US009095545B2

(12) United States Patent (10) Patent No.: US 9,095,545 B2 Borody (45) Date of Patent: * Aug. 4, 2015

(54) METHODS FORTREATING 2004/0106590 A1 6/2004 Eisenstein GASTRONTESTINAL DISORDERS 2004/0126318 A1* 7/2004 Ehrenpreis...... 4249.1 ASSOCIATED WITH PARKINSONS DISEASE, 3.99. A 39: Rayishuila et al. AUTISM, DIABETIC GASTROPARESIS (Continued) (71) Applicant: Thomas Julius Borody, Sydney (AU) FOREIGN PATENT DOCUMENTS (72) Inventor: Thomas Julius Borody, Sydney (AU) WO O3O37310 5, 2003 (*) Notice: Subject to any disclaimer, the term of this WO 2007O22255 2, 2007 patent is extended or adjusted under 35 (Continued) U.S.C. 154(b) by 0 days. This patent is Subject to a terminal dis OTHER PUBLICATIONS claimer. Andrew, Peter J. et al., “Chronic constipation reversed by restoration of bowel flora. A case and a hypothesis”, Euro J. Gast Hep, 1992, (21) Appl. No.: 14/324,924 4:245-7. (22) Filed: Jul. 7, 2014 (Continued) (65) Prior Publication Data Primary Examiner — Jeffrey E. Russel US 2014/O364373 A1 Dec. 11, 2014 (74) Attorney, Agent, or Firm — Gregory P. Einhorn; Greer, Related U.S. Application Data Burns & Crain Ltd. (63) Continuation of application No. 13/499.270, filed as application No. PCT/AU2010/001410 on Oct. 22, (57) ABSTRACT 2010, now Pat. No. 8,772,242. There is disclosed herein a composition for treating gas (30) Foreign Application Priority Data trointestinal or neurological disorders, constipation, func tional constipation, irritable bowel syndrome, diverticulitis, Oct. 26, 2009 (AU) ...... 2009905229 travelers’ , chronic idiopathic nausea, IBD-associ ated constipation and diarrhea, pseudo-obstruction, diabetic (51) Int. Cl. gastroparesis, cyclic Vomiting, reflux oesophagitis, autism A6 IK3I/65 (2006.01) enteropathy, flatulence, halitosis, chronic fatigue, bloating, A6 IK3I/496 (2006.01) proctalgia fugax, Parkinson's disease, MS, Alzheimer's Dis A6 IK38/4 (2006.01) ease, Motor Neurone Disease or autism, the composition A6 IK3I/484 (2006.01) comprising: (i) at least two anti-Clostridial agents selected A6 IK3I/66 (2006.01) from the group consisting of , Vancomycin A6 IK3I/485 (2006.01) derivatives, a multi-valent polymer of Vancomycin, ami A6 IK3I/7036 (2006.01) noglycosides, nitroimidazoles, ansamysins, nifuroxazide, A6 IK3I/7048 (2006.01) colchicine, prucalopride, prokinetic agent and 5-aminosali A6 IK 45/06 (2006.01) cylic acid; or (ii) at least one anti-Clostridial agent selected A6 IK3I/4164 (2006.01) from the above combined with an blocking agent. A6 IK3I/437 (2006.01) There is also disclosed herein a method of treating various (52) U.S. Cl. gastrointestinal or neurological disorders, constipation, func CPC ...... A61K 38/14 (2013.01); A61 K3I/I65 tional constipation, irritable bowel syndrome, diverticulitis, (2013.01); A61 K3I/I66 (2013.01); A61 K travelers’ diarrhea, chronic idiopathic nausea, IBD-associ 31/4164 (2013.01); A61 K31/4184 (2013.01); ated constipation and diarrhea, pseudo-obstruction, diabetic A6 IK3I/437 (2013.01); A61 K3I/485 gastroparesis, cyclic Vomiting, reflux oesophagitis, autism (2013.01); A61 K3I/496 (2013.01); A61 K enteropathy, flatulence, halitosis, chronic fatigue, bloating, 3 1/7036 (2013.01); A61 K3I/7048 (2013.01); proctalgia fugax, Parkinson's disease, MS, Alzheimer's Dis A61K 45/06 (2013.01) ease, Motor Neurone Disease or autism, the method compris (58) Field of Classification Search ing administering orally, via enema or by Suppository: (i) a None composition of the invention; (ii) at least two anti-Clostridial See application file for complete search history. agents selected from the group consisting of Vancomycin, Vancomycin derivatives, a multi-valent polymer of Vancomy (56) References Cited cin, aminoglycosides, nitroimidazoles, ansamysins, nifuroX azide, colchicine, prucalopride, prokinetic agent and 5-ami U.S. PATENT DOCUMENTS nosalicylic acid; or (iii) at least one anti-Clostridial agent 5,523,418 A * 6/1996 Freiberg et al...... 549,270 selected from the above and an opioid blocking agent to a 6.426,338 B1 7/2002 Borody patient in need of Such treatment. 8,772.242 B2 * 7/2014 Borody ...... 514f1 7.5 8,980,872 B2 * 3/2015 Tamaoki et al...... 514, 183 2004/OO77533 A1 4/2004 Sayada 26 Claims, No Drawings US 9,095,545 B2 Page 2

(56) References Cited Associated Diarrhea'. J. Clin Gastroenterol. Nov.-Dec. 2007: 41 (10): 932-933. U.S. PATENT DOCUMENTS Borody, Thomas J. et al., “Bacteriotherapy Using Fecal Flora Toying with Human Motions'. J. Clin. Gastroenterol. 2004; 38475-483. 2007/0213304 A1 9, 2007 Shortis Borody et al., “Oral Vancomycin Can Reverse Idiopathic Constipa 2009/011 1093 A1 4/2009 Wallace et al. tion'. Gastroenterology, 1989, vol. 96, No. 5, Part 2, p. A52. 2011/O136867 A1 6/2011 Justman et al. Brandt L.J. et al., “An Evidence-Based Systematic Review on the 2011/0207124 A1 8/2011 Hakonarson et al. Management of Irritable Bowel Syndrome'. Amer. Journal Gast. 2009; 104 (Supp1) S8-S35. FOREIGN PATENT DOCUMENTS Celik, A.F. et al., “The effect of oral vancomycin on chronic idio WO 2010040O2O A1 4/2010 pathic constipation'. Alimentary Pharmacol, and Ther., 1995; 9:63 WO WO 2010O35751 A1 * 4, 2010 68. WO 2010.093776 A1 8, 2010 Sahara et al., “A Randomized Double-Blind Placebo-Controlled Trial of in Patients with Abdominal Bloating and Flatu OTHER PUBLICATIONS lence'. American Journal of Gastroenterology, 2006, vol. 101, pp. 326-333. Berman, Arthur L., “Efficacy of Rifaximin and Vancomycin Combi nation Therapy in a Patient with Refractory Clostridium difficile * cited by examiner US 9,095,545 B2 1. 