eflornithine; Female; Mice; Mitoguazone; Suramin; Trypanocidal Agents; Trypanosoma; Trypanosoma brucei brucei; Trypanosoma congolense; Trypanosomiasis, African

Based on the antitrypanosomal activity of 1,3-diacetylbenzene bis(guanylhydrazone) (4) and 2,6-diacetylpyridine bis(guanylhydrazone) (17), a number of substituted and heterocyclic 1,3-arylene diketone bis(guanylhydrazone)s were prepared and tested against Trypanosoma brucei infections in mice. A wide range of ED50 values was observed among 5-substituted derivatives of 4. The 5-amino analogue 5 and 5-acetamido analogue 6 were about twice as active as 4. 1,3,5-Triacetylbenzene tris(guanylhydrazone) (12) was about 9 times as active as 4 and was approximately one-half as active as the currently used trypanocide diminazene aceturate in this test system. Other 5-derivatives had activity equivalent to or less than that of the parent compound 4. Three new heterocyclic analogues were all less active than 2,6-diacetylpyridine derivative 17 and benzene derivative 4. Ring substitution ortho to the guanylhydrazone side chains was invariably detrimental to activity. Side-chain homologues 1,3-dipentanoylbenzene bis(guanylhydrazone) and 1,3-diacetylbenzene bis(2-imidazolin-2-ylhydrazone) were essentially inactive.

Topics: Animals; Drug Evaluation, Preclinical; Female; Guanidines; Indicators and Reagents; Magnetic Resonance Spectroscopy; Mice; Mitoguazone; Structure-Activity Relationship; Trypanocidal Agents; Trypanosoma brucei brucei; Trypanosomiasis, African

Methyglyoxal bis (guanylhydrazone) (MGBG) at 0.5 mM had little effect in vitro on Blastocrithidia culicis, Crithidia oncopelti, and Leishmania spp., but completely inhibited growth of Trypanosoma brucei. Inhibition became irreversible after a 3-h exposure of T. brucei culture procyclics. Treated organisms remained motile, but failed to divide. Polyamines, spermidine, and spermine, did not reverse the anti-trypanosome action of MGBG (preloading of cells or concurrent administration). Two intraperitoneal injections of the drug at a concentration of 50 mg/kg body weight at a 1-day interval greatly reduced the parasitemia of T. brucei and T. congolense in rats. Trypanosome infections, however, relapsed and killed the animals in 6 days after treatment. It was evident from the results of tracer experiments with T brucei that MGBF significantly lowered incorporation of [3H]thymidine by culture pocyclics and of [3H]uridine by bloodstream forms; in both stages [3H]leucine incorporation was only slightly inhibited. It is suggested that MGBG interferes with nucleoside incorporation by Trypanosoma and that its mode of action is different in bloodstream and culture procyclics.

Topics: Animals; Eukaryota; Guanidines; Leishmania; Mitoguazone; Pyrimidine Nucleosides; Thymidine; Trypanosoma brucei brucei; Trypanosomiasis, African; Uridine