AU640349B2 - Treatment of gastro-intestinal disorders - Google Patents

Description

F-WINE

ANAh'XJXa0IOF THE LA TER PUBG JBJ7WN OF REWSEC) VERSKCASI OF bVTERNAIONL SEARCH REPORT 2 INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (51) International Patent Classification 4 A61K 39/02, 39/08, 39/10 A61K 39/114, 35/24 Al (11) International Publication Number: (43) International Publication Date: WO 90/01335 22 February 1990 (22.02.90) (21) International Application Number: (22) International Filing Date: Priority data: PI 9613 2 August PJ 3837 21 April PCT/AU89/00328 2 August 1989 (02.08.89) Published With a revised version of international sear'ch report.

Before the expwanion of the time limit for amending the clims and to be republished in the event of the receipt of amenaments.

1988 (02,08.88) 1989 (2 1.04.89) Date of publication tionai scardi report: of the m-evsed vmron of the irncrna.

31 May 1990 (31.05.90) (71X72) Applicant and Inventor, BORO DY, Thomas, Julius (AU/AU]; 144 Great North Road, Five Dock, NSW 2046 (AU).

(74) Agent: SPRUSON FERGUSON; G.P.O. Box 3898, Sydney, NSW 2001 (AU).

(81) Designated States: AT (European patent), AU, BE (European patent), CH (European patent), DE (European patent), FR (European patent), GB (European patent), IT (European patent), LU (European patent), NL (European patent), SE (European patent), US.

640 346 (54) Tltle: TREATMENT OF GASTRO-INTESTINAL DISORDERS (57) Abstract A method of treating chronic disorders associated with the presence of abnormal microflora or an abnormal distribution of microflora in the gastrointestinal tract. The method involves the removal of at least a portion of the host's existing enteric microf- Iota and the substitution of an effective amount of predetermined microflora. Pharmaceutical compositions which comprise viable microorganisms in a composition resembling the host's normal healthy faecal flora are also disclosed.

*(Referred to in PCT Gazette No. 12/1990. Section III WO 90/01335 CI /At 89/00328 1 TREATMENT OF GASTRO-INTESTINAL DISORDERS Technical Field The present invention relates to methods of treating diseases in mammals, in particular to the treatment of chronic disorders associated with the presence of abnormal or an abnormal distribution of microflora in the gastrointestlnal tract. The invention also relates to pharmaceutical compositions suitable for the treatment of such disorders.

Background Art There are large numbers of patients suffering from gastro-lntestinal symptoms referrable to the lower small bowel and large bowel which to date have eluded explanation. These disorders include irritable bowel syndrome (IBS) or spastic colon, idlopathic ulcerative colitis, mucous colitis, collagenous colitis, Crohn's disease, inflammatory bowel disease In general, microscopic colitis, antibiotic-associated colitis, Idiopathic or simple constipation, diverticular disease, and AIDS enteropathy.

Pathophysiology of these disorders eludes logical explanation In spite of decades of research and millions of dollars of research funds. A common underlying factor shared by all these disorders observed by the present inventor Is their onset following some extraneous invading Infection. In all the disorders, the Infection cannot be demonstrated due to our inability to detect infecting agents whose cultural characteristics are unknown to medical science.

Circumstantial evidence which suggests that these disorders are "Infection-related" Includes: onset following a gastro-intestinal Infection which failed to completely resolve; transient Improvement with use of certain antibiotics, but recurrence upon cessation of antibiotics; transient improvement following orthostatic lavac? prior to colonoscopy and; transient symptom improvement with use of "colonic" Irrigation.

It Is Impractical to use long-term antibiotic therapy (with its associated complications) In such patients since cure is not obtained with its use. Furthermore, chronic gut infections with recognised, specific pathogens such as Clostridi-um difficile. Yersinia. enterocolitica or Campylobacter .lei.unl/col are not eradicated with antibiotics. Some previous attempts have been made to alter the enteric microflora In order to eradicate such chronic infections. These measures nevertheless SUBSTITUTE SHEET WO 90/01335 PCT/A L89/00328 2 indicate that alteration of bacterial flora may effect dramatic clinica improvement in conditions characterized by chronic, resistant enterocolitic infection. However there remain many chronic disorders of uncertain aetiology or causation, which are resistant to cure by current therapeutic techniques.

Objects of the Invention It is thus an object of the present Invention to provide novel methods of treating various disease states related to the presence of "abnormal" microflora in the gastrointestlnal tract.

Disclosure of the Invention The present invention recognises chronic Infection/infestation as the underlying pathological process in a wide range of chronic disorders such as Irritable bowel syndrome, particularly when characterised by chronic abdominal pain, bloating, or excessive flatulence, together with chronic diarrhoea or alternating constipation/diarrhoea, and also in spastic colon, mucous colitis, collagenous colitis, ulcerative colitis, Crohn's colitis, microscopic colitis, idiopathic inflammatory bowel disease, antibiotic-associated colitis, idiopathic or simple constipation, divertlcular disease and AIDS enteropathy.

