(12) United States Patent
`Hallgren et al.
`
`US006239120B1
`US 6,239,120 B1
`May 29, 2001
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`(54) METHOD AND MEANS FOR TREATING
`GLOMERULONEPHRITIS
`
`(75) Inventors: Roger Hallgren, Balinge; Bengt
`Fellstrom, Knivsta, both of (SE)
`
`(73) Assignee: Pharmalink AB, Upplands Vasby (SE)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`(21) Appl. No.: 09/266,023
`(22) Filed:
`Mar. 11, 1999
`
`Related US. Application Data
`(60) Provisional application No. 60/080,274, ?led on Apr. 1,
`1998.
`Foreign Application Priority Data
`
`(30)
`
`Mar. 17, 1998
`
`(SE) ................................................. .. 9800905
`
`(51) Int. Cl.7 ........................... .. C07J 71/00; A61K 31/58
`(52) US. Cl. ............................................. .. 514/174; 540/63
`(58) Field of Search ................................... .. 424/451, 464;
`514/174; 540/63
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,840,960 * 6/1989 SterZel et al. ...................... .. 514/356
`5,643,602 * 7/1997 Ulmius ........ ..
`424/462
`5,719,197 * 2/1998 Kanios et al.
`514/772.6
`5,916,910 * 6/1999 Lai ..................................... .. 514/423
`
`Goumenos et al., “Can immunosuppressive drugs sloW the
`progres of igA nephorpathy?”, Nephrol Dial Transplant vol.
`10, pp. 1173—1181, (1995).
`Schmidt et al., “The role of angiotensin I—converting
`enZyme gene polymorphism in renal disease” Nephrology
`and Hypertension, vol. 5, pp. 552—555, (1996).
`Donadio et al., “A Controlled Trial of Fish Oil in lgA
`Nephorpathy”, vol. 331, No. 18, pp. 1194—1199, (1994).
`Trachtman et al., “Vitamin E Ameliorates Renal Injury in an
`Experimental Model of Immunogolbulin A Nephropathy”,
`vol. 40, No. 4, pp. 620—626, (1996).
`Feehally et al., “Immunoglobulin A nephronpathy: ?sh oils
`and beyond”, Nephrology and Hypertension, vol. 5, pp.
`442—446, (1996).
`Donadio et al., “The fate of renal transplants in patients With
`IgA nephropathy”, Clin. Transplanation vol. 11, pp.
`127—133, (1997).
`Odum et al., “Recurrent mesangial IgA nephritis following
`renal transplanation”, Nephrol Dial Transplant vol. 9, pp.
`309—312, (1994).
`Andersson et al., “Effectr of structrual alterations on the
`biotransformation rate of glucocorticosteroids in rat and
`human liver”, Xenobiotica, vol. 17, No. 1, pp. 35—44,
`(1987).
`von Asmuth et al., “IL—6, IL—8 and TNF production by
`cytokine and popplysaccharide—stimulated human renal cor
`tical epithelial cells in vitro”, Chemical Abstracts, vol. 121,
`p. 970, (1994).
`Minami et al., “Preliminary results of short—term combina
`tion immunosuppressions of miZoribine, arathiopine, and
`prednisolone With pretreatment to canine kidney transplan
`tion”, J. Vet. Med., vol. 55, No. 3, pp. 409—414.
`
`FOREIGN PATENT DOCUMENTS
`
`* cited by examiner
`
`0468555
`0502092
`9508323
`9727843
`
`1/1992 (EP) .
`9/1992 (EP) .
`3/1995 (WO) .
`8/1997 (WO) .
`
`OTHER PUBLICATIONS
`
`Alamartine et al., “Comparison of pathological lesion on
`repeated renal biopsies in 73 patients With primary lgA
`glomerulonephritis: value of quantitative scoring and
`approach to ?nal prognosis”, Clinical Nephorlogy, vol. 34,
`No. 2, pp. 45—51, (1990).