2 METHODS FOR TREATING be constipated. Hence, there is a discrepancy between our GASTRONTESTINAL DISORDERS ideas or beliefs and the real cause of constipation. ASSOCIATED WITH PARKINSONS DISEASE, Looking at past therapies, constipation has been treated by AUTISM, DIABETIC GASTROPARESIS methods which have often been found by chance, trial and error, or as a side effect of a novel therapy. Mild constipation CROSS-REFERENCE TO RELATED will respond to change in diet, increase in fibre intake and APPLICATIONS various laxatives including Senna, coloxyl, teas and osmotic laxatives such as lactulose, sorbitol, mannitol and PEG 3350. This application is a continuation of U.S. patent applica Various other laxatives have been described including colchi tion Ser. No. 13/499.270, filed Apr. 25, 2012, now pending, 10 cine, bisacodyl, castor oil, linactolide and prucalopride. which is a national phase patent utility filing under 35 USC Methyl naltrexone and naloxone have also been used in opi ate-induced constipation. Probiotics have been used empiri S371, for International (PCT) Patent Application serial no. cally and serotonin receptor agonists including tagaserod PCT/AU2010/001410, filed Oct. 22, 2010, which claims ben have been used. Cisapride, metoclopromide, mosapride and efit of priority to Australian Patent Application Serial No. 15 domperidone have been shown to increase motility in some 2009905229, filed Oct. 26, 2009. The aforementioned appli patients. cations are expressly incorporated by reference herein in their However, no current literature refers to constipation as entirety for all purposes. being a possible of gut flora with a particular set of bacterial agents that would be mediating constipation via TECHNICAL FIELD bioactive substances produced by these bacteria. Although some have been listed in literature as affecting The present invention relates generally to the field of phar bowel activity when used in constipation including neomy maceutical compositions. More specifically the present cin, clarithromycin, metronidazole and rifaximin the results invention relates to the pharmaceutical composition for treat have been variable and not reproducible Brandt L J et al ing gastrointestinal disorders and uses thereof. 25 Amer Journal Gast 2009; 104 (Suppl): S8-S35. Overall then, previous and current being BACKGROUND OF THE INVENTION developed for the treatment of constipation appear to be deal ing with mechanisms that do not address the underlying The human bowel flora is complex and is composed of mechanism of constipation as described in this patent appli around 24,000 bacterial subspecies. It is considered to be 30 cation. Furthermore, some systemic and neurologic condi virtual organ and is poorly understood because no more than tions are associated with constipation and other bowel disor approximately 15%-20% of the bacterial types have ever been ders which in part may be causally related, for example cultured. Indeed, there is a real need among medical practi Parkinson's disease, MS, Alzheimer's Disease, Motor Neu tioners to better understand the concept of bowel flora being rone Disease also known as ALS, autism and other neuro a virtual organ which is abnormal or infected for example. 35 logic disorders. Bowel flora can be infected either as an acute infection where the infecting agent can be bacteria, viruses or parasites. The OBJECT OF THE INVENTION flora can also be infected for a prolonged period i.e. a chronic infection e.g. C. difficile, Giardia lamblia, Blastocystis homi It is an object of the present invention to overcome or nis, Aeromonas or other pathogens. In this invention the con 40 substantially ameliorate at least one of the above disadvan cept of a chronic bowel flora infection will be expanded and tages or to provide a suitable alternative. addressed. It should also be noted that in spite of knowing Some acute and chronic infective agents the overwhelming SUMMARY OF THE INVENTION majority of agents infecting the bowel flora are yet to be described and discovered. 45 According to a first aspect of the present invention there is Constipation provided a composition for treating gastrointestinal or neu Constipation according to the view taken in this Patent rological disorders, constipation, functional constipation, Application is one such infective disorder of the virtual irritable bowel syndrome, diverticulitis, traveler's diarrhoea, organ the bowel flora. It is considered to be an infection by chronic idiopathic nausea, IBD-associated constipation and a bacterium or bacterial species capable of producing bioac 50 diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic tive substances which affect the bowel wall and the body in Vomiting, reflux oesophagitis, autism enteropathy, flatulence, general. In contrast to the present view of this inventor, many halitosis, chronic fatigue, bloating, proctalgia fugax, Parkin theories have been put forward as to the cause of constipation. son's disease, MS, Alzheimer's Disease, Motor Neuron Dis In the past numerous publications have avoided dealing with ease or autism, the composition comprising: a cause of constipation and addressed associations rather than 55 (i) at least two anti-Clostridial agents selected from the causality. Causality has at times been discussed but has been group consisting of: ascribed to differences in diet, psychological causes, motility Vancomycin, Vancomycin derivatives, a multi-valent poly disturbances, enteric nervous dysplasia and others. Although mer of Vancomycin, aminoglycosides, nitroimidazoles, there are many secondary causes of