The invention has also been found to relate to other gastrolntestlnal disorders of unexplained aetiology such as polyposis coli and colonic polyps, which may well be influenced by the local bowel microflora.

In addition the present Invention also provides a method of treatment of chronic gastrointestinal infections with specific microorganisms such as Clostridium difficile, Yerslnia spp, Camylobacter spp, Aergmonas spp, E.

.LU, CryptosDorldlum spp, Amoebae, Glardia and even chronic viral infections, and of small bowel bacterial overgrowth.

The present invention furthermore, recognises the close association between the intestine and liver disease, and the intestine and migraines and chronic fatigue syndrome, and possibly other neurological syndromes such as, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, Parkinson's disease, Alzheimers disease and other degenerative disorders. Hence, it is proposed that a considerable proportion of currently unexplained diseases of the liver and nervous system of unknown aetiology may be explicable by the chronic storage of pathogens within the small/large intestine and the subsequent passage of antigenic material and pathogenic TOXINS into the portal system (liver damage) or systemic circulation (neurological conditions). Specifically, such hepato/biliary SUBSTITUTE SHEET 3 system disorders as primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver of unknown aetiology, or cryptogenic cirrhosis, may be secondary to chronic pathogen carrier state in the intestine.

The links between the intestine and joint disease are also recognised. Joint diseases such as rheumatoid arthritis, the non-rheumatoid arthritidies including, ankylosing spondylitis, and Reiter's syndrome, may also be causally related to a chronic intestinal carrier state, as may other syndromes with an immune mediated component such as glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes mellitus, Behcet's syndrome, coeliac disease and dermatitis herpetiformis. Similarly, syndromes with an immune complex mediated component, such as scleroderma, systemic lupus erythematosus, mixed cryoglobulinaemia, polyarteritis, familial Mediterranean fever, amyloidosis, and the various presentations of such syndromes, together with such "idiopathic" states as chronic urticaria, may be manifestations of variations of immune regulated responses to related bowel-origin pathogens chronically shedding their antigen(s) into the circulation. Other chronic conditions such as acne, and chronic idiopathic pseudo-obstructive syndrome, may well be influenced by similar mechanisms.

For many of these syndromes present therapy offers only palliation of symptoms and/or the induction of remission of the disease process but not cure. The present inventor theifore recognised the need to find a curative therapy for these wide ranging disease processes associated with considerable morbidity.

Thus according to a first embodiment of the invention there is provided a method of treatment or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a host of abnormal or an abnormal distribution of microflora excluding Salmonella for said host, which method comprises the removal of at least a portion of the host's existing enteric microflora and the substitution of an effective amount of predetermined gastrointestinal or enteric not antibiotic resistant microflora of various genera and excluding Bifidobacteria.

In its preferred form the treatment should effect a cure of the symptoms of such disorders. The change of flora is preferably as "near-complete" as possible and the flora is replaced by viable organisms which will crowd out any remaining, original flora.

The method of the present invention is applicable to animals in general in particular humans and economically significant domestic animals.

In the case of humans, the present invention encompasses methods of 4S123AU1 WO 90/01335 PCT/AL 89/00328 4 treatment of chronic disorders associated with the presence of abnormal enteric microflora, Such disorders include but are not limited to those conditions in the following categories: i) gastro-lntestlnal disorders including Irritable bowel syndrome or spastic colon, ulcerative colitis, mucous colitis, collagenous colitis, Crohn's disease, Inflammatory bowel disease, microscopic colitis, antibiotic associated colitis, Idiopathic or simple constipation, diverticular disease, AIDS enteropathy, small bowel bacterial overgrowth, coellac disease, polyposis coll, colonic polyps, chronic idiopathic pseudo obstructive syndrome; II) chronic gut Infections with specific pathogens including bacteria, viruses, fungi and protozoa; iii) liver disorders such as primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver or cryptogenic cirrhosis; iv) joint disorders such as rheumatoid arthritis, non-rheumatoid arthritldies, ankylosing spondylitis, and Relter's syndrome; v) immune mediated disorders such as glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes mellitus, mixed cryoglobullnaemia, polyarterltis, familial Mediterranean fever, amyloidosis, scleroderma, systemic lupus erythematosus, and Behcet's syndrome; vi) neurological syndromes such as migraine, multiple sclerosis, amyotrophic lateral sclerosis, myasthenia gravis, chronic fatigue syndrome, Parklnson's disease, Alzhelmers disease and other degenerative disorders; vii) dermatological conditions such as, chronic urticaria, acne, dermatitis herpetiformis and vasculitic disorders; The above disorders are all characterised by their response to treatment with the method of the present Invention.

Typically the change in enteric flora comprises: substantially complete removal of existing enteric flora, and introduction of an array of predetermined flora into the gastro-intestlnal system, and thus In a preferred form the method of treatment comprises substantially completely changing enteric flora in patients requiring such treatment.

