True and False Prophylaxis in Experimental Trypanosomiasis

Abstract

It is generally accepted that, during the period of prophylaxis with chemoprophylactic agents, the host remains protected against the immediate infection, as well as against future infections. However, it has been described how Trypanosoma congolense "broke through the protective cover" of prophylactic phenanthridium compounds, inducing an intermittent type of infection in the protected animal; characteristically, these "breakthrough" strains, when transferred to untreated animals, lead to a mortal infection as rapidly as the original trypanosome strain (1). A new diamidine (98/202) of 2-phenyl-thionaphthene (2), in subcutaneous doses of 100 mg/kg protected mice inoculated 20 days later with multiple lethal doses of Trypanosoma venezuelense; when the reactivity of the protected mice to reinoculation was tested 1 1/2 months later, they developed an intermittent parasitaemia beginning the next 3-4 weeks, followed by death (3). The considerable delay in the development of the parasitaemia and its intermittent form we attribute to a residual prophylactic action of the drug, with the corollary that the inoculum injected during an assumed period of protection may develop much later into a lethal infection. This hypothesis that the inoculation may cause a latent infection in the presence of the prophylactic drug without manifesting a detectable parasitaemia, and that the chemotherapeutic prophylaxis is not an all-or-none phenomenon, has been investigated. Materials and methods. T. venezuelense, (T. evansz'), isolated by Dr. Raul Hernandez from a case of equine "derrengadera" in 1969, was maintained since through mouse passages in our laboratory and used for various chemotherapeutic studies. Its virulence for mice and rats was repeatedly titrated: inocula above 100 parasites killed 95% of the injected animals in a time interval (7-16 days) varying according to the heaviness of the inoculum. The standard ip inoculum of 5 X lo5 parasites, as used in the present study, induced detectable parasitaemia within 24 hr in 63 f 3%, within 48 h in 90 k 2%, within 72 hr in 94 k 1.6% of mice. The progressive parasitaemia terminated in death 3--6 days after its appearance. The rats were as sensitive as mice to the standard inoculum containing 5 X lo5 trypanosomes: parasitaemia appeared in 96 k 1% of the animals within 24-72 hr, increasing progressively until death which occurred 1-7 (av. 5.4) days later.In the chemoprophylactic experiments, the sc injection of these drugs to groups of 14-35 mice or rats was followed at various periods by the ip inoculation with 5 X lo5 trypanosomes. During the first period (2-3 weeks) after inoculation, daily observations were made, if the animals showed no parasitaemia during this interval, the observations were reduced to alternate days.The infectivity of a selected number of mice and rats was tested by transferrring blood, and spleen and liver macerates suspended in saline, to groups of 4-5 mice. Occasionally, after a certain period of clearance the animals were reinfected with the standard inoculu...

Ethidium bromide: pharmacokinetics and efficacy against trypanosme infections in rabbits and calves

“…While no curative effect of ethidium was observed under our experimental conditions, there was an apparent prophylactic action following the ethidium treatment of T. congolense-infected rabbits. The concept of 'true or false prophylaxis' was described by Ercoli (1978) in experiments with an aromatic diamidine and our results are in agreement with his finding that apparent chemotherapeutic prophylaxis may merely be an extension of a sub-patent parasitaemia rather than absolute protection. Following a study of the prophylactic actions of ethidium in cattle, Leach et al (1955) commented similarly: 'it is possible that the drug does not protect completely but rather allows the establishment of a suppressed infection which is only occasionally detected in the bloodstream'.…”

Trypanostatic Drug Action: Its Relation to Relapse Following Chemotherapy

“…The occurrence of a trypa nostatic drug action, inferred from the 'false prophylaxis' [1], becomes unequivocal by these findings.…”

“…The atypical (delayed, intermittent and/or slow) course of the reinfection in the other cases mentioned, is attributed to the action of further reduced, but not completely inhibitory, residual drug concentrations. The drug retention 43-52 days after 20-40 mg/kg pentamidine injec tion was not sufficient to influence the de velopment of the reinfection, in accordance with the shorter transient prophylactic effect of this drug, permitting the development of parasitemia on average 21 and 27 days after administration of 35.5 and 75 mg/kg, re spectively [1].…”

“…During this latent period, virulent parasites showing the original drug sensitivity were recovered from the organs and blood, indi cating that only their ability to divide was inhibited in the host. However, higher drug concentrations, obtained either by earlier inoculation following prophylaxis or with larger doses, completely destroy the infec tive inoculum [1], The cryptic infection of the "false pro phylaxis' and the succeeding delayed slow parasitemia recalls the clearing and relapse following chemotherapeutic treatment in trypanosomiasis with subcurative doses, which has no established interpretation. A recent study [2] of Trypanosoma brucei infection in mice attributes relapse to "the trypanosomes escaping the action of the drug, either because they are in an inacces sible situation in the body or in an insuscep tible stage of development', thereby denying the formation of drug-resistant organisms, as is claimed by other authors.…”