PubMed Health⌕ Search

Biomedical subjects

F W Jennings

Publications and source records attributed to F W Jennings.

At least 19 recordsLinked to original sources
PubMed1997

A substance P antagonist, RP-67,580, ameliorates a mouse meningoencephalitic response to Trypanosoma brucei brucei.

Mice infected with the protozoan parasite Trypanosoma brucei brucei and treated subcuratively with the trypanocidal drug diminazene aceturate develop an acute inflammatory meningoencephalitis with associated astrocytic proliferation. This reaction is very similar to that seen in the fatal posttreatment reactive encephalopathies that can occur in human African trypanosomiasis. The 11-amino acid neuropeptide substance P (SP) has recently been identified as a mediator in many inflammatory responses, and the development of potent, highly specific, nonpeptide SP antagonists has provided a new opportunity to investigate the possible involvement of SP in a variety of pathological conditions. We therefore postulated that SP may play a role in the development of the posttreatment inflammatory encephalopathy found in this experimental mouse model of African trypanosomiasis. In the present study RP-67,580, a SP antagonist that binds specifically to NK-1 receptors, was given intraperitoneally at a dose of 2 mg/kg twice daily to mice in which a severe meningoencephalitis had been produced. A significant reduction in both the severity of the inflammatory response (P = 0.0001) as well as the degree of astrocyte activation (P < 0.001) was found in the brains of these animals as compared with control mice that had not received RP-67,580. An inactive enantiomer of this SP antagonist, RP-68,651, had no effect on the central nervous system inflammatory reaction. We conclude from these findings that the neuropeptide SP plays a key role in the development of the severe central nervous system inflammatory response associated with African trypanosomiasis.

Analgesics↗
PubMed1997

The role of the polyamine inhibitor eflornithine in the neuropathogenesis of experimental murine African trypanosomiasis.

The treatment of late-stage human African trypanosomiasis is complicated by a post-treatment reactive encephalopathy, also referred to as a 'reactive arsenical encephalopathy', that may be fatal. This study used a well established experimental mouse system to assess the use of the trypanostatic drug, eflornithine, in the management of this post-treatment reaction. Female CD-1 mice infected with an eflornithine-resistant trypanosome stabilate and treated with the trypanocidal compound diminazene aceturate on or after day 21 post-infection develop a reactive encephalopathy and relapsing parasitaemia. If these animals are re-treated with diminazene aceturate, a severe encephalopathy develops histologically comparable with that of human cases and characterized by a severe meningoencephalitis and astrogliosis. Histopathological and immunocytochemical examination shows that administration of eflornithine before or after the development of this reactive encephalopathy prevented or ameliorated the inflammatory reaction. Since an eflornithine resistant stabilate was used, this effect appears to be independent of the drug's trypanostatic action and illustrates an important, previously unrecognized, pharmacological property of eflornithine. Consideration can now be given to the use of eflornithine for the management of human trypanosomiasis cases, even where trypanosome resistance to eflornithine exists.

Animals↗
PubMed1996

The effect of spiroarsoranes on Trypanosoma brucei brucei and T. b. rhodesiense.

Topical application and intraperitoneal administration of spiroarsoranes were carried out to cure central nervous system (CNS) trypanosomiasis in the chronic Trypanosoma brucei GVR 35 mouse model. Topical application appeared more efficient than intraperitoneal injection. The periods of aparasitaemia after treatment were longer but none of the mice was permanently cured. Combination treatment with eflornithine (DFMO) and the spiroarsoranes failed to show any synergistic effect. In addition, spiroarsorane I was evaluated against the T. b. rhodesiense KETRI 2634 strain, whereby 60-mg/kg treatment produced a noticeable prolongation of the life span of trypanosome-positive animals. These in vivo results suggests that the spiroarsoranes have difficulty in crossing the blood-brain barrier (BBB) and clearing the parasites from the CNS or, alternatively, that these strains are less sensitive to pentavalent arsenicals than the T. b. brucei CMP fast strain, which in the present study was more sensitive to spiroarsoranes whose lipophilicity corresponded to a log-P value ranging from 2.5 to 3.7.

Animals↗
PubMed1996

The importance of 2,3-dimercaptopropinol (British anti-lewisite, BAL) in the trypanocidal activity of topical melarsoprol.

Both melarsomine dichlorhydrate (mel Cy, Cymelarsan) and melarsen oxide can be dissolved in dimethylsulfoxide and converted into a gel by the addition of hydroxypropylcellulose. When Trypanosoma brucei brucei-infected mice are treated topically with these gels the circulating trypanosomes are rapidly cleared from the circulation but the infections relapse soon after the last application. However, when these two compounds are allowed to react with 2,3-dimercaptopropinol (British anti-lewisite, BAL) and form "melarsoprol" their efficacy, especially in the case of mel Cy, is restored to that of commercial melarsoprol (Arsobal) and trypanosomes in the central nervous system (CNS) can be eliminated. This would indicate that the dimercaptopropinol portion of the molecule does not act solely as an "antidote" to arsenic toxicity, but also plays an important role in the absorption of melarsoprol through the skin and/or blood-brain barrier into the CNS and/or into the trypanosome.