Furthermore, in some of these disorders a short course of antibiotics may be required to rid tissue-invasive pathogens originating in the bowel lumen. For example, In Crohn's disease, anti-tuberculosis therapy may be required for six to twelve weeks before the bowel is cleared out and the flora content exchanged for a predetermined flora.

SUBSTITUTE SHEET Preferably the removal of existing enteric flora is effected by lavage of the gastrointestinal tract. This can be effected by methods known 'to those skilled in the art such as ingestion of lavage solutions such as orthostatic salt and polyethylene glycol solution, enemas or small bowel intubation and lavage.

Turning to the introduction of an array of predetermined flora into the gastrointestinal system, this can be effected by enemas or per-colonoscope, via untubation of the small bowel using for example a large bore catheter equipped with distal balloon to effect rapid passage down the jejunum, or via the oral route with enteric-coated capsules.

The predetermined array of normal bowel microflora preferably comprises a composition of disease screened fresh homologous faeces, equivalent freeze-dried and reconstituted faeces or a "synthetic" faecal composition. The fresh homologous faeces does not include an antibiotic resistant population.

In a preferred form the synthetic faecal composition comprises a preparation of viable flora which preferably in proportional content, resembles normal healthy human faecal flora which does not include antibiotic resistant populations. Suitable microorganisms may be selected from the following: Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E. coli, Gemmiger, Clostridium, Desulfomonas, species and, more specifically, bacteria selected from Table 1. Preferably fungi are also present such as Monilla.

According to a second embodiment of the invention there is provided a pharmaceutical composition useful for the treatment and/or prophylaxis of chronic disorders associated with the presence in the gastrointestinal tract of a non-avian host of abnormal or an abnormal distribution of microflora excluding Salmonella for said host, which composition comprises a selection of viable microorganisms of various genera excluding Streptococcus faecium in appropriate proportions such that the composition substantially resembles the host's normal healthy, faecal flora.

In practice suitable microorganisms include those selected from Bacteroldes, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E. coll, Gemmiger, Clostridium, Desuffomnonas, and Monilia species, and more specifically from those set out in Table 1.

In a preferred form the composition comprises a liquid culture of Bacteroides and E.

coll.

The pharmaceutical composition of the present invention is preferably lyophilised, pulverised and powdered. It may then be infused, dissolved such as in saline, as an enema. Alternatively the powder may be encapsulated as enteric-coated capsules for oral administration. As a I :\WPUS9Atii8Wi)oo8 :tCW WO 90/01335 PCI/A I.9/00328 6 powder It can preferably be provided In a palatable form for reconstitution for drinking. The composition can be combined with other adjuvants such as antacids to dampen bacterial Inactivation In the stomach. Acid secretion In the stomach could also be pharmacologically suppressed using H2-antagonlsts or omeprazole. The powder may be reconstituted also to be Infused via naso-duodenal Infusion.

The present composition Is therefore preferably In the form of: I) an enema composition which can be reconstituted with an appropriate diluent; II) enteric-coated capsules, or 1ii) powder for reconstitution with an appropriate diluent for naso-enteric infusion or colonoscopic Infusion, or iv) powder for reconstitution with appropriate diluent, flavouring and gastric acid suppression agent for oral Ingestion.

Furthermore the present Invention also relates to the treatment of animals, in particular to the treatment of gastrointestinal disorders in eccomically important domestic animals, such as cattle, sheep, horses, pigs, goats etc. The method of the present Invention has been found to be especially useful in the treatment of the various forms of necrotlsing enterocolitis which can be a major problem in ailmal stocks.

Obviously in the treatment of animals the appropriate composition of microflora will vary according to the species being treated and the constituent normal flora known to inhabit the gut. Thus the composition according to the invention would comprise, a preparation of viable flora which preferably in proportional content, resembles the normal healthy faecal flora of the species involved. The compositions may be prepared in any of the forms already described and administered accordingly.

Best Method of Performina the Invention Typically the method of the invention is applicable to a patient suffering from a chronic disorder associated with the presence of abnormal microflora in the gastrointestinal tract such as irritable bowel syndrome.

In the practice of the invention the patients existing enteric flora is removed by gastrointestinal lavage effected by ingestion of about 3 litres of a balanced salt solution with polyethylene glycol. Lavage is continued until the removal of the existing flora is as near complete as possible.

A composition of predetermined flora in the form of a liquid culture of Bacteroldes and col is then Infused into the patient per colonoscope SUBSTITUTE SHEET WO 90/01335 90/ 1335 C1 A I.89/00328 -7 in an amount sufficient to replace the removed flora, and reverse the disease process. Alternatively fresh homologous faeces obtained from a disease screened donor are liquefied and mixed with unprocessed bran. The mixture is then homogenised anaerobically under CO 2 cover and infused into the patient per colonoscope.

Cure or remission of symptoms is then monitored subjectively and by assessment of rIool frequency or other appropriate criteria.

