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Biomedical subjects

F W Jennings

Publications and source records attributed to F W Jennings.

At least 37 records · Page 2Linked to original sources
PubMed1991

Immunopathology of experimental African sleeping sickness: detection of cytokine mRNA in the brains of Trypanosoma brucei brucei-infected mice.

The immunopathology of Trypanosoma brucei brucei in the central nervous system was studied by using an experimental model of chronic meningoencephalitis in outbred CD-1 mice. Mice infected with T. b. brucei were treated with a subcurative dose of the trypanocidal compound diaminazine aceturate. These mice relapsed and were again drug treated. The brains were examined histologically and by immunocytochemistry to identify activated astrocytes. The polymerase chain reaction was used to detect cytokine RNA transcripts. The infected and treated animals developed severe chronic meningoencephalitis characterized by large numbers of inflammatory cells and widespread astrocyte proliferation. In uninfected controls, only interleukin 1 and beta-actin RNA transcripts were detected while transcripts for beta-actin, tumor necrosis factor alpha, macrophage inflammatory protein 1 and interleukins 1 and 4 were demonstrated in the brains of infected animals. Gamma interferon and interleukin 6 were also detected in a few of the infected animals, but interleukin 2 was not found in any of these animals.

Animals↗
PubMed1991

Chemotherapy of trypanosomiasis: the potentiation of antimonial compounds by difluoromethylornithine (DFMO).

The currently available anti-leishmanial antimonial drugs, together with other antimony compounds were individually tested, in combination with difluoromethylornithine (DFMO), against experimental murine trypanosomiasis with central nervous system involvement. Satisfactory cure rates could be achieved using a combination treatment of DFMO with most of these anti-leishmanial drugs, but in general, only when they were administered at least twice daily. Of the compounds tested, the most effective was antimony dimercaptosuccinate (Astiban).

Animals↗
PubMed1991

Chemotherapy of CNS-trypanosomiasis: combination chemotherapy with a 5-nitroimidazole (MK 436), an arsenical (Cymelarsan) and suramin.

A detailed study of the combined effect of suramin, MK 436 (5-nitroimidazole) and Cymelarsan (melaminylthioarsenate) was investigated in the murine CNS-trypanosomiasis model. Using a combination of Cymelarsan and MK 436 without preliminary suramin, complete cures were obtained with a 2 day treatment of 15.0 mg/kg MK 436 and 5.0 mg/kg Cymelarsan. If the MK 436 was reduced to 10 mg/kg then 4 consecutive daily treatments were required. If the Cymelarsan was reduced to 2.5 mg/kg either a 3 day treatment in combination with 15.0 mg/kg or a 4 day treatment with 10 mg/kg MK 436 was necessary. Utilizing the single suramin (20 mg/kg) dose followed by combined MK 436/Cymelarsan a 2 day treatment with 10 mg/kg (or twice daily 5.0 mg/kg) MK 436 and 2.5 mg/kg Cymelarsan gave complete cures. Maximum cure rate for suramin followed by a one day treatment with 15 mg/kg MK 436 and 5.0 mg/kg Cymelarsan was 4/6 mice, indicating that a one day treatment regimen might be possible with slightly increases dose rates of the two trypanocides. A two day treatment period for CNS-trypanosomiasis is therefore feasible with the dose levels used in these experiments provided a combination chemotherapeutic regimen of suramin, MK 436, Cymelarsan are employed.

Animals↗
PubMed1991

Chemotherapy of CNS-trypanosomiasis: the combined use of the arsenicals and nitro-compounds.

In trypanosomiasis chemotherapy the main mode of action of the nitro-compounds, including the 5-nitroimidazoles or nitrofurans (nifurtimox) is to increase the oxidative stress on the organism either directly by the production of peroxides or indirectly by "futile redox cycling". If this is the case, then these nitro-compounds and the arsenicals should act in combination on the trypanothione oxidation-reduction reaction of the trypanosome. In this paper this has been demonstrated to occur with all those nitro-compounds which have exhibited reasonable trypanocidal action in monotherapy or other combination chemotherapeutic regimens. A major advantage is the short treatment period of approximately 5 days. Pretreatment with a single dose of suramin increased the efficacy of the nitroimidazole-arsenical combination.

Animals↗
PubMed1988

The potentiation of arsenicals with difluoromethylornithine (DFMO): experimental studies in murine trypanosomiasis.

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.

Animals↗
PubMed1988

The relapse of Trypanosoma brucei brucei infections after chemotherapy in rabbits.