`Lai et al., “lgA nephronpathy: common nephritis leading to
`end—stage renal failure”, The International Journal ofArti?
`cal Organs, vol. 17, No. 9, pp. 457—460, (1994).
`Scheinman et al., “lgA Nephropathy: To Treat or Not to
`Treat?”, Nephron, vol. 75, pp. 251—258, (1997).
`Shu et al. “Serum immunoglobulin E in primary lgA neph
`ronpathy”, Clinical Nephronlogy, vol. 44, No. 2, pp. 86—90
`(1995).
`
`Primary Examiner—José G. Dees
`Assistant Examiner—Konata M. George
`(74) Attorney, Agent, or Firm—BroWdy and Neimark
`(57)
`ABSTRACT
`
`The invention provides the use of a glucocorticoid having a
`?rst pass metabolism in the liver of at least 90% as active
`substance, for the manufacturing of a medicament for oral or
`rectal administration in the treatment of glomerulonephritis
`by releasing the active substance in the intestine. The
`invention also provides a method for treatment of glomeru
`lonephritis in a native kidney or a kidney transplant With the
`glucocorticoid as de?ned above. The invention also com
`prises a composition comprising the active substance and a
`pharmaceutically acceptable carrier, adjuvant or diluent
`designed for oral or rectal administration.
`
`14 Claims, No Drawings
`
`Exhibit 1010
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`US 6,239,120 B1
`
`1
`METHOD AND MEANS FOR TREATING
`GLOMERULONEPHRITIS
`
`CROSS REFERENCE TO RELATED
`APPLICATION
`
`This application claims the bene?t of US. provisional
`application No. 60/080,274 ?led Apr. 1, 1998.
`
`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 in?ammation. An in?ammatory attack in
`the glomeruli is termed glomerulonephritis and can be
`classi?ed into subgroups such as membraneous
`glomerulonephritis, focal segmental glomerulosclerosis,
`mesangial diffuse proliferative glomerulonephritis,
`endocapillary or eXtracapillary proliferative glomerulone
`phritis. Using histopathological techniques these subgroups
`vary With respect to microscopical or immunohistochemical
`picture. One cause of in?ammation 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 glomerulonephri
`tis is based on different investigation results. The most
`important ?ndings are 1) the degree of urinary eXcretion of
`protein (proteinuria) and 2) the ?ltering 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 depen
`dent upon the histological and the immunohistochemical
`?ndings 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
`Various treatments for glomerulonephritis are knoWn. For
`eXample substances Which act on the immune system, eg
`Cyclophosphamide, AZathioprine and Cyclosporine have
`been used. Glucocorticoids have also been used (mainly
`prednisone or prednisone acetate) Which may be adminis
`tered orally or by venous infusion (5, 6). Unfortunately,
`these treatments cause severe side effects and are not par
`ticularly effective. Other suggested treatments include ACE
`inhibitors (7), polyunsaturated fatty acid-preparations (8)
`and vitamin E
`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 insuf
`?ciency 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 sub
`sequently 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 nephr
`opathy and in other types of glomerulonephritis are charac
`
`2
`terised by a substantial gastrointestinal absorption after oral
`administration, aiming to eXert a direct effect on circulating
`leukocytes and cells that have in?ltrated the kidney or the
`renal transplant, thus having a systemic effect. Such a
`systemic effect is also achieved if glucocorticoids are admin
`istered as an intravenous infusion. Systemic administration
`of glucocorticoids may have in?uenced the outcome of IgA
`nephropathy in some cases.
`
`BRIEF DESCRIPTION OF THE INVENTION
`Surprisingly, it has noW been found that glucocorticoid
`having a ?rst pass metabolism in the liver of at least 90%,
`Which minimises the systemic effect, is effective in control
`ling glomerulonephritis and especially IgA nephropathy in a
`native kidney or a kidney transplant. The substance prefer
`ably 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 in?amed 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 sys
`temic glucocorticiods used in prior art therapy.