Using liquid cultures of Batrie and E-co~li the inventor has achieved total reversal of colitis, irritable bowel syndrome and consti pation.

As indicated i the method of treatment aspect of the Invention, a preparatory course of appropriate antibiotics may be used. For example, Septriri for chronic yersiniasis, Metronidazole for ulcerative colitis, anti-TB therapy in Crohn's disease, or Vancomycin in chronc Clotriiu isfiie infestations.

TabJle 1 of fJ-oab.

11.8(0.90) 9. 9(0. 83) 8.9(0.78) 6. 6(0. 68) 6.0(0.64) 4. 4(0. 55) 3. 5(0.49) 3.0(0.45) 2.8(0.44) 2. 7(0.43) 2. 6(0. 43) 2.2(0.39) 2.1(0.38) 1 .M(.35) 1 .7(0.34) 1.6(0.33) 1.5(0.32) 1.4(0.31) 1.3(0.29) 1.2(0.29) Oruani sm(s) Bacteroides fragilis ss. vulgatus Eubacterium aerofaciens Bacteroides fragilis ss. thetaiotaomicron Peptostreptococcus productus II Bacteroides fragilis ss. distasonis Fusobacterium prausnitzi i Coprococcus eutactus, Eubacteriun aerofaciens III Peptostreptococcus productus I Ruminococcus bromi i Bifidobacterium adolescentis Genniger formicills, Bifidobactertum longum Eubacteriun siraeuni Runi nococcus torques Eubacterium rectale III-i Eubacterium, rectale IV. Eubacterium eligens Bacteroides eggerthi i Clostridlun leptum Bacteroides fragilis ss. a Eubacteriurn bi forme SUBSTITUTE

SHEET

WO 90/01335 WO 9001335PCT/A 1989/00328 8- 0.91 (0.25) 0.84(0.24) 0.57(0.20) 0.50(0.18) 0.43(0.17) 0.36(0.16) 0.30(0.14) 0.23(0.12) 0. 17(0. 10) 0.10(0.08) 0.05(0.05) B11fidobacterium infantis Eubacterium rectale III-F Coprococcus comes, Bacteroides capillosus Ruminococcus albus, Eubacterium formicigenerans, Eubacterium hallil, Eubacterium ventriosum I, Fusobacterium russi Ruininococcus obeum, Eubacterium rectale II, Clostridium ramosum I, Lactobacillus leichmanhi Ruminococcus ,M~ldus, Butyrivibrio crossotus Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides, fragilis ss. fragilis, Bacteroides AR Coprococcus catus, Eubacterium hadrum, E. cylindroides, E. ruminantium, Eubacterium CH-1, Staphylococcus epidermidi s Peptostreptococcus BL, Eubacterium limosum, Bacteroides praeacutus, Bacteroldes L, Fusobacterium mortiferum I, F. naviforme, Clostridium innocuum, C. raniosum, Propionibacterium acnes, Ruminococcus flavefaciens Ruminococcus AT, Peptococcus AU-i, Eubacterlum AG, -AK, -AL, -AL-1, -AN; Bacteroides fragilis ss. ovatus, -ss. d, -ss. f; Bacteroides L-1, L-5; Fusobacterium nucleatum, F.

mortiferui, Esherichia coli, Streptococcus morbillorum Peptococcus magnus, Peptococcus G, -ALI..2, S+,reptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO, Genimiger X, Coprococcus BH, -CC; Eubacterium tenue, Eubacterium ramulus, Eubacterium AE, -AG-H, -AG-M, -43, 414-1; Bacteroides clostridilformis ss. clostridiiform's, B. coagulans, B. oralis, B. ruminicola ss. brevis, -ss.

ruminicola, Bacteroides spianichnicus, Desulfomonas pigra, Bacteroides L-4, -14-i; Fusobacterium H, Lactobacillus G.

ttcinivibrio A b The percentage of the fecal population (the standard deviation of the estimate is given In parentheses).

The invention will now be further described with reference to the following non-limiting examples.

SUBTITUTE SHEEF"O WO 90/01335 PCT/A I89/00328 9 -9- Example 1 A 28 year old male presented with bloody diarrhoea, 7 to 12 times per day, weight loss, anaemia, arthritis, marked liver-function blood test abnormalities, colonoscopic findings of "pancolitis" and histologic diagnosis of active chronic colitis. Following two years of "standard" anti-colitis therapy he improved markedly. The anaemia was corrected, he gained weight and his liver functions Improved somewhat. However, he continued to experience three to four stools per day In spite of 9 x 500 mg salazopyrin tablets per day and second-nightly sterlod enemas (Predsol Enemas). Furthermore, liver function tests remained elevated. Following one week of metronldazole tablets 200 mg x 4 per day, and oral ingestion of three litres balanced salt solution with polyethylene glycol (GLYCOPREP), he received fresh, liquefied homogenized human donor faeces from a disease-screened donor were Infused into the patient. Prior to infusion unprocessed bran was added to the faeces and homogenization was carried out anaerobically under CO 2 cover.