Infections of T. brucei in the rabbit were found to relapse after chemotherapy. The results indicated that 25 mg/kg diminazene aceturate given 3 days after infection resulted in a complete cure but if given 7 days after infection relapses frequently occurred. However, treatment was apparently successful if delayed until 14 or 21 days. Six of the rabbits originally treated with diminazene aceturate on day 7 were treated with suramin 21 days later; in 3 rabbits the infections relapsed. In all rabbits in which drug treatment was not curative, the clinical condition nevertheless improved. An attempt to locate a cryptic focus of infection in rabbits was unsuccessful.

Amidines↗
PubMed1987

Chemotherapy of trypanosomiasis: the use of guanylhydrazone compounds in the treatment of experimental murine trypanosomiasis.

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.

Animals↗
PubMed1987

Effect of tetracycline administration on the efficacy of diminazene aceturate therapy and prophylaxis in Trypanosoma brucei infections of mice.

The simultaneous administration, to Trypanosoma brucei infected mice, of rolitetracycline or oxytetracycline and diminazene aceturate appeared to have no effect on the initial trypanocidal action of the diminazene aceturate in that trypanosomes were cleared from the circulation. It also had no effect on the duration of the aparasitaemic period which follows diminazene aceturate treatment and the mice remained free of circulating trypanosomes for some time. However, if used prophylactically, relatively large amounts of tetracyclines (4 x 10 mg kg-1) administered with 40 mg kg-1 diminazene aceturate caused a reduction of the prophylactic period compared with those mice given only diminazene aceturate. This reduction in the prophylactic period is unlikely to have any practical significance in the combination diminazene aceturate/tetracycline treatment of domestic animals as diminazene aceturate is used therapeutically and not prophylactically in the control of trypanosomiasis.

Amidines↗
PubMed1985

Induction of human serum-sensitive Trypanosoma brucei stabilates into human serum-resistant "T. rhodesiense".

When chronic Trypanosoma brucei infections of mice are treated with 20 mg/kg suramin, those trypanosomes which have escaped chemotherapy because they are residing in the brain, exhibit a higher degree of human serum resistance than the original infection. This resistance increases if the chronic infection is retreated for a second time, before the trypanosomes in the brain are tested by the blood incubation infectivity test. The transformation is not due to a selection of T. rhodesiense from a T. brucei/T. rhodesiense mixture in the original stabilates as cloned derivatives also exhibit these same characteristics. The implications of this finding are discussed.

Animals↗
PubMed1984

The use of 2-substituted 5-nitroimidazoles in the treatment of chronic murine Trypanosoma brucei infections with central nervous system involvement.

Chronic infections of Trypanosoma brucei GVR 35/2 in mice, normally relapse after conventional chemotherapy because infective trypanosomes in the brain escape the action of the drug and are able to multiply and eventually re-establish a parasitaemia. However, if treatment consists of a single dose of 1 x 20 mg/kg suramin followed 3 or 4 days later by a 2-substituted 5-nitroimidazole, given intraperitoneally, either as a single dose or as a course of daily injections, relapses rarely occur and the majority of the mice are permanently cured. The minimum effective levels for the three 5-nitroimidazole compounds (Merck Sharp and Dohme, Rahway, NJ, USA) were two doses of 10 mg/kg of L611,744; four doses of 10 mg/kg of MK 436; and three doses of 10 mg/kg of L634,549. Generally it was more effective to divide a given total dose into two or more daily doses, rather than to give the 4-nitroimidazole as a single treatment. The effective dose levels are low enough to be of practical significance and, if the 5-nitroimidazoles were ever licensed for humans, might well prove to be an alternative to melarsoprol treatment for the elimination of trypanosomes from the central nervous system.

Animals↗
PubMed1984

Experimental studies on the interaction between infections of Ostertagia leptospicularis and other bovine Ostertagia species.

Experimental infections of calves were carried out with either isolates of predominantly Ostertagia ostertagi, pure O. leptospicularis or a mixed isolate of equal numbers of both these species. The total worms established on day 21 for the mixed species from a total inoculum of 100 000 infective larvae, was 1.2 times greater than from 100 000 larvae of the O. ostertagi isolate and 3.3 times that of the pure O. leptospicularis isolate. The increased establishment in the mixed inoculum referred to both O. ostertagi and O. leptospicularis (days 17 and 21). These differences were both highly significant (P less than 0.01). The severity of the pathological changes was also greater in the mixed infections. It is suggested that these findings must be taken into account when control measures involving alternate grazing of sheep and cattle are being employed.

Abomasum↗
PubMed1983

The use of the 2 substituted 5-nitroimidazole, Fexinidazole (Hoe 239) in the treatment of chronic T. brucei infections in mice.

