Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Parasitic organism or component thereof or substance...
Reexamination Certificate
1999-11-30
2001-04-10
Dudash, Diana (Department: 1619)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Parasitic organism or component thereof or substance...
C424S269100, C424S265100, C424S400000, C424S529000, C424S530000, C424S531000, C435S252300, C435S258200, C435S258100
Reexamination Certificate
active
06214357
ABSTRACT:
The present invention relates to treatment of diabetes mellitus, specifically treatment of non-insulin dependent diabetes mellitus.
Diabetes is sub-divided on clinical grounds into insulin-dependent and non-insulin dependent diabetes mellitus (IDDM and NIDDM respectively, also known as Type 1 and Type 2 respectively). The two forms of the disease are distinguished by a number of features.
In IDDM there is profound insulin deficiency such that even the low levels of insulin which would normally prevent lipolysis and cytogenesis cannot be sustained. Without replacement of insulin, IDDM patients become ketotic and die. IDDM patients therefore generally show high levels of glucose and low levels of insulin. As IDDM progresses, the pancreatic islets are damaged or destroyed, and less and less insulin can be produced.
NIDDM is a common and complex disorder which results from a combination of defects in insulin secretion and impaired insulin sensitivity in peripheral tissues. NIDDM is characterized by hyperglycaemia in both the fasted and fed states, variable degrees of hyperinsulinaemia and obesity. Current therapy includes diet, sulphonylurea to enhance insulin secretion, insulin itself, and biguanides to reduce insulin resistance. There is a need for new antidiabetic agents, since biguanides are quite toxic while sulphonylurea is ineffective in patients with severely impaired islet cell function, and after 10 years of treatment, 50% of patients will have become resistant.
Clinically, the two forms of diabetes are often viewed as two different diseases, and entirely separate treatments are needed for the two forms. In general treatments for the two forms of the disease do not overlap.
In humans, the normal level of glucose in the blood is about 7 mmol/l. Patients are said to be hypoglycaemic at levels of less than about 2.2 mmol/l and hyperglycaemic at levels of above about 10-11 mmol/l.
One of the complications of malaria infection is hypoglycaemia, although the mechanism responsible has not been firmly established. In patients treated with quinine, the drop in glucose levels is often attributed to the hyperinsulinaemic action of quinine, for example by Phillips et al in Q.J. Med. 1993 volume 86, pp 233-240. A few cases in which hypoglycaemia and hyperinsulinaemia preceded treatment with quinine have been reported, for example by Looareesuwna et al in Lancet 1985 ii:4-8.
A single case of a diabetic patient who contracted malaria is reported by Shalev et al in Postgrad. Med. J. 1992 vol. 68, pp 281-282. The patient still became hypoglycaemic during the course of the malaria infection.
Infection of normal mice with blood-stage
P. yoelii
and
P. chabaudi
malaria can induce hypoglycaemia in the normal mice (Elased et al, Clin. Exp. Immunol. 1995, vol. 99, pp 440-444). It is thought that this effect may be due to induction of a burst of insulin which reduces the glucose levels. In the same article, it was reported that malaria infection in insulin-dependent diabetes mellitus (IDDM) induced by administration of streptozotocin induced a profound drop in blood glucose and restored insulin secretion, although severely diabetic mice (again induced by streptozotocin) remained hyperglycaemic with no changes in insulin levels. This supports the theory that the effect is due to induction of a burst of insulin, since mice severely affected with IDDM will have few or no residual islets which can be stimulated to produce insulin.
In NIDDM, the insulin levels are already raised, and there is significant insulin resistance. The inventors have unexpectedly found that administration of malaria parasites to mice which provide a model of human NIDDM will result in lowering of glucose levels. This is entirely unexpected, since previously it was thought that the reduction of glucose levels seen on giving malaria parasites to Type 1 (IDDM) diabetic mice was due to the induction of a burst of insulin. The mechanism of action in NIDDM treatment will inevitably be different.
A further complication of NIDDM is obesity. It has long been known that increasing body weight is associated with increasing levels of insulin resistance, seen in NIDDM. The interaction between obesity and diabetes is explored by Sigal et al in Current Opinion in Endocrinology and Diabetes 1996, volume 3, pp. 3-9. Control of NIDDM can often be achieved by regulation of the diet, and of total food intake. However, this is often unsuccessful as individuals may find it difficult to maintain a diet and to cut food intake.
We have found that administration of malaria parasites or an extract thereof to a mouse model of human NIDDM results in reduced voluntary food intake, with consequent weight loss.
Although not wishing to be bound by this theory, it appears possible that the malaria parasite or extract thereof may act synergistically with the high levels of insulin in the NIDDM sufferer to enhance glucose transport since when normal mice are treated with the killed parasite, the reduction in glucose levels was much less prolonged.
The invention provides the use of killed malaria parasites or an extract thereof in the preparation of a medicament for the treatment of non-insulin dependent diabetes mellitus (NIDDM). The malaria parasite may be any organism responsible for malaria infection. Examples include
Plasmodium yoelii, P. falciparum, P. vinckei, P. vivax, P. chabaudi, P. berghei, P. knowlesi
and
P. coatenyi.
The killed malaria parasites or extracts thereof are particularly effective when collected at the blood stage of infection.
The medicament may be provided in the form of killed malaria parasites or an extract of the parasites, for example fixed in formalin. Other suitable forms include soluble malaria preparations prepared by lysis of parasitised red cells by detergents such as Triton X100 or N-octyl glucoside, which may be followed by fractionation, for example on molecular weight or charge-based columns, and also preparations derived from supernatants of overnight culture of parasitised blood.
The preparation of parasites or the extract can be administered in a variety of dosage forms, for example orally such as in the form of tablets, capsules, sugar- or film-coated tablets, liquid solutions or suspensions or parenterally, for example intramuscularly, intravenously or subcutaneously. The parasites or extracts thereof may therefore be given by injection or infusion.
The dosage of the parasite preparation or the extract depends on a variety of factors including the age, weight and condition of the patient and the route of administration.
It is envisaged that the malaria parasites or active ingredients derived therefrom will be given in a dosage of from 10
7
to 10
11
, preferably 10
8
to 10
10
parasites or parasite equivalents. By “parasite equivalents” herein is meant the number of parasites needed to prepare an extract.
The killed malaria parasites or the extract may be given to the patient in a single dose, which it is expected will be sufficient to reduce hyperglycaemia for a period of up to 24 hours. Alternatively, lower dosages may be provided a number of times per day, for example 3 or 4 times daily. It is further envisaged that a single, larger dose could be provided for longer term treatment.
The parasites or extracts thereof are formulated for use as pharmaceutical or veterinary compositions also comprising a pharmaceutically or veterinarily acceptable carrier or diluent. The compositions are typically prepared following conventional methods and are administered in a pharmaceutically or veterinarily suitable form.
For example, the solid oral forms may contain, together with the active material, diluents such as lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants such as silica, talc, stearic acid, magnesium or calcium stearate and/or polyethylene glycols; binding agents such as starches, arabic gums, gelatin, methylcellulose, carboxymethylcellulose, or polyvinyl pyrrolidone; disintegrating agents such as starch, alginic acid, alginates or sodium starch glycolate; effervescing mixture
De Souza Joseph Brian
Elased Khaled
Playfair John Hugh Lyon
Dudash Diana
Haliday Emily M.
Rademacher Group Limited
Seperack Peter K.
Sharareh Shahnam
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