o
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`to
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`U.S. PATENT AND TRADEMARK OFFICE
`PROVISIONAL APPLICATION FOR PATENT COVER SHEET
`
`This is a request for filing a PROVISIONAL APPLICATION FOR PATENT
`under 37 C.F.R. §1.53(c).
`
`Page 1 of 1
`
`Atty. Docket: HALLGREN=1
`
`INVENTOR(s)/APPLICANT(s)
`
`LAST NAME
`
`HALLGREN
`FELLSTROM
`
`FIRST NAME
`
`MIDDLE
`INITIAL
`
`RESIDENCE (CITY AND EITHER STATE OR FOREIGN COUNTRY)
`
`Roger
`Bengt
`
`Balinge, Sweden
`Knivsta, Sweden
`
`[ ] Additional inventors are being
`
`sheets attached hereto.
`named on separately numbered
`
`TITLE OF THE INVENTION (280 characters max)
`
`NEW THERAPY IN GLOMERULONEPHRITIS
`
`CORRESPONDENCE ADDRESS
`
`BROWDY AND NEIMARK, P.L.L.C.
`419 Seventh Street, N.W., Suite 300
`Washington, D.C. 20004
`
`ENCLOSED APPLICATION PARTS (check all that apply)
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`[XXI Specification (cid:9)
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`is enclosed to cover the Provisional filing fee of
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`The Commissioner is hereby authorized to charge any deficiency in the filing fees and credit any overpayment
`to Deposit Account Number 02-4035.
`
`•
`
`The invention was made by an agency of the United States Government or under a contract with an agency of the United States Government.
`
`[XX] No [ ] Yes, the name of the U.S. Government agency and the Government contract number are:
`
`Date: 01 April 1998
`
`SN:bcs
`f:\user3 98apr hall.ptr
`
`Respectfully submitted,
`
`BROWDY A 0 N
`
`.L.L.C.
`
`By:
`
`Shetidan Nei
`Registration No.: 20,520
`
`Exhibit 1042
`ARGENTUM
`IPR2018-00080
`
`000001
`
`

`

`NEW THERAPY IN GLOIVIERULONEPHRITIS
`
`Field of Invention
`
`The present invention provides a new treatment for glomerulonephritis.
`
`5
`
`Background to 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
`
`10 (cid:9)
`
`glomerulosclerosis, mesangial diffuse proliferative glomerulonephritis, endocapillary or
`
`extracapillary proliferative glomerulonephritis. Using histopathological techniques these
`
`subgroups vary with respect to microscopical or immunhistochemical picture. One cause
`
`of inflammation is due to the deposition of irnmunoglobulin A (IgA) in glomeruli. This
`
`condition is termed IgA nephropathy (1-3), which is the most common form of
`
`15 (cid:9)
`
`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
`
`20 (cid:9)
`
`serum creatinine (s-creatinine). 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 immunhistochemical findings in a renal biopsy. Patients with IgA
`
`nephropathy having a constant proteinuria often develop renal failure and uraemia after 5
`
`25 (cid:9)
`
`to 520 years of illness (4).
`
`Various treatments for glomerulonephritis are known. For example substances which act
`
`on the immune system, e.g. Cyclophospharnide, Azathioprine and Cyclosporine have
`
`been used. Glucocorticoids have also been used (mainly prednisone or prednisone
`
`000002
`
`

`

`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
`
`5 (cid:9)
`
`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
`
`10 (cid:9)
`
`uraemia due to glornerulonephritis frequently suffer from recurrence of
`
`glomerulonephritis in the transplant and subsequently a gradual loss of transplant function
`
`(11, 12). This is most common in patients who previously suffered from IgA
`
`nephropathy. Today there is no effective treatment against recurrence of
`
`glomerulonephritis in a transplant.
`
`15
`
`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
`
`20 (cid:9)
`
`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.
`
`It has now surprisingly been found that a giticocorticoid substance which has a minimal
`
`25 (cid:9)
`
`systemic effect, but exerts its effect preferably in the intestinal wall of a certain part of the
`
`gut (the lower third of the small intesitne and the upper fourth of the large intestine), is
`
`effective in controlling IgA nephropathy in a native kidney or a kidney transplant. It
`
`would not be expected that treatment of an apparently healthy intestine has an effect on an
`
`inflamed kidney. This discovery represents a breakthrough in the treatment of
`
`000003
`
`