constipation Such as ansamysins, nifuroxazide, colchicine, prucalopride, proki hypothyroidism and various medications, the most common 60 netic agent and 5-aminosalicylic acid; or cause of constipation remains obscure. Indeed, patients and (ii) at least one anti-Clostridial agent selected from the doctors remain baffled by the fact that the common variety above combined with an opioid blocking agent. everyday constipated patient generally eats an average According to a second aspect of the present invention, there amount or an excessive amount of fibre, drinks enough water is provided a method of treating various gastrointestinal or and has an average exercise programme—and yet remains 65 neurological disorders, constipation, functional constipation, constipated—sometimes for days on end. It is also known that irritable bowel syndrome, diverticulitis, travelers' diarrhoea, taking fibre away from normal people does not cause them to chronic idiopathic nausea, IBD-associated constipation and US 9,095,545 B2 3 4 diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic Those skilled in the art will appreciate that the invention Vomiting, reflux oesophagitis, autism enteropathy, flatulence, described herein is susceptible to variations and modifica halitosis, chronic fatigue, bloating, proctalgia fugax, Parkin tions other than those specifically described. It is to be under son's disease, MS, Alzheimer's Disease, Motor Neuron Dis stood that the invention includes all Such variations and modi ease or autism, the method comprising administering orally, fications. The invention also includes all of the steps, features, via enema or by Suppository: compositions and compounds referred to or indicated in this (i) a composition of the invention; specification, individually or collectively, and any and all (ii) at least two anti-Clostridial agents selected from the combinations or any two or more of said steps or features. group consisting of All the references cited in this application are specifically Vancomycin, Vancomycin derivatives, a multi-valent poly 10 incorporated by reference are incorporated herein in their mer of Vancomycin, aminoglycosides, nitroimidazoles, entirety. Inclusion herein of any given reference is not ansamysins, nifuroxazide, colchicine, prucalopride, proki intended to indicate that the reference is generally known in netic agent and 5-aminosalicylic acid; or Australia or elsewhere. (iii) at least one anti-Clostridial agent selected from the 15 above and an opioid blocking agent to a patient in need of DETAILED DESCRIPTION OF THE PREFERRED Such treatment. EMBODIMENTS In one embodiment, the agents are administered simulta neously or consecutively in any order. There is disclosed herein a composition for treating gas According to a third aspect of the present invention there is trointestinal or neurological disorders, constipation, func provided use of: tional constipation, irritable bowel syndrome, diverticulitis, (i) at least two anti-Clostridial agents selected from the travelers’ diarrhoea, chronic idiopathic nausea, IBD-associ group consisting of Vancomycin, Vancomycin derivatives, a ated constipation and diarrhoea, pseudo-obstruction, diabetic multi-valent polymer of Vancomycin, aminoglycosides, gastroparesis, cyclic Vomiting, reflux oesophagitis, autism nitroimidazoles, ansamysins, nifuroxazide, colchicine, pru 25 enteropathy, flatulence, halitosis, chronic fatigue, bloating, calopride, prokinetic agent and 5-aminosalicylic acid; or proctalgia fugax, Parkinson's disease, MS, Alzheimer's Dis (ii) at least one anti-Clostridial agent selected from the ease, Motor Neurone Disease or autism, the composition above combined with an opioid blocking agent in the manu comprising: facture of a medicament for treating various gastrointestinal (i) at least two anti-Clostridial agents selected from the or neurological disorders, constipation, functional constipa 30 group consisting of Vancomycin, Vancomycin derivatives, a tion, irritable bowel syndrome, diverticulitis, travelers' diar multi-valent polymer of Vancomycin, aminoglycosides, rhoea, chronic idiopathic nausea, IBD-associated constipa nitroimidazoles, ansamysins, nifuroxazide, colchicine, pru tion and diarrhoea, pseudo-obstruction, diabetic, calopride, prokinetic agent and 5-aminosalicylic acid; or gastroparesis, cyclic Vomiting, reflux oesophagitis, autism (ii) at least one anti-Clostridial agent selected from the enteropathy, flatulence, halitosis, chronic fatigue, bloating, 35 above combined with an opioid blocking agent. proctalgia fugax, Parkinson's disease, MS, Alzheimer's Dis As required, the composition may include a pharmaceuti ease, Motor Neurone Disease or autism. cally acceptable carrier. According to a fourth aspect of the present invention there In one embodiment the Vancomycin derivative is carbohy is provided use of at least one anti-Clostridial agent selected drate-modified Vancomycin, Vancomycin-disulfide deriva from the group consisting of 40 tive, lipidated Vancomycin, chlorobiphenyl-desleucyl-Vanco Vancomycin, Vancomycin derivatives, a multi-valent poly mycin, oritavancin, telavancin, or chlorobiphenyl mer of Vancomycin, aminoglycosides, nitroimidazoles, Vancomycin. ansamysins, nifuroxazide, colchicine, prucalopride, proki In one embodiment the aminoglycoside is selected from netic agent and 5-aminosalicylic acid; the group consisting of , , framycetin, combined with an anti-opioid blocking agent in opioid 45 , ribostamycin, kanamycin, amikacin, arbeka induced constipation. cin, beanamycin, dibekacin, tobramycin, spectinomycin, hygromycin