title: The story of CGP 40 215: studies on its efficacy and pharmacokinetics in African green monkey infected with Trypanosoma brucei rhodesiense.
abstract: CGP 40 215 is an inhibitor of S-adenosylmethionine decarboxylase, a key enzyme in trypanosomal polyamine biosynthesis. It is highly active against Trypanosoma brucei rhodesiense and T. b. gambiense in vitro and in the corresponding rodent models, and therefore was a promising candidate for further development as a new drug against human African trypanosomiasis. We conducted initial pharmacokinetic and efficacy studies in African green monkeys: based on two dose-finding studies, an infection-treatment and a pharmacokinetic study in eight monkeys infected with T. b. rhodesiense in the 1st stage of infection. PK analysis revealed curative drug levels in the serum but complete absence of the drug in the cerebrospinal fluid. No adverse effects of the drug were observed, although in rats CGP 40 215 had caused hypotension. The following PK parameters were calculated using a two-compartment model: t1/2=1.8 h, VSS/f=0.4 l/kg, CL/f=3.0 ml/min x kg and AUC=21 900 ng x h/ml. Six of the eight monkeys were cured, one animal relapsed on day 222 and one animal died of unknown reasons, but was aparasitaemic. The study confirmed the curative potential of CGP 40 215 for 1st stage T. b. rhodesiense infection. Unfortunately, it was also found that the compound did not pass the blood-brain barrier, a pre-requisite for cure of 2nd stage (CNS) infection. As the majority of sleeping sickness patients seeking treatment are in the 2nd stage of the disease, further development of the compound was stopped.
authors.affiliation: Swiss Tropical Institute, Basel, Switzerland. reto.brun@unibas.ch
authors.forename: R
authors.initials: R
authors.lastname: Brun
authors.forename: C
authors.initials: C
authors.lastname: Burri
authors.forename: C W
authors.initials: CW
authors.lastname: Gichuki
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000037:antagonists & inhibitors*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001812:Blood-Brain Barrier / Q000187:drug effects; D002522:Chlorocebus aethiops; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D016903:Drug Monitoring; D005260:Female; D012370:Robenidine / Q000031:analogs & derivatives / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D013997:Time Factors; D014344:Trypanocidal Agents / Q000097:blood / Q000737:chemistry / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016833:Trypanosoma brucei rhodesiense / Q000187:drug effects* / Q000201:enzymology*; D014353:Trypanosomiasis, African / Q000097:blood / Q000188:drug therapy* / Q000469:parasitology*
chemical_list: D014344:Trypanocidal Agents; C102850:bis((3-(aminoiminomethyl)phenyl)methylene)carbonimidic dihydrazide trihydrochloride; D012370:Robenidine; D012437:Adenosylmethionine Decarboxylase