`

`3
`
`glomerulonephritis since it has the advantage of reduction of severe side effects on the
`
`body, including effects on skeleton, metabolism and muscles, caused by systemic
`
`talucocorticiods.
`
`5 (cid:9)
`
`Summary of the Invention
`
`According to the invention there is provided the use of a glucocorticoid substance which
`
`has a minimal systemic effect in the manufacture of a medicament for oral or rectal
`
`administration for use in the treatment of glomerulonephritis.
`
`10 (cid:9)
`
`According to the invention there is further provided a method of treating a patient
`
`suffering from glomerulonephritis which comprises administering orally or rectally to the
`
`patient a therapeutically effective amount of a glucocorticoid substance which has a
`
`minimal systemic effect.
`
`15 (cid:9)
`
`According to the invention there is further provided a pharmaceutical composition
`
`comprising a glucocorticoid substance which has a minimal systemic effect for oral or
`
`rectal administration in association with a pharmaceutically acceptable diluent, adjuvant or
`
`carrier, which composition is for use in the treatment of glomerulonephritis_
`
`20 (cid:9)
`
`Detailed Description of the Invention
`
`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 glomerulonephrius, focal segmental proliferative glomerulonephritis, diffuse
`
`mesangioproliferative glomerulonephritis, endocapillary or extracapillary proliferative
`
`25 (cid:9)
`
`glomerulonephritis, depending on where the inflammation is located. This invention is
`
`preferably used to treat the IgA nephropathy type of glomerulonephritis. The invention is
`
`particularly suitable for treating patients who have suffered form glomerulonephritis
`
`(particularly IgA nephropathy), had a transplant, and suffered from a recurrence of
`
`glomerulonephritis (particularly IgA nephropathy) in the transplanted kidney.
`
`000004
`
`

`

`4
`
`The glucocorticoid substance used in the present invention is preferably one which has a
`
`first pass metabolism of at least 90% for the minimisation of the systemic effects_ The
`
`first pass metabolism of a glucocorticoid substance can be determined using the method
`
`5 (cid:9)
`
`disclosed previously (13). More preferably it is budesonide, rofleponide or derivatives
`
`thereof, belcornethasone dipropionate, belcomethasone monopropionate, ciclesonide,
`
`tipredane, flunisolide, traimcinolone acetonide or flutiscasone propionate_ Budesonide,
`
`which is a 16,17-bytylidenedioxy-11p,21-dihydroxypregna-1,4-diene-3,20-dione, is
`
`particularly prefered.
`
`10
`
`The glucocorticoid substance when administered orally is generally administered in the
`
`form of tablets, pills, capsules, syrups, powders or granulates and when it is
`
`administered rectally, is in the form of foams, suppositories or enemas.
`
`15 (cid:9)
`
`The glucocorticoid substance may be administered on its own or as a pharmaceutical
`
`composition in combination with a pharmaceutically acceptable diluent, adjuvant or
`
`carrier. particularly preferred are compositions not containing material capable of causing
`
`an adverse, e.g. an allergic reaction.
`
`20 (cid:9)
`
`The glucocorticoid substance may be admixed with an adjuvant or a carrier, e.g. lactose,
`
`saccharose, sorbitol, niannitol, starches such as potato starch, corn starch or amylopectin,
`
`cellulose derivatives, a binder such as gelatine or poIyvinlypyrrolidone, and a lubricant
`
`such as magnesium stearate, calcium stearate, polyethylene glycol, waxes and/or paraffin,
`
`and then compressed into tablets. If coated tablets are required, the cores, prepared as
`
`25 (cid:9)
`
`described above, may be coated with a concentrated sugar solution which may contain
`
`e.g. gum arabic, gelatine, talcum and/or titanium dioxide. Alternatively, the tablet may be
`
`coated with a suitable polymer dissolved in a readily volatile organic solvent, The tablet
`
`000005
`
`

`

`5
`
`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.
`
`5 (cid:9)
`
`For the preparation of soft gelatine capsules, the glucocorticoid substance may be
`
`admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine 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 gelatine.
`
`Also liquid or semisolid formulations of the glucocorticoid substance may be filled into
`
`10 (cid:9)
`
`hard gelatine 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
`
`Inixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid
`
`15 (cid:9)
`
`preparations may contain colouring agents, flavouring agents, saccharine and
`
`carboxymethylcellulose 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
`
`20 (cid:9)
`
`substance in a pharmaceutically 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 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
`
`25 (cid:9)
`
`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 that there is a
`
`000006
`
`