Administration, Topical↗
PubMed1996

Topical chemotherapy for experimental African trypanosomiasis with cerebral involvement: the use of melarsoprol combined with the 5-nitroimidazole, megazol.

Megazol, one of a number of related 5-nitroimidazoles, can be dissolved in dimethylsulphoxide and the solution can be converted into a gel by the addition of hydroxypropylcellulose which facilitates the ease and accuracy of administration. This megazol gel, when used in combination with melarsoprol (3.6%) in propylene glycol gel, will cure experimental CNS-trypanosomiasis in mice. A single application of 0.1 ml of melarsoprol (3.6%) gel plus 0.1 ml of either 8 or 16 mg/ml megazol gel successfully treated experimental CNS-trypanosomiasis while two consecutive days' treatment with 0.05 ml melarsoprol and 0.1 ml of 16 or 32 mg/ml megazol gels also produced satisfactory cures.

Administration, Topical↗
PubMed1996

Topical chemotherapy for experimental murine African CNS-trypanosomiasis: the successful use of the arsenical, melarsoprol, combined with the 5-nitroimidazoles, fexinidazole or MK-436.

The 5-nitroimidazoles, MK-436 and fexinidazole dissolved in dimethylsulphoxide can be converted by the addition of hydroxypropylcellulose into gels which facilitates the ease and accuracy of administration. When these gels are used in combination with melarsoprol gel they are capable of curing experimental murine CNS-trypanosomiasis with a one-day treatment. The use of melarsoprol/MK-436 was more efficient than melarsoprol/fexinidazole gels. Thus while a single treatment with 0.1 ml 3.6% melarsoprol gel with 0.1 ml (14.3 mumol) fexinidazole gel cured the infected mice, the same dose of melarsoprol gel with 0.1 ml (4.0 mumol) of MK-436 gel was equally effective. It was also possible to prepare a combined melarsoprol/MK-436 gel which cured experimental CNS-trypanosomiasis with a single treatment. Topical treatment with this melarsoprol/MK-436 gel mixture also resolved clinically the hind leg paralysis which is associated with post-treatment reactive encephalopathy caused by non-curative treatment of CNS-trypanosomiasis.

Administration, Topical↗
PubMed1993

Combination chemotherapy of CNS trypanosomiasis.

The progress which has been made in the treatment of experimental CNS trypanosomiasis with combination chemotherapy is reviewed. The most significant has been the use of four specific 5-nitroimidazoles in combination with either suramin or the arsenicals. The latter combination of MK 436 and Mel Cy, producing a rapid cure of CNS trypanosomiasis with only a two dose regimen and thus, would make an ideal universal treatment for both early- and late-stage trypanosomiasis. However, the 5-nitroimidazoles, because they are Ames' positive, are unlikely to be developed for use in humans. The combination chemotherapeutic regimen of eflornithine and arsenicals would allow the use of reduced quantities of melarsoprol to be used with similar or increased efficacy. As these drugs are already approved for use in humans, they could be applied immediately to the human disease; however, the quantities of eflornithine required for cures and the basic cost of this compound may limit its use in human medicine. Investigations of the post-treatment reactive encephalopathies (PTRE) which occur after non-curative treatment of trypanosome infections have shown that they are essentially caused by the presence of a residual focus of living trypanosomes in the CNS. If all trypanosomes are eliminated from the CNS (curative treatment) then there are no PTRE and when non-curative treatment is used the reaction can be reduced or ameliorated by supportive treatment with anti-inflammatory drugs such as prednisolone, dexamethasone or azathioprine.

Arsenicals↗
PubMed1992

Subcurative chemotherapy and fatal post-treatment reactive encephalopathies in African trypanosomiasis.

The treatment of late-stage African sleeping sickness in man is often complicated by a post-treatment reactive encephalopathy. The bases of this pathological reaction was investigated in a mouse model of African trypanosomiasis. Subcurative treatment with diminazene aceturate, which did not clear parasites from the central nervous system, resulted in a post-treatment meningoencephalitis similar to that seen in man. By contrast, a curative regimen of melaminylthioarsenite and 5-nitroimidazole, which cleared parasites from the central nervous system, did not cause any pathological reaction in the mice. This result indicates that subcurative treatment leads to the development of the post-treatment encephalopathy. Evidence that this may also be the case in man was provided by the detection of trypanosome DNA with the polymerase chain reaction in the brains of 9 patients who had died as the result of a post-treatment reaction. Our findings suggest that more aggressive treatment regimens, which ensure the elimination of trypanosomes from the central nervous system, may prevent post-treatment reactions in patients.

