Acta Leidensia最新文献

It is clear from both laboratory and clinical studies that the blood-stage malaria parasite does not itself directly cause most of the serious complications of the disease, with the possible exception of anaemia. For example, T cell- deprived mice with lethal infections survive longer and mice can be protected against early death by vaccines that appear not to affect parasitaemia. In certain cases antibodies to TNF have the same effect. Clinically it has been known for over 50 years that children in endemic areas develop immunity to the serious toxic aspects of malaria several years before their parasitaemias start to fall. Recent work on the induction of cytokines such as tumour necrosis factor (TNF) by exoantigens of the blood-stage parasite and on the role of cytokines in this and other toxic diseases suggests that an appropriate vaccine might induce antibody that blocks the effect of the exoantigens, thus conferring on young children the anti-disease immunity that normally takes years to appear. Such vaccines might be less hampered by the antigenic variation that makes anti-parasite immunity slow to develop. Characterisation of the molecules involved is a high priority.

Following the development of a unique claim structure encompassing both nematode and arthropod species, ivermectin was first introduced as a veterinary parasiticide in 1981. For cattle(c), sheep(s), horses(h) and pigs(p) injectable(c,s,p), oral(c,s,h) and topical(c) products are available delivering ivermectin at 200 to 500 micrograms/kg. Efficacy extends to nematodes of the gastrointestinal and respiratory tracts, conjunctival sac and soft tissues. Among the arthropod parasites claims have been established for the biting fly Haematobia irritans(c), the screw-worm Chrysomyia bezziana(c), larvae of the oestrid flies Hypoderma spp.(c), Dermatobia hominis(c), Oestrus ovis(s) and Gastrophilus spp.(h), lice(c,p), mange mites(c,s,p) and the ticks Boophilus spp.(c) and Ornithodorus savignyi(c). In the dog two oral formulations are available for the prevention of heartworm disease caused by Dirofilaria immitis by administration of 6 micrograms/kg once monthly during the mosquito season.

Initial clinical trials with ivermectin were performed in patients with both roundworm infestation and onchocerciasis. Obvious clinical safety allowed for rapid progression through 5-30-50-100-150-200 mcg/kg in infected patients. Initial studies showed some effect at 50 mcg/kg; subsequent double-blind controlled studies, either with placebo or diethylcarbamazine (DEC), confirmed the efficacy of ivermectin as well as further defining its safety profile. Absence of adverse eye findings or serious systemic reactions justified the further open trials. Studies of patients treated at 6, 12, or 18 month intervals showed a long lasting effect of ivermectin in reducing skin microfilaria counts. Phase III studies confirmed safety and efficacy and further refined the dose to 150 mcg/kg every 12 months. Large trials in Liberia and other countries in West Africa, and subsequently under Onchocerciasis Control Program (OCP), included approximately 120,000 persons carefully followed during which few patients with serious adverse experiences were reported. These extensive field trials confirmed the relative safety allowing for broad distribution of ivermectin in programs not able to provide physician monitoring.

Community trials were started to address questions concerning the safety of ivermectin during large scale treatment, its potential for transmission control, its effect in preventing ocular onchocercal disease, its acceptability and the organization of large scale treatment. A summary is presented of the major, latest results on the short-term epidemiological impact of large scale ivermectin treatment, as observed in eight community trials undertaken in the Onchocerciasis Control Programme in West Africa (OCP). Ivermectin treatment resulted in a 96%-99% reduction in the mean load of microfilariae (mf) in the skin in treated patients. The subsequent mf-repopulation of the skin was faster than in the clinical trials and after 12 months the mean loads had returned to more than 40% of the pre-treatment load. Ocular mf loads were also greatly reduced and a post-treatment regression of early lesions of the anterior segment of the eye was observed. The transmission of Onchocerca volvulus was reduced by some 60% during the first year after treatment in one trial but no additional reduction was observed after the second treatment round. These results, and other recent research findings, have been used to quantify an epidemiological model for the transmission and control of onchocerciasis. Preliminary results of computer simulations of the predicted long-term epidemiological impact of large scale ivermectin treatment indicate that ivermectin treatment may play a very important role in disease control but that it is unlikely to become a practical tool for transmission control in endemic foci. Ivermectin treatment appears to be the most appropriate method for control of recrudescence of infection in an area where the parasite reservoir has been virtually eliminated by vector control, such as in the core area of the OCP.