Following infusion, the patient has remained well and off all treatment for three months to date. Liver function tests have returned to normal. He has one formed stool per day and has begun to put on weight.

He has no arthralgia.

Similar methods were used to treat 55 patients suffering with either constipation, diarrhoea, abdominal pain, ulcerative colitis or Crohn's disease. Patients were treated when other forms of therapy had failed to control their symptoms. Following bowel flora alteration 20 patients were deemed "cured", 9 improved, while 26 failed to Improve. The following cases illustrate "cures" using the method of the Invention over a follow up period of 1 to 12 months.

Casei1 Chronic constipation A 31 year old female who had a history of chronic constipation commencing at birth with a frequency of once per week without laxatives.

Following bowel flora alteration she has had daily or second stool frequency, without resort to laxatives and remains well at six month follow-up.

Case2 Chronic Pain-Predominant IBS This 21 year old female was thoroughly Investigated over a four year period for severe colickly abdominal pain, requiring frequent admissions and narcotic pain relief. Multiple investigations Included endoscopy, SUBSTITUTE

SHEET

WO 90/01335 I' C/AL'89/00328 10 laparoscopy and laparotomy. Five days following alteration of her bowel flora she was pain free and remains pain free at four months follow-up.

Case3 Chronic Diarrhoea-Predominant IBS A 35 year old female presented with a history of several years of diarrhoea (2-10/d) and associated abdominal pain. Her only abnormal Investigation was +ve stool latex test for clostridium difficile toxin.

This failed to clear after a course of Vancomycin and she underwent bowel flora alteration with resolution of her chronic diarrhoea. Diarrhoea and pain have not recurred at one month follow-up.

Case Chronic Ulcerative Colitis This 45 year old man presented with an 18 month history of ulcerative colitis and elevated liver transamlnases. Pancolitis was confirmed on colonoscopy. Sulfasalazine caused a rash while olsalazine gave inadequate relief. The patient underwent exchange of bowel flora improving adequately enough to come off treatment within days. At three months he continues to feel well, has no diarrhoea and is on no medication. His liver transamlnases have returned to normal. Colonoscopy is now normal and mucosal biopsies are now normal.

Case 5 Crohn's Disease This 31 year old man was admitted to hospital with small bowel obstruction subsequently shown on small bowel enema to be Crohn's disease of the terminal ileum. This was confirmed on terminal ileal biopsy. In spite of prednisone and sulfasalazine, hypoproteinaemia with ankle oedema was prominent presumably due to protein losing enteropathy. Three days following bowel flora alteration his ankle oedema and serum proteins returned to normal. He remains free of symptoms, off therapy 4 months later.

CAs 6 Irritable bowel/chronic fatique syndrome This 42 year old woman presented with symptoms of irritable bowel syndrome characterised by diarrhoea and pain, and also complained of profound tiredness. Faecal infusion reversed the bowel symptoms. In addition the profound tiredness suddenly disappeared. Similar results were obtained in 4 related cases.

SUBSTITUTE SHEET

Claims (28)

