Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Phosphorus containing other than solely as part of an...
Patent
1994-12-05
1998-03-10
Travers, Russell
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Phosphorus containing other than solely as part of an...
514738, 424520, A61K 3166, A61K 3512, A61K 3104
Patent
active
057261660
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/00084 filed Jan. 1, 1993.
The present invention relates to the treatment and prevention of malaria and certain other infectious diseases, especially to materials for use in such treatment and prevention.
Malaria is caused by organisms of the genus Plasmodium which infect and multiply within erythrocytes. Blood-stage infection is usually characterised by severe fever, sometimes accompanied by anaemia, hypoglycemia, pulmonary oedema, renal or hepatic failure, and coma which may occasionally prove fatal. Immunity may develop so as to reduce the severity of infection but takes many years and in individuals living in endemic areas complete elimination of parasites rarely occurs. Nevertheless, children from these areas do appear to develop resistance to the above clinical manifestations of infection even while carrying heavy parasite loads.
The conventional approaches to controlling malaria have aimed at: or not been effective in controlling the mosquito due to the rapid development of resistance and also present environmental difficulties rendering this approach unsatisfactory. Chemotherapy has been relatively effective but is expensive; there are dangers to the patient if the parasites are killed too rapidly and supportive measures are generally required to deal with the major effects of the disease, such as hypoglycaemia which is treated by administration of glucose. Experimental vaccines aimed at eliminating one or other stages of the parasite are under trial but do not seem to protect all individuals. None of these control measures have been fully successful and the disease is on the increase world wide. Protection can be provided by various drugs for those travelling to endemic regions, but this is not a practical solution for the whole at-risk population.
Various investigators have observed that the major clinical problems raised by episodes of malarial disease are associated with the over-secretion of tumour necrosis factor (TNF), and possibly, other cytokines and that secretion of cytokines by macrophages can be stimulated in vitro by malaria antigens. This originally led the present inventors and their collaborators to postulate that antigens which stimulated cytokine release by macrophages would be particularly useful in generating anti-disease resulting in work on "antigen 7" published in, for instance, PCT/DK90/00159 (WO-A-90/15621). It has now been appreciated that these antigens could themselves induce many of the clinical problems associated with malaria and that they would be unlikely to be acceptable for use in humans. Others have proposed that secretion of TNF and other cytokines might be prevented by various agents acting directly to destroy or disable the macrophages, or have attempted to remove circulating cytokines from the bloodstream, for instance using anti-TNF antibodies. However both techniques have disadvantages in that they might compromise aspects of the patient's immune response to this and other diseases. Moreover a patient's macrophage population rapidly recovers from the action of direct-acting agents and this makes it unlikely to be practical to treat malaria in this manner.
On the basis of further investigations the present inventors believe that TNF and other cytokines are secreted by sensitive macrophages as a direct result of binding of malaria antigens to specific receptors on the macrophages; by interrupting this binding they consider that it is possible to treat or prevent the clinical manifestations of malaria. The strategy avoids the disadvantages of techniques used or proposed by others and would afford control of the disease while allowing the immune system of the patient to control the infection. It is not important that TNF should be the only or even the main cytokine induced by the disease organism, only that the organisms produce antigens which stimulate the relevant receptors on sensitive macrophages
Following this theory, the inventors have identified certain features of the cytokine-stimulating antigens and the receptor e
REFERENCES:
Mintzer et al, 1988, Antimicrobial Agents and Chemotherapy vol. 32(3) pp. 391-394.
Bate Clive Alan Winston
Playfair John Hugh Lyon
Taverne Janice
British Technology Group Limited
Travers Russell
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