B, paromomycin Sulfate, Streptomycin, gentami DEFINITIONS cin, netilmicin, Sisomicin, isepamicin, Verdamicin, astromi cin and mixtures thereof. The following definitions are intended as general defini 50 In one embodiment the nitroimidazole is selected from the tions and should in no way limit the scope of the present group consisting of metronidazole, tinidazole, nimorazole, invention to those terms alone, but are put forth for a better secnidazole, ordinazole and mixtures thereof. understanding of the following description. In one embodiment the ansamycin is selected from the Unless the context requires otherwise or specifically stated group consisting of rifaximin, rifampicin, rifabutin, rifapen to the contrary, integers, steps, or elements of the invention 55 tine and mixtures thereof. recited herein as singular integers, steps or elements clearly In one embodiment the prokinetic agents are selected from encompass both singular and plural forms of the recited inte the group consisting oftegaserod, domperidone, metoclopra gers, steps or elements. mide, mosapride, erythromycin and mixtures thereof. Throughout this specification, unless the context requires In one embodiment the 5-aminosalicylic acid is selected otherwise, the word “comprise', or variations such as “com 60 from , , and mixtures prises' or “comprising, will be understood to imply the thereof. inclusion of a stated Step or element or integer or group of In one embodiment the anti-opioid blocking agent is steps or elements or integers, but not the exclusion of any selected from methyl naltrexone or naloxone hydrochloride. other step or element or integer or group, of elements or In one embodiment the composition includes the combi integers. Thus, in the context of this specification, the term 65 nation of Vancomycin and metronidazole. “comprising means “including principally, but not necessar In another embodiment the composition includes the com ily solely'. bination of Vancomycin and rifaximin. US 9,095,545 B2 5 6 In one embodiment the composition includes the combi and colchicine; the combination of Vancomycin and methyl nation of rifaximin and prucalopride. maltrexone or naloxone hydrochloride; the combination of In one embodiment the composition includes the combi naloxone hydrochloride, Vancomycin and metronidazole; the nation rifaximin, metronidazole and colchicine. combination of naloxone hydrochloride and colchicines; the In one embodiment the composition includes the combi combination of naloxone hydrochloride, Vancomycin, and nation Vancomycin, metronidazole and colchicine. rifaximin; or the combination of naloxone hydrochloride and In one embodiment the composition includes the combi rifaximin. nation Vancomycin, aminoglycoside and colchicine. In another embodiment, the present invention relates to use In one embodiment the composition includes the combi of: nation rifamycin, colchicine and metronidazole. 10 (i) at least two anti-Clostridial agents selected from the In one embodiment the composition includes the combi group consisting of: nation Vancomycin together with a prokinetic agent. Vancomycin O064 Vancomycin FREE, Vancomycin In one embodiment the composition includes the combi derivatives, a multi-valent polymer of Vancomycin, ami nation Vancomycin, olsalazine and colchicine. noglycosides, nitroimidazoles, ansamysins, nifuroxazide, In one embodiment the composition includes the combi 15 colchicine, prucalopride, prokinetic agent and 5-aminosali nation of Vancomycin and methyl naltrexone or naloxone cylic acid; or hydrochloride. (ii) at least one anti-Clostridial agent selected from the In one embodiment the composition includes the combi above combined with an opioid blocking agent. nation of naloxone hydrochloride, Vancomycin and metron in the manufacture of a medicament for treating various idazole. gastrointestinal or neurological disorders, constipation, func In one embodiment the composition includes the combi tional constipation, irritable bowel syndrome, diverticulitis, nation of naloxone hydrochloride and colchicines. travelers’ diarrhoea, chronic idiopathic nausea, IBD-associ In one embodiment the composition includes the combi ated constipation and diarrhoea, pseudo-obstruction, diabetic nation of naloxone hydrochloride; Vancomycin, and rifaxi gastroparesis, cyclic Vomiting, reflux oesophagitis, autism min. 25 enteropathy, flatulence, halitosis, chronic fatigue, bloating, In one embodiment the composition includes the use of proctalgia fugax, Parkinson's disease, MS, Alzheimer's Dis naloxone hydrochloride and rifaximin. ease, Motor Neurone Disease or autism. In another embodiment, the present invention relates to a The description of the invention is tied to the description of method of treating various gastrointestinal or neurological the causality. Mentioned above is the concept of the bowel disorders, constipation, functional constipation, irritable 30 flora being a virtual organ, consisting largely of various bac bowel syndrome, diverticulitis, travelers diarrhoea, chronic teria most of which are not known to mankind. A number of idiopathic nausea, IBD-associated constipation and diar clinical observations have led the inventor to this conceptu rhoea, pseudo-obstruction, diabetic gastroparesis, cyclic alization of the mechanisms which have led to the invention. Vomiting, reflux oesophagitis, autism enteropathy, flatulence, Firstly when patients with constipation take multiple antibi halitosis, chronic fatigue, bloating, proctalgia fugax, Parkin 35 otics e.g. for treatment