`SUMMARY OF THE INVENTION
`The invention relates to the use of a glucocorticoid having
`a ?rst 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 treat
`ment of glomerulonephritis. More speci?cally the invention
`relates to the use of the glucocorticoid de?ned 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 ?rst 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 speci?cally 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 composi
`tion 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.
`
`15
`
`25
`
`35
`
`45
`
`55
`
`65
`
`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
`
`000002
`
`

`

`US 6,239,120 B1
`
`3
`chronic glomerulonephritis. Glomerulonephritis may be
`divided into subtypes such as membranous
`glomerulonephritis, focal segmental proliferative
`glomerulonephritis, diffuse mesangioproliferative
`glomerulonephritis, endocapillary or extracapillary prolif
`erative glomerulonephritis, depending on Where the in?am
`mation 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 glomerulo
`nephritis (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 pref
`erably one Which has a ?rst pass metabolism in the liver of
`at least 90% minimising the systemic effects. The ?rst pass
`metabolism in the liver of a glucocorticoid substance can be
`determined using the method disclosed previously (13).
`More preferably it is budesonide, ro?eponide or derivatives
`thereof, beclomethasone dipropionate, beclomethasone
`monopropionate, ciclesonide, tipredane, ?unisolide, traim
`cinolone acetonide or ?utiscasone propionate. Budesonide,
`Which is a 16,17-butylidenedioxy- 116,21
`dihydroxypregna-1,4-diene-3,20-dione, is particularly pre
`ferred.
`The glucocorticoid, When administered orally, is gener
`ally administered in the form of tablets, pills, capsules,
`poWders or granules, especially in the form of capsules
`comprising microcapsules. Also liquid preparations such as
`syrups and suspensions are conceivable. When administered
`rectally, it is in the form of foams, suppositories or enemas.
`The glucocorticoid may be administered as such or as a
`pharmaceutical composition in combination With a pharma
`ceutically acceptable diluent, adjuvant or carrier. Particu
`larly preferred are compositions not containing material
`capable of causing an adverse, eg an allergic reaction.
`The glucocorticoid substance may be admixed With an
`adjuvant or a carrier, e.g. lactose, saccharose, sorbitol,
`mannitol; starches such as potato starch, corn starch or
`amylopectin; cellulose derivatives; a binder such as gelatin
`or polyvinlypyrrolidone; and a lubricant such as magnesium
`stearate, calcium stearate, polyethylene glycol, Waxes and/or
`paraf?n, and then compressed into tablets. If coated tablets
`are required, the cores, prepared as described above, may be
`coated With a concentrated sugar solution, Which may con
`tain e.g. gum arabic, gelatin, talcum and/or titanium dioxide.
`Alternatively, the tablet may be coated With a suitable
`polymer dissolved in a readily volatile organic solvent. The
`tablet preferably has an enteric coating to alloW release of
`the glucocorticoid substance in the loWer intestine. Suitable
`capsules may be prepared by using the methods described in
`EP-A-502092, WO 97/27843 or WO 95/08323.
`For the preparation of soft gelatin capsules, the glucocor
`ticoid substance may be admixed With e. g. a vegetable oil or
`polyethylene glycol. Hard gelatin capsules may contain
`granules of the substance using either the above mentioned
`excipients for tablets, e.g. lactose, saccharose, sorbitol,
`mannitol, starches, cellulose derivatives or gelatin. Also
`liquid or semisolid formulations of the glucocorticoid sub
`stance may be ?lled into hard gelatin capsules.
`Liquid preparations of oral application may be in the form
`of syrups or suspensions, for example solutions containing
`the glucocorticoid substance, the balance being sugar and a
`mixture of ethanol, Water, glycerol and propylene glycol.
`Optionally such liquid preparations may contain colouring
`agents, ?avouring agents, saccharine and carboxymethylcel
`
`15
`
`25
`
`35
`
`45
`
`55
`
`4
`lulose as a thickening agent or other excipients knoWn to
`those skilled in the art.
