Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Cyclopentanohydrophenanthrene ring system doai
Reexamination Certificate
1999-03-11
2001-05-29
Dees, José G. (Department: 1616)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Cyclopentanohydrophenanthrene ring system doai
C540S063000
Reexamination Certificate
active
06239120
ABSTRACT:
FIELD OF INVENTION
The present invention relates to a method and means for treating glomerulonephritis.
BACKGROUND OF THE INVENTION
The functional units of the kidney, such as the glomeruli may suffer from inflammation. An inflammatory attack in the glomeruli is termed glomerulonephritis and can be classified into subgroups such as membraneous glomerulonephritis, focal segmental glomerulosclerosis, mesangial diffuse proliferative glomerulonephritis, endocapillary or extracapillary proliferative glomerulonephritis. Using histopathological techniques these subgroups vary with respect to microscopical or immunohistochemical picture. One cause of inflammation is due to the deposition of immunoglobulin A (IgA) in glomeruli. This condition is termed IgA nephropathy (1-3), and is the most common form of glomerulonephritis in a global perspective.
Assessment of the degree of severity of glomerulonephritis is based on different investigation results. The most important findings are 1) the degree of urinary excretion of protein (proteinuria) and 2) the filtering function of the kidney, which can be assessed by serum creatinine (screatinine). Histological examination of material from kidney (renal biopsy) yields information about the type of renal damage as well as the severity of the injury. The outcome of a glomerulonephritis is variable and is dependent upon the histological and the immunohistochemical findings in a renal biopsy. Patients with IgA nephropathy having a constant proteinuria often develop renal failure and uraemia after 5 to 20 years of illness (4).
Various treatments for glomerulonephritis are known. For example substances which act on the immune system, e.g. Cyclophosphamide, Azathioprine and Cyclosporine have been used. Glucocorticoids have also been used (mainly prednisone or prednisone acetate) which may be administered orally or by venous infusion (5, 6). Unfortunately, these treatments cause severe side effects and are not particularly effective. Other suggested treatments include ACE-inhibitors (7), polyunsaturated fatty acid-preparations (8) and vitamin E (9). The treatment results for these therapies for IgA nephropathy have been quite disappointing and it has been concluded that an effective treatment against progressive IgA nephropathy is basically missing (10). For this reason, a substantial number of patients with IgA nephropathy, 20-30%, will eventually develop renal insufficiency and uraemia (1-4). The available treatment for uraemia today is dialysis or kidney transplantation. Renal transplant patients who have been transplanted because of uraemia due to glomerulonephritis frequently suffer from recurrence of glomerulonephritis in the transplant and subsequently a gradual loss of transplant function (11, 12). This is most common with patients who previously suffered from IgA nephropathy. Today there is no effective treatment against recurrence of glomerulonephritis in a transplant.
The glucocorticoids that have been used in IgA nephropathy and in other types of glomerulonephritis are characterised by a substantial gastrointestinal absorption after oral administration, aiming to exert a direct effect on circulating leukocytes and cells that have infiltrated the kidney or the renal transplant, thus having a systemic effect. Such a systemic effect is also achieved if glucocorticoids are administered as an intravenous infusion. Systemic administration of glucocorticoids may have influenced the outcome of IgA nephropathy in some cases.
BRIEF DESCRIPTION OF THE INVENTION
Surprisingly, it has now been found that glucocorticoid having a first pass metabolism in the liver of at least 90%, which minimises the systemic effect, is effective in controlling glomerulonephritis and especially IgA nephropathy in a native kidney or a kidney transplant. The substance preferably exerts its effect in the intestinal wall of a certain part of the gut (the lower third of the small intestine and the upper fourth of the large intestine). A man skilled in the art would not have expected that treatment of an apparently healthy intestine should have an effect on an inflamed kidney. This discovery represents a breakthrough in the treatment of glomerulonephritis since it has the advantage of reducing the severe side effects on the body, such as effects on skeleton, metabolism and muscles, caused by therapy with the systemic glucocorticiods used in prior art therapy.
SUMMARY OF THE INVENTION
The invention relates to the use of a glucocorticoid having a first pass metabolism in the liver of at least 90%, which gives a minimal systemic effect, for the manufacturing of a medicament for oral or rectal administration for the treatment of glomerulonephritis. More specifically the invention relates to the use of the glucocorticoid defined above for the manufacturing of a medicament for the treatment of glomeluronephritis, especially IgA nephropathy, in a native kidney or kidney transplant. The medicament is provided in a form by which the active substance is released in a pharmacologically effective amount, in the apparently healthy intestine when it passes the lower third of the small intestine and the upper fourth of the large intestine. The invention also relates to a method for the treatment of glomeluronephritis, by oral and rectal administration of a pharmacologically effective amount of a glucocorticoid preparation having a first pass metabolism in the liver of at least 90%, minimising the systemic effect. In the method according to the invention the preparation is released in the intestine when passing the lower third of the small intestine and the upper fourth of the large intestine. The invention relates more specifically to the treatment of IgA nephropathy by administering 0.1 mg to 40 mg of the active substance daily to a subject in need thereof.
According to the invention there is further provided a pharmaceutical composition comprising the glucocorticoid, in association with a pharmaceutically acceptable diluent, adjuvant or carrier, which composition is for use in the treatment of glomerulonephritis. For oral use the composition is preferably administered in a form selected from tablets, pills, capsules, syrups, suspensions, powders and granules. The solid forms of the preparation comprise a carrier and an enteric coating, and are most preferably in t he form of a capsule comprising microcapsules. When used rectally the active substance is preferably administered in a form selected from foams, suppositories, and enemas.
DETAILED DESCRIPTION OF THE INVENTION
The medicament and method according to the invention is preferably used to treat a patient who suffers from acute or chronic glomerulonephritis. Glomerulonephritis may be divided into subtypes such as membranous glomerulonephritis, focal segmental proliferative glomerulonephritis, diffuse mesangioproliferative glomerulonephritis, endocapillary or extracapillary proliferative glomerulonephritis, depending on where the inflammation is located. The medicament and method according to this invention is preferably used to treat the IgA nephropathy type of glomerulonephritis. The invention is particularly suitable for treating patients who suffered from glomerulonephritis (particularly IgA nephropathy), had a transplant, and suffered from a recurrence of glomerulonephritis (particularly IgA nephropathy) in the transplanted kidney.
The glucocorticoid used in the present invention is preferably one which has a first pass metabolism in the liver of at least 90% minimising the systemic effects. The first pass metabolism in the liver of a glucocorticoid substance can be determined using the method disclosed previously (13). More preferably it is budesonide, rofleponide or derivatives thereof, beclomethasone dipropionate, beclomethasone monopropionate, ciclesonide, tipredane, flunisolide, traimcinolone acetonide or flutiscasone propionate. Budesonide, which is a 16,17-butylidenedioxy-11&bgr;,21-dihydroxypregna-1,4-diene-3,20-dione, is particularly preferred.
The glucocorticoid, when administered orally, is generally administered in the
Fellstrom Bengt
Hallgren Roger
Browdy and Neimark
Dees Jos,e G.
George Konata M.
Pharmalink AB
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