1. 2. The method of claim 1 wherein the existing enteric microflora is substantially completely removed.
2. 3. The method of claim 1 or 2 wherein the predetermined microflora is in the form of a composition of disease screened fresh homologous faeces, equivalent freeze-dried and reconstituted faeces or a synthetic faecal. composition.
3. 4. The method of claim 3 wherein the synthetic faecal composition comprises a preparation of a selection of viable microorganisms in appropriate proportiri-s such that the preparation substantially resembles the host's normal, healthy, faccal flora. The method of claim 3 or claim 4 wherein the predetermined flora comprises at least two microorganisms selected from the group consisting of: Bacteroides, Eubacteria, Fusobacteria, Propionibacterla, Lactobacilli, anaerobic cocci, Ruminococcus, E. coil, Gemmiger, Clostridiurn, Desulfombonas, and Monilla species.
4. 6. The method of claim 5 wherein the predetermined microflora oomprises at least two of the microorganisms listed in the following group: Bacteroides fra gills ss. vulgatus, Eubactettwm aerofaciens, Bacteroides fra gills ss. thetaiotaomicron, Peptostreptococcus productus II, Bacteroides fragilis ss. distasonis, Fusobacteriwan prausnitzii, C'oprococcus eutactus, Eubacterluin aerofaciens HII, Peptostreptococcus producwus 1, Ruminococcus bromi, Gemmiger formicilis, Eubactcriun: siraeurn, Runinococcus torques, Eubacteriwn rectale 111-H, Eubacterium rectale IV, Eubacterium eligens, Bacteroides eggerthit, Clostridiurn lepturn, Bacteroides fra gills ss. a, Eubacterlurn b~forme, Eubacteriwni rectale I1l-F, Coprococcus comes, Bacteroides capillosus, Rwninococcus albus, Eubacteriurn forindigenerans, Eubacteriun: haillil, Eubacteriwn vent riosun 1, Fusobacteriwan russi, Rwninococcus obewn, Euba eteriurn rectale 11, Ciostridiwn ramoswn 1, Lactobacillus leichrnanil, Rwninococcus callidus, Buiyrivibrlo, crossotus, Acidaininococcusfrrmentans, Eubacteriwn ventrloswn, Bacteroides AR, Bacteroides fra gills, ss. fra gills, Coprococcus catus, Eubacteriwn hadrum, E. cyllndroldes, E. runlnanuiwn, Eubacteriwn CI- 1, Staphylococcus epldertnldls, Peptostreptococcus BL, Eubacteri ur litnosurn, Bacteroides praeacutus, Dacteroldes L. Fusobacteriurn mortiferurn 1, F. navitbnne, Clostridium innocuurn, C. ramosum, Propionibacteriwn acnes, Rurninococcus flavefaciens, Rurninococcus AT, Peptococcus AU-i, Eubacteriumi AG, -AK, AL, -AL-1, -AN; Bacteroides fraglills ss. ovanis, -ss. d, o-ss. f; Bacteroides L-1, L-5; Fusobacteriwn nucleation, F. moriferum, Esherichia coi, 6612SAUI Streptococcus morbillorun, Peptococcus magnus, Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO, Gemmiger X, Coprococcus BH, -CC; Eubacterium tenue, Eubacterium ramulus, Eubacteriau AE,-AG-H, -AG-M, -AJ, -BW-1, Bacteroides clostridliformis ss. clostridilfornis, B. coagulans, B. oralis, B. ruminicola ss. brevis, -ss. ruminicola. Bacteroides splanchnicus, Desuffomonas pigra, Bacteroides L-4, Fusobac tian H, Lactobacillus G, and Succinivibrio A.
5. 7. The method of any one of claims 3, 5 or 6 wherein the predetermined microflora is in the form of a liquid culture of Bacteroldes and E. coll.
6. 8. The method of any one of claims 1 to 7 wherein the host is a human.
7. 9. The method of any one of claims 1 to 8 wherein the chronic disorder is a gastrointestinal disorder. The method of claim 9 wherein said gastrointestinal disorder is irritable bowel syndrome, spastic colon, ulcerative colitis, mucous colitis, coliagenous colitis, Crohn's disease, inflammatory bowel disease, microscopic colitis, antibiotic associated colitis, idiopathic or simple constipation, diverticular disease, AIDS enteropathy, small bowel bacterial overgrowth, coeliac disease, polyposis coli, colonic polyps, chronic idiopathic pseudo obstructive syndrome or chronic enteric infections.
8. 11. The method of claim 9 or 10 wherein the ch'onic enteric infection is caused by a bacteria other than Salmonella, virus, protozoa or fungi.
9. 12. The method of any one of claim, 1 to 8 wherein the chronic disorder is a liver disorder.
10. 13. The method of claim 12 wherein said liver disorder is primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver or cryptogenic cirrhosis.
11. 14. The method of any one of claims 1 to 8 wherein the chronic disorder is a joint disorder. The method of claim 14 wherein said joint disorder Is rheumatoid arthritis, a non-rheumatoid arthritidies, ankylosing spondylitis, or Reiter's syndrome.
12. 16. The method of any one of claims 1 to 8 wherein the chronic disorder is an immune mediated disorder.
13. 17. The method of claim 16 wherein said immune mediated disorder is glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes mellitus, mixed cryoglobulinaemia, polyarteritis, familial Mediterranean fever, amyloidesis, scleroderma, systemic lupus erythematosus, or Behcet's syndrome.
14. 18. The method of any one of claims 1 to 8 wherein the chronic disorder is a neurological disorder.
15. 19. The method of claim 18 wherein said neurological disorder is migraine, multiple sclerosis, ainyotrophic lateral sclerosis, myasthcnia gravis, chionic fatigue syndrome, Parkinson's disease, or Alzheimers disease. OI 13 The method of any one of claims 1 to 8 wherein the chronic disorder is a dermatological disorder.