`

`6
`
`high local concentration of glucocorticoid substance in these parts of the intestine such
`
`that the glucocorticoid substance exerts its effect preferably in the intestinal wall of these
`
`parts of the intestine.
`
`5 (cid:9)
`
`The invention is illustrated by the following examples where budesonide was
`
`administered orally using the EntocortTM preparation (tablet form) to patients suffering
`
`from IgA nephropathy in native kidneys or kidney transplants.
`
`Example 1
`
`10 (cid:9)
`
`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
`
`medical drugs but the proteinuria increased and in 1990 he had developed renal
`
`insufficiency and later that year he developed uraemia which in turn necessitated dialysis
`
`15 (cid:9)
`
`treatment. In 1993 he received a kidney from a deceased person. The transplanted kidney
`
`was working satisfactorily for the first 24 months and the patient was treated with
`
`glucocorticoid substance with systemic effect (prednisolone) as well as with an
`
`immunosuppressive drug (Cyclosporine). In 1995 the first signs of renal disorder of the
`
`transplanted kidney were detected with increased proteinuria and reduced renal function as
`
`20 (cid:9)
`
`measured 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 (Entocorr, 9 mg/day) was
`
`initiated. Before commencement of treatment he had a considerable proteinuria (3.1 g
`
`alburnin/day; normal range 0.3 glday) and a reduced renal filtering capacity (serum
`
`creatinine 264 timolf1; normal range 80-115 umo1/1). After treatment with budesonide both
`
`the. protemuria and the renal function improved significantly as shown in Table 1.
`
`000007
`
`

`

`Table 1
`
`Time (weeks)
`
`U-albumin (mg/24h)
`
`S-creatinine (µm01/1.)
`
`011110110
`
`0
`
`6
`
`12
`
`3089
`
`624
`
`347
`
`264
`
`213
`
`203
`
`Example 2
`
`5 (cid:9)
`
`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 slight
`
`increase of mesangial matrix, but no cellular proliferation. She had earlier been treated
`
`with immunosuppressive and antihypertensive drugs but without any success regarding
`
`improvement of renal function or decrease of proteinuria. Treatment with budesonide
`
`10 (cid:9)
`
`(9 mg/day) was initiated and after three months of treatment a 50% reduction of
`
`proteinuria was detected as disclosed in Table 2.
`
`Table 2
`
`Time (weeks)
`
`U-albumin (mg/24h)
`
`S-creatinine (p.mol/1)
`
`0
`
`6
`
`12
`
`899
`
`745
`
`421
`
`85
`
`75
`
`75
`
`15
`
`Example 3
`
`A 47-year old patient (male) with IgA nephropathy which was diagnosed in August 1996.
`
`Histological examination of material from renal biopsy showed a slight to moderate
`
`widening of the mesangium, slight increase of mesangial matrix and a slight mesangial
`
`20 (cid:9)
`
`proliferation. Furthermore, focal chronic inflammation was present in the interstitium and
`
`000008
`
`

`

`there was•focal fibrosis 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 !Unction (serum creatinine) was Improved as shown in Table 3.
`
`5 (cid:9)
`
`Table 3
`
`Time (weeks)
`
`U-albumin (mg/24h)
`
`S-creatinine (iuno1/1)
`
`0
`
`6
`
`12
`
`1349
`
`1050
`
`1067
`
`147
`
`142
`
`129
`
`Example 4
`
`A 37-year old patient (male) with IgA nephropathy. where histological examination of the
`
`10 (cid:9)
`
`renal biopsy demonstrated that 2/15 glomerull were sclerotic and the other &mend' had
`
`IRCVnal I9145ative ch"ues. A sliuht focal interstitial fibrosis 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.
`
`15
`
`Table 4
`
`Time (weeks)
`
`U-albumin (mg/24h)
`
`S-creatinine (timoV1)
`
`0
`
`6
`
`12
`
`1244
`
`964
`
`1078
`
`116
`
`113
`
`112
`
`Table 6
`
`Time (weeks)
`
`U-alburnin (mg/24h)
`
`S-creatinine (11m01/1)
`
`0
`
`6
`
`12
`
`1449
`
`1398
`
`1100
`
`91
`
`97
`
`90
`
`000009
`
`

`

`9
`
`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
`
`5 (cid:9)
`
`was also slight interstitial fibrosis and tubular atrophy present. Treatment with budesonide
`
`(9 mg/day) was initiated and after 12 weeks of treatment the proteinuria was reduced and
`
`the renal function was possibly improved as shown in Table 5.
`
`Table 5
`
`Time (weeks) (cid:9)
`
`U-albumin (mg/24h) (cid:9)
`
`S-creatinine (gmo1/1)
`
`0
`
`6
`
`12
`
`634
`
`516
`
`431
`
`106
`
`107
`
`100
`
`10
`
`Exempel 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 of treatment the proteinuria was
`
`15 (cid:9)
`
`reduced as shown in Table 6.
`
`Table 6
`
`Time (weeks)
`
`U-albumin (mg/24h)
`
`S-creatinine (umo1/1)
`
`0
`
`6
`
`12
`
`1449
`
`1398
`
`1100
`
`91
`
`97
`
`90
`
`000010
`
`