`Rectal enema formulations can be in the form of simple
`suspensions of the glucocorticoid substance in a pharma
`ceutically acceptable carrier or may be in the form of a rectal
`foam formulation, for example as described in EP-A
`468555.
`The glucocorticoid substance is preferably administered
`at a dosage regime from 0.1 to 40 mg, more preferably from
`0.5 to 20 mg, most preferably from 1 to 10 mg, either as a
`single dose or in divided doses from 2 to 4 times per day. The
`pharmaceutical composition for oral administration used in
`the present invention should preferably be prepared in such
`a Way that the glucocorticoid substance is released during
`the passage of the loWer third of the small intestine and the
`upper fourth of the large intestine. This is in order to achieve
`a high local concentration of glucocorticoid in these parts of
`the intestine so that the glucocorticoid exerts its effect,
`preferably through the intestinal Wall of these parts of the
`intestine.
`The invention is illustrated by the folloWing examples
`Where budesonide Was administered orally using the Ento
`cortTM preparation (tablet form) to patients suffering from
`IgA nephropathy in native kidneys or kidney transplants.
`
`EXAMPLE 1
`
`A 52-year old man fell ill With signs of renal disorder as
`indicated by proteinuria and red blood cells in the urine in
`1982. After renal biopsy and histological analysis of renal
`tissue he Was diagnosed With IgA nephropathy. He Was
`treated With various antihypertensive drugs but the pro
`teinuria increased and by 1990 he had developed renal
`insufficiency and later that year he developed uraemia Which
`in turn necessitated dialysis treatment. In 1993 he received
`a kidney from a deceased person. The transplanted kidney
`Was Working satisfactorily for the ?rst 24 months and the
`patient Was treated With glucocorticoid substance With sys
`temic effect (prednisolone) as Well as With an immunosup
`pressive drug (Cyclosporine). In 1995 the ?rst signs of renal
`disorder of the transplanted kidney Were detected With
`increased proteinuria and reduced renal function as mea
`sured by changes in serum-creatinine concentrations. After
`renal biopsy of the transplant folloWed by histological
`analysis it Was shoWn that the tissue Was affected by IgA
`nephropathy. At this stage, treatment With budesonide
`(EntocortTM, 9 mg/day) Was initiated. Before the treatment
`commenced he had a considerable proteinuria (3.1 g
`albumin/day; normal range 0.3 g/day) and a reduced renal
`?ltering capacity (serum creatinine 264 pmol/l; normal
`range 80—115 pmol/ 1). After treatment With budesonide both
`the proteinuria and the renal function improved signi?cantly
`as shoWn in Table 1.
`
`Time
`(Weeks)
`
`0
`6
`12
`
`TABLE 1
`
`U-albumin
`(mg/24 h)
`
`3089
`624
`347
`
`S-creatinine
`(,umol/l)
`
`264
`213
`203
`
`EXAMPLE 2
`A 29-year old patient (female) With IgA nephropathy,
`Where histological examination of material from a renal
`biopsy disclosed irregular Widening of the mesangium and a
`
`000003
`
`

`

`5
`slight increase of mesangial matrix, but no cellular prolif
`eration. She had earlier been treated With immunosuppres
`sive and antihypertensive drugs Without any success as
`regards improvement of renal function or decrease of pro
`teinuria. Treatment With budesonide (9 mg/day) Was initi
`ated and after three months of treatment a 50% reduction of
`proteinuria Was detected as disclosed in Table 2.
`
`Time
`(Weeks)
`
`0
`6
`12
`
`TABLE 2
`
`U-albumin
`(mg/24 h)
`
`S-creatinine
`(,umol/l)
`
`899
`745
`421
`
`85
`75
`75
`
`EXAMPLE 3
`
`A 47-year old patient (male) suffered from IgA
`nephropathy, Which Was diagnosed in August 1996. Histo
`logical examination of material from renal biopsy shoWed a
`slight to moderate Widening of the mesangium, slight
`increase of mesangial matrix and a slight mesangial prolif
`eration. Furthermore, focal chronic in?ammation Was
`present in the interstitium and there Was focal ?brosis and
`partial atrophic tubuli present. Treatment With budesonide (9
`mg/day) Was initiated and after 12 Weeks of treatment the
`proteinuria Was reduced and the renal function (serum
`creatinine Was improved as shoWn in Table 3.