16. 21. The method of claim 20 wherein said dermatological disorder is chronic urticaria, acne, dermatitis herpetiformis or a vasculitic disorder.
17. 22. The method of any one of claims 1 to 7 wherein the host is selected from cows, sheep, horses, goats or pigs.
18. 23. The method of claim 22, wherein the chronic disorder is necrotising enterocolitis.
19. 24. The method of any one of claims 1 to 23 wherein the removal of existing flora is carried out by gastrointestinal lavage with orthostatic salt solution and polyethylene glycol solution. The method of claim 24 wherein gastrointestinal lavage is effected by enemata, oral ingestion or per enteral infusion.
20. 26. The method of any one of claims 1 of 25 wherein the predetermined flora is introduced into the patients gastrointestinal system by ingestion or by per enteral infusion.
21. 27. The method of any one of claims 1 to 26, further comprising the administration of an effective amount of at least one antibiotic prior to the removal of the existing flora.
22. 28. A pharmaceutical composition useful for the treatment and/or prophylaxis of chronic disorders associated with the presence in the gastrointestinal tract of a non-avian host of abnormal or an abnormal distribution of microflora excluding Salmonella for said host, which composition comprises a selection of viable microorganisms of various genera excluding Streptococcus faecium in appropriate proportions such that the composition substantially resembles the host's normal healthy, faecal flora.
23. 29. Tue composition of claim 28 wherein the microorganisms are selected from the group consisting of: Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E. colil, Gemiger, Clostridium, Desulfomonas, and Monilia species. The composition of claim 29 wherein the microorganisrms are selected from those listed in the following group: Bacteroides fragilis ss. vulgatus, Eubacterium aerofaciens, Bacteroices fragilis ss. thetaioraomicron, Peptostreptococcus productus II, Bacteroides fragills ss. distasonis, Fusobacterium prausnitzil, Coprococc,:s eutactus, Eubacterium aerofaciens III, Peptostreptococcus productus I, Ruminococcus bromii, Gemmigerfonnicills, Eubacterium slroeum, Ruminococcus torques, Eubacterium rectale III-H, Eubacterium rectale IV, Eubacterium eligens, Bacteroides eggerthll, Clostridium leptum, Bacteroldesfragilis ss. a, Eubacterium biforme, Eubacterium rectale III-F, Coprococcus comes, Bacteroides t> capillosus, Ruminococius albus, Eubacterium formicigenerans, Eubacterium hallii, Eubacterium ventrioswn I, Fusobacterium russii, Ruminococcus obeum, Eubacteriun (ti\APUSWtltWKICOOteCW 14 -ss. f; Bacteroides L-l, L-5; Fusobacterium nucleatum, F. mortiferum, Esherichia coli, Streptococcus morbillorwn, Peptococcus magnus, Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO, Gemmiger X, Coprococcus BH, -CC; Eubacterium tenue, Eubacterium ramulus, Eubacterium AE,-AG-H, -AG-M, -AJ, -BW-1, Bacteroides clostridiiformis ss. clostridiiformis, B. coagulans, B. oralis, B. ruminicola ss. brevis, -ss. ruminicola, Bacteroides splanchnicus, Desulfomonas pigra, Bacteroides L-4, Fusobacterium H, Lactobacillus G, and Succinivibrio A.
24. 31. The composition of claims 29, or 30 wherein the predetermined microflora is in the form of a liquid culture of Bacteroides and E. coli.
25. 32. The composition of any one of claims 29 to 31, in the form of an enema, enteric coated capsule or powder suitable for reconstitution.
26. 33. A pharmaceutical composition useful for the treatment and/or prophylaxis of chronic disorders associated with the presence in the gastrointestinal tract of a host of abnormal or an abnormal distribution of microflora excluding Salmonella for said host which composition is substantially as herein described with reference to Example 1 or 2.
27. 34. A method for the treatment and/or prophylaxis of a chroni: disorder associated with the presence in the gastrointestinal tract of a host of abnormal or an abnormal distribution of microflora excluding Salmonella for said host, which method is substantially as herein described with reference to Example 1 or 2. DATED this 26 February, 1993 Thomas Julius Borody Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON 86123AUI INTERNATIONAL S1UARCH REPOR~T 1 1. CLASSIFICATION' OF SUB=J~ MATrER it s eve ra l c Las s International Application No. PCT/AJJ89/00328 ification symbols apply, indicate all) 6 1 Accordin to international Patent Classi ficat ion (ITPC) or to both National Classi ficat Ion and IPC Int. Cl. A61K 39/02, 39/08, 39/10, 39/11. 35/24 1 UI. FIUhI SeAP Minimum Documentation Searched 7 Classification System Classification Sym'ioLs IFC A61K 39/02, 39/08. 39/10, 39/11, 35/24 Documentation Searched other than Minimum Documentation to the Extent that such Documents are IncLudec' in the fields Seasrched B AU; IPC as above