of Helicobacter pylori infection, it was son disease, MS, Alzheimer's Disease, Motor Neurone Dis noticed their constipation resolves and remains much better ease or autism, the method comprising administering orally, for several days even after they stop the antibiotics, suggest via enema or by Suppository: ing that constipation is mediated by an infection of the bowel (i) a composition of the invention; flora which was suppressed by the antibiotics. Furthermore, (ii) at least two anti-Clostridial agents selected from the 40 the use of Vancomycin alone has been previously described in group consisting of constipation and these points to constipation being caused by Vancomycin, Vancomycin derivatives, a multi-valent poly a Clostridial infection (Andrews etal Euro J. Gast Hep 1992: mer of Vancomycin, aminoglycosides, nitroimidazoles, 4:245-7, and Celik A Fetal, Alimentary Pharmacol and Ther. ansamysins, nifuroxazide, colchicine, prucalopride, proki 1995: 9:63-68). However, the inventor recognised that the use netic agent and 5-aminosalicylic acid; or 45 of Vancomycin alone is inefficient and requires an improve (iii) at least one anti-Clostridial agent selected from the ment because not all patients respond and respond but par above and an opioid blocking agent to a patient in need of tially to be clinically effective. Nevertheless, such an obser Such treatment. vation has strongly pointed to bowel flora abnormality or In one embodiment the agent is administered in doses bowel flora infection as the primary cause of most cases ranging from 50 mg per day to 5000 mg per day. 50 idiopathic constipation. The inventor's beliefthat the etiology In one embodiment when present, the colchicine is admin of constipation being infection was further strengthened by istered in doses of 0.005 mg to 5 mg per day and the 5-ami the use of faecal bacteriotherapy i.e., when transplantation nosalicylic acid is administered in doses of 100 mg to 3 gm of bowel flora was shown to reverse constipation (TJ Borody per day. et al J. Clin Gastroenterol 2004; 38:475-483). The implanta In various embodiments, the agents are administered 55 tion of new bacteria from a healthy donor has been defini simultaneously such as in the form of a single composition of tively shown to produce prolonged reversal of constipation in the invention or are administered separately in any order. In the occasional patients treated (Andrews PJ et al European various embodiments, the agents administered may be those Gastroenterology and Hepatology 1992: 4:245-247). listed above as combinations. For example, the combination Hence the mechanism of the abnormality appears to be an of Vancomycin and metronidazole; the combination of van 60 infective one and probably similar to that of Clostridium comycin and rifaximin; the combination of rifaximin and Botulinum which also causes severe constipation as one of its prucalopride; the combination rifaximin, metronidazole and first symptoms in babies infected with this agent. It is likely colchicine; the combination Vancomycin, metronidazole and that such Clostridia release neuro-active opioid-like sub colchicine; the combination Vancomycin, aminoglycoside stances which then paralyse the bowels motor activity peri and colchicine; the combination rifamycin, colchicine and 65 stalsis which is in effect, the mechanism for constipation in metronidazole; the combination Vancomycin together with a most patients. Such bacterial Substances enter the circulation prokinetic agent; the combination Vancomycin, olsalazine and may also paralyse the Small bowel, so causing accumu US 9,095,545 B2 7 8 lation of gas in the Small bowel which clinically presents as metronidazole and colchicine—colchicine in doses of 0.005 bloating. Such circulating Substances are likely also to reduce mg-5 mg per day. This combination can also be as an enteric gastric emptying by partial paralysis slow gastric emptying coated product to limit absorption. A combination of Vanco and by relaxing the tone of the lower oesophageal sphincter mycin, aminoglycosides and colchicine is yet another com causing reflux oesophagitis—the mechanism of oesophagitis position. Rifamycin, colchicine and metronidazole is yet known to be frequently associated with constipation. Block another combination. ade of these neuro-active opioid-like substances by their A further set of agents which can be added to single anti antagonists would be therefore expected to further help biotics or combined antibiotics include prokinetic agents resolve the dysmotility of the colon, small bowel, stomach Such as tegaserod, domperidone, metoclopramide, and oesophagus. These would include methyl naltrexone and 10 mosapride, erythromycin and 5-aminosalicylic acid products naloxone hydrochloride in doses ranging from 0.01 mg to which also inhibit Clostridia including mesalazine, olsalazine 1000 mg per day. and balsalazide. In respect to these, one could combine van Hence, the appropriate approach to the treatment of con comycin with olsalazine—the latter 100 mg-3 gm per day, or stipation would be to treat the causal infective agentoragents, Vancomycin with any other prokinetic agent used in accepted even though they may not be able to be cultured and block the 15 appropriate doses. In a further combination the use of Vanco opioid neuropeptides they secrete. mycin, olsalazine and colchicine can be combined. In fact any Given the background given above and the results from the of the groups above can be combined in two or more combi treatment of numerous patients, the invention constitutes