`
`20
`
`25
`
`Time
`(Weeks)
`
`0
`6
`12
`
`TABLE 3
`
`U-albumin
`(mg/24 h)
`
`S-creatinine
`(,umol/l)
`
`1349
`1050
`1067
`
`147
`142
`129
`
`EXAMPLE 4
`A patient, 37-years old, (male) With IgA nephropathy,
`Where histological examination of the renal biopsy demon
`strated that 2/15 glomeruli Were sclerotic and the other
`glomeruli had mesangial proliferative changes. A slight
`focal interstitial ?brosis and tubular atrophy could also be
`demonstrated. Treatment With budesonide (9 mg/day) Was
`initiated and after 12 Weeks of treatment the proteinuria Was
`reduced and renal function Was basically unchanged as
`shoWn in Table 4.
`
`Time
`(Weeks)
`
`0
`6
`12
`
`TABLE 4
`
`U-albumin
`(mg/24 h)
`
`S-creatinine
`(,umol/l)
`
`1244
`964
`1078
`
`116
`113
`112
`
`35
`
`40
`
`45
`
`50
`
`55
`
`EXAMPLE 5
`A 52-year old patient (female) With IgA nephropathy,
`Where the histological examination of material from renal
`biopsy shoWed substantial segmental sclerotic changes in
`2—4/ 15 glomeruli and slight mesangial proliferative changes
`in the rest of the glomeruli. There Was also slight interstitial
`?brosis and tubular atrophy present. Treatment With budes
`onide (9 mg/day) Was initiated and after 12 Weeks of
`
`60
`
`65
`
`US 6,239,120 B1
`
`6
`treatment the proteinuria Was reduced and the renal function
`Was possibly improved as shoWn in Table 5.
`
`Time
`(Weeks)
`
`0
`6
`12
`
`10
`
`TABLE 5
`
`U-albumin
`(mg/24 h)
`
`S-creatinine
`(,umol/l)
`
`634
`516
`431
`
`106
`107
`100
`
`EXAMPLE 6
`
`A 26-year old patient (male) With IgA nephropathy Was
`studied before and during the treatment With budesonide (9
`mg/day). After 12 Weeks roteinuria Was reduced as shoWn in
`Table 6.
`
`Time
`(Weeks)
`
`0
`6
`12
`
`TABLE 6
`
`U-albumin
`(mg/24 h)
`
`S-creatinine
`(,umol/l)
`
`1449
`1398
`1100
`
`91
`97
`90
`
`EXAMPLE 7
`
`A 27-year old patient (female) With IgA nephropathy,
`Where histological examination of material from the renal
`biopsy shoWed an irregular Widening of the mesangium and
`a focal increase of mesangial matrix and a slight mesangial
`proliferation. The interstitium, tubuli, and vessels had nor
`mal appearances. Treatment With budesonide (9 mg/day)
`Was initiated and after 12 Weeks of treatment the proteinuria
`Was reduced as shoWn in Table 7.
`
`TABLE 7
`
`Time
`(Weeks)
`
`0
`6
`12
`
`U-albumin
`(mg/24 h)
`
`S-creatinine
`(,umol/l)
`
`311
`212
`167
`
`82
`81
`81
`
`EXAMPLE 8
`
`A 36-year old patient (male) With IgA nephropathy, Where
`histological examination of material from renal biopsy
`shoWed that 14/28 glomeruli Were entirely sclerotic and in
`the rest of glomeruli there Was a Widening of the mesangium
`and a slight mesangial proliferation and an increase of
`mesangial matrix. Focal ?brosis Was also found in the
`interstitium. Treatment With budesonide (9 mg/day) Was
`initiated and after 6 Weeks of treatment the proteinuria Was
`reduced and renal function Was improved as shoWn in Table
`8.