`

`10
`
`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,
`
`5 (cid:9)
`
`tubuli, and vessels had normal 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)
`
`U-albumin (mg/24h)
`
`S-creatinine (p.mo1/1)
`
`0
`
`6
`
`12
`
`311
`
`212
`
`167
`
`82
`
`81
`
`81
`
`10 (cid:9)
`
`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 fibrosis was also found in the
`
`15 (cid:9)
`
`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.
`
`Table 8
`
`Time (weeks) (cid:9)
`
`U-albumin (mg/24h) (cid:9)
`
`S-creatinine (p.mo1/1)
`
`0
`
`6
`
`829
`
`596
`
`171
`
`152
`
`20
`
`000011
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`11
`
`Claims
`
`1. (cid:9) Use of glucocorticoid substance which has a minimal systemic effect in the
`
`manufacture of a medicament for oral or rectal administration for use in the treatment
`
`of glornerulonepluitis.
`
`S
`
`2. Use according to claim 1 wherein the medicament is for use in the treatment of a
`
`patient who has had a kidney transplant.
`
`3. Use according to claim 1 or 2 wherein the medicament is for use in the treatment of a
`
`10 (cid:9)
`
`patient who is suffering from recurrence of glomerulonepinitis in a kidney transplant.
`
`4. Use according to claim 1, 2 or 3 wherein the medicament is for use in the treatment of
`
`IgA nephropathy.
`
`15 (cid:9)
`
`5. Use according to any one of claims I to 4 wherein the medicament comprises
`
`budesonide in an amount which provides a daily dose of from 0.1 to 40 mg.
`
`6. Use according to any one of claims 1 to 4 wherein the medicament is administered as
`
`a single daily dose or in from 2 to 4 divided doses.
`
`10
`
`7. A method of treating a patient suffering from glornerulonephritis which comprises
`
`administering orally or rectally to the patient a therapeutically effective amount of a
`
`glucocorticoid substance which has a minimal systemic effect.
`
`25 (cid:9)
`
`A method according to claim 7 wherein the medicament is for use in the treatment of a
`
`patient who has had a kidney transplant.
`
`000012
`
`

`

`14
`
`9. A method according to claim 7 wherein the medicament is for use in the treatment of a
`
`patient who is suffering from recurrence of glomen.ilonephritis in a kidney transplant.
`
`10. A method according to claim 7, 8 or 9 wherein the medicament is for use in the
`
`treatment of IgA nephropathy.
`
`11. A method according to any one of claims 7 to 10 wherein the medicament comprises
`
`budesonide in an amount which provides a daily dose of from 0.1 to 40 mg.
`
`10 (cid:9)
`
`12. A method according to any one of claims 7 to 11 wherein the medicament is
`
`administered in a single daily dose or in from 2 to 4 divided doses.
`
`13. A pharmaceutical composition comprising a glucocorticoid substance which has a
`
`minimal systemic effect, but exerts its effect preferably in the intestinal wall of a
`
`15 (cid:9)
`
`certain part of the gut, for oral or rectal administration in association with a
`
`pharmaceutically acceptable diluent, adjuvant or carrier, which composition is for use
`
`in the treatment of glomerulonephritis.
`
`14. A composition according to claim 13 for use in the treatment of a patient who has had
`
`20 (cid:9)
`
`a kidney transplant.
`
`15_ A composition according to claim 13 or 14 for use in the treatment of a patient who is
`
`suffering from recurrence of glomenilonephritis in a kidney transplant.
`
`25 (cid:9)
`
`16. A composition according to claim 13, 14 or 15 for use in the treatment of IgA
`
`nephropathy.
`
`000013
`
`

`

`13
`
`17. A composition according to any one of claims 13 to 16 wherein the medicament
`
`comprises budesonide in an amount which provides a daily dose of from 0.1 to 40 mg.
`
`18. A composition according to claim 17 which is administered as a single daily dose or
`
`5 (cid:9)
`
`in from 2 to 4 divided doses.
`
`Abstract
`
`The invention provides the use of a glucocorticoid substance which has a minimal
`
`systemic effect in the manufacture of a medicament for oral or rectal administration for use
`
`10 (cid:9)
`
`in the treatment of glomerulonephritis, especially IgA nephropathy.
`
`References
`
`1. Clarkson et al. In Diseases of teh Kidney, Braun & Co, 1988, pp 2061-2090.
`
`2. Alarmaatine et al. Clin Nephrol 34 (2): 45, 1990.
`
`15 (cid:9)
`
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`000014
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