28. 111. DOCUMEWS CONISIEM TO BE Rfl.EAWT 9 Category* I Citation of Document, I' with indication. 1 &ere appropriate, R"eent 1 of the retevant passages Claim Nc X AU,B, 53298/79 (526326) 10 JULY 1980 (10.07.80) I(22-24,26) ISee page 2 lines 7-1.1, page 4 Lines 20-27 an~d claims X IUSIA. 37130336 30 JAN'1W~ 1973 (30.01.73) see rolumn 1 I(22) lines 24-26, 40-44, Cal=r 3 Limas 48-57I X USIA, 4335107 (SNOEYEBOS) 2.5 JUE 1982 (15.06.82) See column 1 (22,26) ILines 43-52, colum 2 lines Z7,28, claimsI X GB.A, 1271674 (NI.SS1MI FCIR MILLIM 00) 26 APRIL 1972 (26.04.72) 1(22,23,26) See pae 8 Limes 1-4, 13-16, page 9 Example I mA~ clais *Special. categories of cited documents: 10 Lter document published after the *A.international filing date or priority date *,document defining the general state of the and not in conflict with the application b-it art which is not considered to be of cited to understand the principle or theory particular relevance underlying the invention *9 earlier document but published on or 1X document of particular relevancel the after the international, filing date claimed invention cannot be considered novel LV document which may throw doubts on priority or cannot be considered to involve an cliaim(s) or which is cited to establish the inventive stop pultlication date of another Citation or 'Y document of particular relevance: the other special reason (as specified) claimed invention cannot be considered to document referring to an orat disclosure. involve aii inventive step when the document use, exhibition or other means is combined with one or more other such OP document published prior to the documents, Such combination being obvious to international filing date but Later than a person Skilledi In the art. the priority date claimed IV* document member of the same patent family I Date of the Actual, Completion of the I Date of %ailing of this International IInternational Search ISearch Report i's NovEM3P amup Iq 1920Ny9!1 International Searching Authority I Sionature of Authorized Officer Autrlfm~ Patent Office ~T HIflH Form PCT/tSA/210 (second Sheet) (january 1963) Internationat AppLication No. [CT/AU 89/00328 R=M WOAINM-MFMMOMM IX E.A. 2134179 (Sa1ULR) 25 JANUAKZ 1973 (25.01.73) See claims (22,23.26) X IFR.M, 1275 (FOE ET AL) 2 MAY 1962 (02.05.62) I(22,23,26) X FRAM 5528 (CAP=A) 18 =1B 1967 (18.12.67) j(22,26) X FRM 2427 (MJRIMCA 1964 See page 1 Lines 1-8, cl&ims I(22,23,26) X jFR,A, 2244464 (LAB8A MTh SEZYM) 18 APR11 1975 (18.04.75) See page 1 Lines 1-3, lines 17-20 pages 3-4, examples, claims X Patents Abstraces of Japan. C-46 page 141, JPA, 54-35214 (22,23.26) I(HISSHM SIMW 15 HARM 1979 (15.03.79) I MM V. U OBEVAICKS VIOM CEAMI CL.AM VM MMbU UNSEAMM~E I This international search report has not been established in respect of certain claims under Article 17(2)(s) for the following reasons: I .CX3 Claim numbers 1-21. because they relate to subject matter not required to be searched by this Authority, namely: Methods of treatment of the human body by surgery or therapy. 1 2.E3 Claim number& because they relate to parts of the international application that do not co&wpty with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically: 3.[3 Claim numbers because they are dependent claims and are not drafted in accordance with the second and third sentences of PCT Rute 6.4 IVi. OBSERVATIMt VE UN= OF fv=2C'1' 7 I F 2 This IntenationsL searching Authority found multiple invention% in this international application Ias foLLowt: I .C 3 As aLL required additional search fe-)s were timely paid by the applicant, this international sees-ch report covers all searchable claims of the international application. 1 2.C As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims of the international application for which fees were paid. specifically claims: I3.C No required additional search fees were timely paid by the applicant. Cinset~uentty. this international search report is restricted to the invention first mentioneo in the claims: it is covered by claim numbers: 4. As all searchable claims could be searched without effort justifying an additional fee. Ithe International Searching Authority did not invite payment of any additional fee, IRemark on Protest IC3the additional search feet were accompanied b~y apolicants protest. IC3No protest accompanied the payment of additional search fees. Fore PCt/ISA/210 (supplemental sheet (January 198S) Int~rnationaL Apptt~ation N.R/U8'02 No. PCT/AU 89,100328 1 111. MCJOTt COSM TO BE RELEARU (MtI'lMU FFW ThE SEC=D MM') Category* Citation of Document, with indication, where appropriate, Relevant u I Iof the relevant passages IClaim No I- A FR,M, 2828 (NflJVEL) 2 $JVE21B 1964 (02.11.64) see page 1 Ilines 1-34, claims A AIJ,B, 37580/85 (583.198) (FARMfS 5 SEPTDHM 1985 (05.09.85) See claim 1 I(22, 1(22) U.,26)1 fare PCT/ISA/210 (extra sheet) (January M9S) ANNEX TO THE INTERNATIONAL SEARCH REPORT ON IRNATIONAL APPLICATION NO. PCT/AU 80328 This Annex lists the kown publication level patent family members relating to the patent documents cited in the above-mentioned international search report. The Australian Patent Office is in no way liable for these particulars which are merely given for the purpose of information. Patent Document Cited in Search Patent Family Members Report AU 526326 US 3713836 AT 296923 BE 747129 CA 933409 CH 542281 DE 2010654 ES 377347 FR 2068543 GB 1300446 IT 1142151 JP 50038682 LU 60508 NL 167724 SE 371209 US 4335107 AT 11641 DK 154927 EP 6695 IE 42298 JP 1007049 GB 1271674 DE 1934652 FR 2014544 FR M 1275 FR M 5528 FR M 2427 LU 44002 END OF ANNEX