`
`Time
`(Weeks)
`
`0
`6
`
`TABLE 8
`
`U-albumin
`(mg/24 h)
`
`829
`596
`
`S-creatinine
`(,umol/l)
`
`171
`152
`
`000004
`
`

`

`US 6,239,120 B1
`
`7
`References
`
`1. Clarkson et al. In Diseases of the Kidney, Braun & Co,
`1988, pp 2061—2090.
`. Alarmaatine et al. Clin Nephrol 34 (2): 45, 1990.
`. Lai et al. Int J Artif Organs 17 (9): 457, 1994.
`Scheinman et al. Nephron 75: 251, 1997.
`. Shu et al. Clin Nephrol 44: 86, 1995.
`Goomanos et al. NDT 10: 1173, 1995.
`. Schmidt et al. Curr Op Nephrol Hypertension 5: 552,
`1996.
`8. Donadio et al. NEJM 3: 1194, 1994.
`9. Trachtman et al. Ped Res 40: 620, 1996.
`10. Feehally et al. Curr Op Nephrol Hypertension 5: 442,
`1996.
`11. Frohnert et al. Clin Transpl 11: 127, 1997.
`12. Odum et al. NDT 9: 309, 1994.
`13. Andersson P et al. Xenobiotica 17: 5, 1987.
`What is claimed is:
`1. A method of treating acute or chronic glomerulone
`phritis in a patient in need thereof comprising administering
`to said patient a pharmacologically effective amount of a
`glucocorticoid having a ?rst pass metabolism in the liver of
`at least 90% in contact With the intestinal Wall area.
`2. The method according to claim 1 Wherein the gluco
`corticoid eXerts its effect When passing the loWer third of the
`small intestine and the upper fourth of the large intestine.
`3. The method according to claim 1, Wherein the gluco
`corticoid is selected from budesonide, ro?eponide, beclom
`ethasone mono-propionate, beclomethasone di-propionate,
`ciclesonide, tipredane, ?unisolide, traimcinolone acetonide
`and ?uticasone propionate.
`4. The method according to claim 3, Wherein the gluco
`corticoid is budesonide.
`
`15
`
`25
`
`8
`5. The method according to claim 1, Wherein said gluco
`corticoid is administered in a daily dosage of 0.1 mg to 40
`mg, as a single dose or in divided doses 2 to 4 times per day.
`6. The method according to claim 1, Wherein the gluco
`corticoid is administered orally.
`7. The method according to claim 6, Wherein the gluco
`corticoid is administered in a form selected from the group
`consisting of tablets, pills, capsules, poWders, syrups, solu
`tions and granules.
`8. The method according to claim 7, Wherein said admin
`istration from comprises a carrier and an enteric coating and
`is preferably in the form of capsules comprising microcap
`sules.
`9. The method of claim 1, Wherein the glucocorticoid is
`administered rectally in a form selected from the group
`consisting of suppositories, foams, and enemas.
`10. The method according to claim 1 for treating IgA
`nephropathy in a native kidney or a kidney transplant.
`11. The method according to claim 3, Wherein said
`glucocorticoid is administered in a daily dose of 0.1 mg to
`40 mg as a single dose or in divided doses 2 to 4 times per
`day.
`12. The method according to claim 4, Wherein said
`glucocorticoid is administered in a daily dose of 0.1 mg to
`40 mg as a single dose or in divided doses 2 to 4 times per
`day.
`13. The method according to claim 1, Wherein said
`glucocorticoid is administered in a daily dose of 0.5 mg to
`20 mg as a single dose or in divided doses 2 to 4 times per
`day.
`14. The method according to claim 1, Wherein said
`glucocorticoid is administered in a daily dose of 1 mg to 10
`mg as a single dose or in divided doses 2 to 4 times per day.
`
`*
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`*
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`*
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`*
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`*
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`000005
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