an nations to control the constipation of bacterial infection. antimicrobial combination therapy that would pass down the Apart from describing the various compositions useful in bowel and Suppress or eradicate the culprit infective agent or the treatment of various gastrointestinal disorders, it should agents and in Some circumstances opioid blockers to make the be mentioned that a number of often disparate disorders have treatment more effective. Various agents are capable of inhib been noticed to respond well to these combinations, indicat iting Clostridia and cause taxation. The foremost of these is ing a microbiologic etiology of such disorders. These include Vancomycin or Vancomycin derivative when used orally as it constipation, functional constipation, irritable bowel syn is mostly not absorbed by the gut. The antimicrobial agents 25 drome, diverticulitis, traveler's diarrhoea, chronic idiopathic include Vancomycin, a multi-valent polymer of Vancomycin, nausea, IBD-associated constipation and diarrhoea, pseudo aminoglycosides including streptomycin, neomycin, fra obstruction, diabetic gastroparesis, cyclic Vomiting, reflux mycetin, paromomycin, ribostamycin, kanamycin, amikacin, oesophagitis, autism enteropathy, flatulence, halitosis, arbekacin, beanamycin, dibekacin, tobramycin, spectinomy chronic fatigue, bloating and proctalgia fugax and in the cin, hygromycin B, paromomycin Sulfate, streptomycin, gen 30 above neurological disorders. tamicin, netilmicin, Sisomicin, isepamicin, Verdamicin and The invention will now be described with reference to the astromicin. Other anti-infective agents that can be used following examples which should not be construed as limit include nitroimidazoles such as metronidazole, tinidazole, ing on the invention. nimorazole, secnidazole and ordinazole. Another group of agents that is active is rifaximin, a semi synthetic rifamicin 35 EXAMPLES based agent from a larger family of Ansamycins which includes rifampicin and rifabutin as well as rifapentine. Example 1 Rifaximin is preferable because it is not absorbed from the intestine. Another useful agent to be in combination with A 38 year old female patient with life-long constipation, those mentioned includes nifuroxazide-another non-ab 40 defecating between 0-2 times per week, had multiple inves sorbed product. Various medications which can increase tigations carried out and no abnormalities were found with water secretion in the bowel such as colchicine and prucalo respect to the colon or the bowel flora, and had failed known pride can also be effectively combined. Opioid blocking standard therapies. She was not hypothyroid and had other agents include methyl naltrexone and naloxone hydrochlo wise normal blood tests. She was given a trial of Vancomycin ride. 45 500 mg bid and Metronidazole 200 mg bid and began def The pharmacological combinations that have been found ecating by day 3 of the treatment. She was able to continue to be useful include a composition of two or more anti defecating normally with her constipation completely being Clostridial alone or anti-Clostridial agents combined with reversed while she took the therapy for 4 weeks. After stop other medications enumerated. The invention describes com ping the therapy, within 2 weeks the constipation started positions and use thereof for the manufacture of a 50 recurring. Restarting the treatment again allowed her to def for the treatment of constipation and constipation-associated ecate normally. Apart from the constipation her bloating was conditions. The best disclosed compositions include that of markedly reduced during treatment, and her sensation of Vancomycin and metronidazole, Vancomycin and rifaximin, fullness was improved and her reflux symptoms also less Vancomycin and naloxone hydrochloride and rifaximin and ened. Her previous tiredness was markedly reduced during naloxone hydrochloride. These can be taken orally in doses of 55 treatment. these medications ranging from 0.01 mg per day through to 5000 mg per day. The combination can be taken as the cur Example 2 rently available capsules and tablets in single or divided dos ing regimens. Another and preferable combination is that of a An elderly gentleman with severe constipation requiring 6 capsule or tablet which is enteric coated so that it opens in the 60 coloxyl tablets per day and Parkinson's disease was com distal Small bowel or the large bowel so reducing any absorp menced on Vancomycin 500 mg bd, Metronidazole 400 mg tion of absorbable drugs e.g. metronidazole. The medication bd and Colchicine 0.5 mgbd. Within 3 days he was defecating can be taken long term to Suppress the Clostridial Super normally and was able to stop taking the Coloxyl. Unexpect infection of the bowel flora which so helps to increase gut edly, by week 4 his Parkinson's disease had improved quite motility. Other combinations include rifaximin and prucalo 65 dramatically. In spite of still continuing to take Sinemet in his pride in same covered dose ranges in single or divided doses, original dose, he no longer experiences any tremor and over rifaximin, metronidazole and colchicine, and Vancomycin, the period of several months his gait improved and Glabellar US 9,095,545 B2 10 tap test reversed to normality. Continuing the treatment for Although the invention has been described with reference over a year—his constipation remained completely gone, his to specific examples, it will be appreciated to those skilled in Parkinson's was virtually undetectable and he was able to the art that the invention may be