Adolescent↗
PubMed1992

Changes in atrial natriuretic factor and plasma renin activity in dogs infected with Trypanosoma brucei.

When beagle dogs were infected with Trypanosoma brucei, a marked reduction in the plasma concentration of atrial natriuretic factor (ANF) occurred in the terminal stage of the disease during weeks 3 and 4. At the same time there was an increase in plasma renin activity (PRA) after infection. Ultrastructural studies of the atria of these dogs demonstrated a reduction in ANF granules. The changes in ANF and PRA occurred in association with severe pancarditis and the development of heart failure. By impairing the ability of the heart and kidneys to regulate blood volume, the alterations in ANF and PRA could be involved in the pathogenesis of heart failure in T. brucei-infected dogs.

Animals↗
PubMed1992

Isolation of drug-resistant strains of Trypanosoma congolense from the lower Shabelle region of southern Somalia.

Drug resistance by pathogenic trypanosomes in Somali livestock has been suspected for some time but there have been few attempts to examine this problem in detail. Field isolations from two areas in the Lower Shabelle Region were obtained by injecting blood from trypanosome infected cattle into a recipient calf. Once the calf became parasitaemic it was treated with a standard dose of isometamidium chloride (Samorin, RMB) at 0.5 mg/kg. When a subsequent relapse infection developed, indicative of drug resistance, blood was taken and injected into groups of cattle and mice and these were treated with a range of doses of isometamidium chloride and diminazene aceturate (Berenil, Hoechst AC) to determine the degree of drug resistance. Both isolates showed remarkably high levels of drug resistance to both isometamidium chloride and diminazene aceturate, with minimum curative doses in cattle of > 2.0 mg/kg and 7.5 mg/kg for the two drugs respectively. Minimum curative doses in mice were approximately ten-fold those in cattle. Fortunately there have been a very few reports from Africa of such high levels of resistance of Trypanosoma congolense to this normal "sanative pair" of drugs. The results indicate that drug resistance could be an important constraint on the use of trypanocidal drugs to control trypanosomosis in Somalia.

Animals↗
PubMed1992

The rapid development of drug-resistance by Trypanosoma evansi in immunosuppressed mice.

The effect of immunosuppression on the development of drug resistance by trypanosomes was investigated in mice infected with Trypanosoma evansi. As a result of frequent passage in immunosuppressed mice given subcurative drug treatments clones of T. evansi rapidly developed high levels of resistance to mel Cy, diminazene aceturate and isometamidium chloride. Similar protocols in normal immunocompetent mice infected with the same parent clones did not lead to the development of drug-resistance. The resistant populations developed in immunosuppressed mice maintained their high levels of resistance when tested in normal mice. The mel Cy resistant clone was tested for cross-resistance to other trypanocides and was found to be also highly resistant to diminazene and pentamidine. The results indicate that impairment of the host immune system may lead to the rapid development of drug-resistance by T. evansi under experimental conditions in mice and may possibly play a role in the development of drug resistance by trypanosomes in the field.

Animals↗
PubMed1992

Correlation of autoantibody titres with central nervous system pathology in experimental African trypanosomiasis.

CD-1 mice infected with the protozoan parasite Trypanosoma brucei brucei developed few signs of central nervous system pathology associated with the invasion of the central nervous system by these parasites and did not survive beyond 5-6 weeks with deaths common before this time point. However, use of the trypanocidal drug diminazene aceturate (40 mg/kg), which fails to cross the blood-brain barrier, on day 21 post-infection led to the development of central nervous system pathology similar to that seen in the fatal post-treatment reactive encephalopathies that can occur in human African trypanosomiasis. Enzyme-linked immunosorbent assays were used to measure autoantibody titres to double-stranded DNA, myelin basic protein and to the myelin-specific galactocerebrosides and gangliosides in groups of infected mice, with or without the post-treatment reaction, on day 30 post-infection and compared with uninfected controls. Infection with T. brucei brucei raised the titres of all of these autoantibodies. Treatment of infected mice with diminazene aceturate resulted in elevated levels of all of these autoantibodies compared to the untreated animals. There was a strong positive correlation between the central nervous system pathology and the levels of autoantibodies to myelin basic protein, galactocerebrosides and gangliosides, but not to double-stranded DNA. The elevated titres observed may be a consequence of the polyclonal B cell activation that is believed to occur in African trypanosomiasis, parasite epitopes that are cross-reactive with these central nervous system (CNS)-specific antigens or result from the CNS damage associated with sub-curative chemotherapy.

Animals↗
PubMed1992

The use of azathioprine to ameliorate post-treatment encephalopathy associated with African trypanosomiasis.