Relapse of chronic T. brucei infections was completely prevented by treating with either diminazene aceturate (Berenil) at 40 mg/kg or suramin (Germanin) at 20 mg/kg followed by four doses of the 2-substituted 5-nitroimidazole (Fexinidazole) (Hoe 239). None of these drugs administered singly elicited 100% permanent cures although a high percentage of the mice were cured with four doses of Fexinidazole at 250 mg/kg. A single dose of 20 mg/kg suramin followed by four daily doses of 30 mg/kg Fexinidazole will effectively eliminate all the trypanosomes from the brains of chronically infected mice.

Animals↗
PubMed1983

Treatment with suramin and 2-substituted 5-nitroimidazoles of chronic murine Trypanosoma brucei infections with central nervous system involvement.

Mice infected with either of two isolates of Trypanosoma brucei, GVR 23/1 or GVR 35/1, develop a chronic infection in which trypanosomes are localized in the central nervous system. These infected mice were used to evaluate the efficacy of a combination drug treatment comprising suramin and one of three 2-substituted 5-nitroimidazoles. None of the three 5-nitroimidazoles tested alone, cured mice when administered 21 days after infection. However, it was found that T. brucei GVR 23/1 infections could be cured by a single dose of 20 mg/kg suramin followed by a single dose of 80 mg/kg L611,744 [3a,4,5,6,7,8,9,9a-octahydro-3-(1-methyl-5-nitroimidazol-2yl)cycloocta(D) isoxazole]. The single dose of 20 mg/kg suramin had to be followed by four doses of 80 mg/kg L611,744 to cure mice infected with another stabilate, T. brucei GVR 35/1. A single dose of 20 mg/kg suramin followed either by four doses of 250 mg/kg MK 436 [3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5nitro-1H-imidazol-2-yl)-1, 2-benzisoxazole] or four doses of 70 mg/kg of a dihydroxy analogue of MK 436 [cis-3a,4,5,6,7,7a-hexahydro-3-(1-methyl-5-nitro-1H-imidazol-2-yl)-1, 2-benzisoxazole-6,7-diol] also permanently cured all T. brucei GVR 35/1.

Animals↗
PubMed1983

Immune mechanisms in C57Bl mice genetically resistant to Trypanosoma congolense infection. I. Effects of immune modulation.

The effect of immune modulation on the pattern and course of infection with T. congolense was investigated in a strain of mice (C57Bl) which is known to possess a significant degree of trypanotolerance, and a susceptible strain (CFLP) which rapidly succumbs to infection. Immunosuppression of C57Bl mice by splenectomy, cyclophosphamide treatment or gamma irradiation reduced their survival to near that of susceptible strains of mice. In contrast, attempts to enhance the immune response of susceptible CFLP mice using either a variety of immunostimulants, simultaneous vaccination with irradiated parasites at the time of infection, passive immunization or reducing the number of parasites used for infection, failed to confer a level of protection comparable to that of C57Bl mice. It was concluded that the basis of trypanotolerance, although immunological in nature, is associated with, as yet, undetermined factors.

Adjuvants, Immunologic↗
PubMed1983

Immune mechanisms in C57B1 mice genetically resistant to Trypanosoma congolense infection. II. Aspects of the humoral response.

Some aspects of the humoral response in trypanotolerant C57B1 mice and susceptible A/J mice were investigated to determine the possible basis of trypanotolerance. When the hepatic uptake of 75Se-labelled T. congolense by infected mice was measured as an index of antibody production, it was found that only C57B1 mice could remove circulating labelled parasites, this ability persisting for several weeks after infection. Estimation of the immunoglobulin concentrations in both strains of mice showed that C57B1 mice developed a pronounced IgM response during the first parasitaemic wave, while A/J mice did not. Over the same period the IgM concentrations in C57B1 mice initially fell, but recovered at the time of peak parasitaemia. In contrast, A/J mice showed a continual fall in total IgG concentrations in the circulation until death 10 days after infection. Finally, it was shown that during the initial rising parasitaemia, the plaque forming cell responses of both strains of mice to sheep red blood cells were normal indicating that neither strain of mice was immunosuppressed. Also, A/J mice vaccinated with irradiated T. brucei on day 4 and C57B1 mice vaccinated either on day 4 or day 60 of a T. congolense infection were able to mount an effective immune response to the vaccine, as judged by the hepatic uptake of radiolabelled parasites. All of the results indicate that the trypanotolerance of C57B1 mice depends, at least in part, on their more efficient antibody response.

Animals↗