embodiment in many other reduce his dose of Sinemet, Suggesting his Parkinson's dis forms. ease neurotoxicity may have originated from the bowel-flora. What is claimed is: Example 3 1. A method of treating or Substantially ameliorating a Parkinson's disease in Subjects also exhibiting constipation A 41 year old female with a 10 year constipation history comprising administering to an individual in need thereof: associated bloating, tiredness and headaches was com 10 (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi menced on 500 mg of Vancomycin twice daily and Rifaximin Valent polymer of Vancomycin, a carbohydrate-modified 200 mg twice daily. After a week's treatment her constipation Vancomycin, a Vancomycin-disulfide, a lipidated Vanco improved markedly but the Rifaximin had to be increased to 400 mg twice daily for the constipation and other symptoms mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori to be virtually completely undetectable. Progressively her 15 tavancin, or a telavancin, or a combination thereof. bloating improved and her tiredness and headaches (b) an ansamysin; and improved. She continued on treatment now for over 3 months (c) a colchicine. and continues well on the therapy not wanting to stop the 2. The method of claim 1, wherein: treatment because she feels so well. (a) the Vancomycin, chlorobiphenyl Vancomycin, multi Valent polymer of Vancomycin, carbohydrate-modified Example 4 Vancomycin, Vancomycin-disulfide, lipidated Vancomy cin, chlorobiphenyl-desleucyl-Vancomycin, oritavan An 8 year old male with constipation alternating at times cin, telavancin, or combination thereof is administered with diarrhea with Autism Spectrum Disorder was com orally, via enema or by Suppository; menced on Vancomycin 250 mg twice daily together with 25 (b) an ansamysin is administered orally, via enema or by Naloxone hydrochloride 10 mg twice daily. After 3 weeks of Suppository; or treatment the constipation was completely resolved but in (c) a colchicine is administered orally, via enema or by addition his behavior and lethargy changed. He became affec Suppository. tionate and relatively calm, achieving toilet retraining which 3. The method of claim 1, wherein the ansamycin is he had never previously achieved. His vocabulary began to 30 selected from the group consisting of rifaximin, rifampicin, increase quite rapidly, his on task performance, compliance rifabutin, rifapentine and mixtures thereof. with parental requests and awareness of Surroundings 4. The method of claim 1, wherein: improved quite quickly and he was engaging in positive (a) the Vancomycin, chlorobiphenyl Vancomycin, multi activities. Repetitive and self-stimulatory behaviors were Valent polymer of Vancomycin, carbohydrate-modified reduced. The improvement lasted for the duration of four 35 Vancomycin, Vancomycin-disulfide, lipidated Vancomy months treatment as various parameters kept on improving. cin, chlorobiphenyl-desleucyl-Vancomycin, oritavan cin, telavancin, or combination thereof, or the Example 5 ansamysin, is administered in doses ranging from 0.01 mg per day to about 5000 mg per day; or Elderly male with severe constipation, bloating and 40 (b) the colchicine is administered in doses of 0.005 mg to abdominal pain and early Parkinson's disease characterized about 5 mg per day. by stiffness was commenced on Vancomycin 500 mg twice 5. The method of claim 1, wherein the method further daily together with Rifaximin 500 mg twice daily and Nalox comprises administering a prokinetic agent. one hydrochloride 10 mg twice daily. Within a week he was 6. The method of claim 1, wherein the method further defecating normally. I was able to stop the various teas and 45 comprises administering a prucalopride; a metronidazole; an NORMACOLTM together with MOVICOLTM which he was aminoglycoside; anolsalazine; a methyl naltrexone; a nalox using for constipation. By week 6 his stiffness had markedly one hydrochloride; or any combination thereof. improved, he had stopped “freezing” while attempting to 7. The method of claim 6, wherein the method further initiate walking and his fine tremor, previously present, was comprises administering a naloxone hydrochloride and a no longer detectable. Cogwheel rigidity also improved and he 50 metronidazole. was able to reduce his anti-Parkinsonian treatment by about 8. A method of treating or Substantially ameliorating a 30% at this stage. He continued the treatment for 6 months gastrointestinal disorder comprising administering to an indi and his Parkinsonian symptoms further regressed although vidual in need thereof: they were not completely undetectable at this stage. (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi 55 Valent polymer of Vancomycin, a carbohydrate-modified Example 6 Vancomycin, a Vancomycin-disulfide, a lipidated Vanco mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori A 52 year old female with lifelong constipation associated tavancin, a telavancin, or a combination thereof; with marked bloating was commenced on 500 mg Vancomy (b) an ansamysin; cin twice daily, 500 mg Rifaximin twice daily and Naloxone 60 (c) a prucalopride; a metronidazole; an aminoglycoside; an hydrochloride 10 mg twice daily. After one week of treatment olsalazine; a methyl naltrexone; or a naloxone hydro her constipation improved markedly and kept on improving chloride; or any combination thereof, and over the next 2-3 weeks. Her bloating took some time to (d) analoxone hydrochloride and a metronidazole; resolve and about 5 weeks she was notable to detect bloating wherein optionally