The treatment of human African sleeping sickness is complicated by a post-treatment meningoencephalitis that may be fatal. Using a mouse model this study assesses the use of the non-steroidal anti-inflammatory drug, azathioprine, in the management of this post-treatment reaction. Female NIH mice treated with the trypanocidal compound diminazene aceturate (40 mg/kg), 28 days after infection, developed a similar post-treatment reaction to that seen in humans. Administration of azathioprine (100 mg/kg) for 5 days before and 5 days after trypanocidal chemotherapy abrogated the pathology in the central nervous system although this returned approximately 15 days after cessation of azathioprine. Activated astrocytes associated with the later stages of the infection did not appear to be affected by the use of azathioprine.

Animals↗
PubMed1992

Astrocyte activation correlates with cytokine production in central nervous system of Trypanosoma brucei brucei-infected mice.

BACKGROUND: During the late-stage disease associated with human African trypanosomiasis, caused by infection with either Trypanosoma gambiense or T. rhodesiense, parasites invade the central nervous system (CNS), eventually leading to development of CNS pathology. This can be exacerbated by subcurative chemotherapy. The mechanisms through which the inflammatory processes within the CNS are controlled remain unclear. EXPERIMENTAL DESIGN: Mice infected with T. b. brucei were treated with a trypanocidal drug regimen on day 28 postinfection that cleared parasites from all sites except the brain. Brains of mice killed at different times during infection and after chemotherapy were analyzed, using immunocytochemistry for astrocyte activation and polymerase chain reaction assisted amplification of RNA to detect cytokine transcripts. RESULTS: Drug-treated animals developed a posttreatment meningoencephalitis similar to that which can occur in humans with late-stage African trypanosomiasis. Between days 14 and 21 postinfection, before chemotherapy and the subsequent development of inflammatory lesions in the brain, astrocytes became activated. The production of several cytokines correlated with this astrocyte activation. Low levels of interleukin-1 alpha transcripts were detected in uninfected controls, but levels increased with astrocyte activation in the infected animals. Transcripts for the macrophage inflammatory protein-1 and tumor necrosis factor-alpha were first detected on day 21 postinfection, with higher levels in mice after development of the posttreatment meningoencephalitis, whereas granulocyte macrophage-colony stimulating factor was detected only in animals that developed posttreatment reaction. Interleukin-6 and interferon-gamma were also first detected on day 21 postinfection, correlating with astrocyte activation but subsequently declined with time in both treated and untreated mice. CONCLUSIONS: These results indicate that cytokines are being produced within the CNS before any inflammation and that astrocytes may be the source of some of these cytokines. Thus astrocyte activation may be key in the control and development of the CNS inflammatory processes that occur in African sleeping sickness.

Animals↗
PubMed1992

Chemotherapy of CNS-trypanosomiasis: the combined use of diminazene aceturate or pentamidine with DL-alpha-difluoromethylornithine (DFMO).

The chemotherapy of CNS-trypanosomiasis with DL-alpha-difluoromethylornithine (Eflornithine, DFMO) with the diamidine, pentamidine (Lomidine) or diminazene aceturate (Berenil) was examined using the mouse model for CNS-trypanosomiasis. Although combined DFMO/pentamidine therapy can give complete cures, one or more doses of 100 mg/kg pentamidine was required with continuous administration of DFMO for 14-16 days, and even this treatment failed to cure the mice in a repeat experiment. Diminazene aceturate was more efficient and provided a 40 mg-kg dose was utilised, it was possible to reduce the period of DFMO to approximately 12 days. Attempts to reduce the dose rate of diminazene to less than 40 mg-kg failed. Of the two compounds, diminazene aceturate was the more successful and could possibly be used in combination with DFMO in the treatment of CNS-trypanosomiasis.

Animals↗
PubMed1991

Elevation of the concentration of acute phase proteins in dogs infected with Trypanosoma brucei.

Plasma concentrations of the acute phase proteins (APP), C-reactive protein (CRP) and haptoglobin (Hp), increased markedly following experimental infection of dogs with Trypanosoma brucei. The highest concentrations of CRP were observed immediately after peaks of parasitaemia. Treatment with curative doses of the trypanocidal drug suramin caused a rapid decrease in CRP. Relapse infections after subcurative treatment were followed by a reappearance of high plasma CRP concentrations. Haptoglobin remained elevated during the course of the disease. Curative treatment with suramin caused a gradual but slow decrease in Hp while subcurative treatment caused no significant changes. Thus, the estimation of CRP was useful in determining the presence of active infection and the success of chemotherapy. High Hp levels in severely anaemic dogs indicated that intravascular haemolysis does not contribute significantly to the anaemia associated with T. brucei infections in dogs. These conclusions need confirmation from a larger experiment.

Animals↗