the agents are administered simulta even though she may have eaten a fatty meal. She continued 65 neously, the agents simultaneously in the form of a on therapy for 6 months without changing and she was single composition, or the agents are administered sepa asymptomatic at that time. rately in any order. US 9,095,545 B2 11 12 9. A method of treating or substantially ameliorating a mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori gastrointestinal disorder comprising administering to an indi tavancin, a telavancin, or a combination thereof; and vidual in need thereof: (b) an ansamysin; (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi wherein optionally the agents are administered simulta Valent polymer of Vancomycin, a carbohydrate-modified 5 neously, the agents simultaneously in the form of a Vancomycin, a Vancomycin-disulfide, a lipidated Vanco single composition, or the agents are administered sepa mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori rately in any order, tavancin, a telavancin, or a combination thereof; and wherein the gastrointestinal disorder is a diabetic gastro (b) an ansamysin; paresis. wherein the gastrointestinal disorder is constipation alter 10 nating at times with a diarrhea with Autism Spectrum 15. A method of treating or substantially ameliorating a Disorder. gastrointestinal disorder comprising administering to an indi 10. A method of treating or substantially ameliorating a vidual in need thereof: gastrointestinal disorder comprising administering to an indi (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi vidual in need thereof: 15 Valent polymer of Vancomycin, a carbohydrate-modified (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi Vancomycin, a Vancomycin-disulfide, a lipidated Vanco Valent polymer of Vancomycin, a carbohydrate-modified mycin, a chlorobiphenyl-desleucyl-vancomycin, an ori Vancomycin, a Vancomycin-disulfide, a lipidated Vanco tavancin, a telavancin, or a combination thereof; and mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori (b) an ansamysin; tavancin, a telavancin, or a combination thereof; and wherein optionally the agents are administered simulta (b) an ansamysin; neously, the agents simultaneously in the form of a wherein the gastrointestinal disorder is an irritable bowel single composition, or the agents are administered sepa syndrome. rately in any order, 11. A method of treating or substantially ameliorating a wherein the gastrointestinal disorder is a cyclic vomiting. gastrointestinal disorder comprising administering to an indi 25 16. A method of treating or substantially ameliorating a vidual in need thereof: gastrointestinal disorder comprising administering to an indi (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi vidual in need thereof: Valent polymer of Vancomycin, a carbohydrate-modified (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi Vancomycin, a Vancomycin-disulfide, a lipidated Vanco Valent polymer of vancomycin, a carbohydrate-modified mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori 30 Vancomycin, a Vancomycin-disulfide, a lipidated Vanco tavancin, a telavancin, or a combination thereof; and mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori (b) an ansamysin; tavancin, a telavancin, or a combination thereof; and wherein the gastrointestinal disorder is a traveler's diar (b) an ansamysin; rhea. wherein optionally the agents are administered simulta 12. A method of treating or substantially ameliorating a 35 neously, the agents simultaneously in the form of a gastrointestinal disorder comprising administering to an indi single composition, or the agents are administered sepa vidual in need thereof: rately in any order, (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi wherein the gastrointestinal disorder is a reflux oesophagi Valent polymer of vancomycin, a carbohydrate-modified t1S. Vancomycin, a Vancomycin-disulfide, a lipidated Vanco 40 17. The method of claim 1, wherein the agents are admin mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori istered simultaneously, or the agents are administered simul tavancin, a telavancin, or a combination thereof; and taneously in the form of a single composition. (b) an ansamysin; 18. The method of claim 9, wherein the agents are admin wherein the gastrointestinal disorder is a flatulence. istered simultaneously, or the agents are administered simul 13. A method of treating or substantially ameliorating a 45 taneously in the form of a single composition. gastrointestinal disorder comprising administering to an indi 19. The method of claim 10, wherein the agents are admin vidual in need thereof: istered simultaneously, or the agents are administered simul (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi taneously in the form of a single composition. Valent polymer of Vancomycin, a carbohydrate-modified 20. The method of claim 11, wherein the agents are admin Vancomycin, a Vancomycin-disulfide, a lipidated Vanco 50 istered simultaneously, or the agents are administered simul mycin, a chlorobiphenyl-desleucyl-Vancomycin, an ori taneously in the form of a single composition. tavancin, a telavancin, or a combination thereof; and 21. The method of claim 12, wherein the agents are admin (b) an ansamysin; istered simultaneously, or the agents are administered simul wherein optionally the agents are administered simulta taneously in the form of a single composition. neously, the agents simultaneously in the form of a 55 22. The method of claim 1, wherein the agents are admin single composition, or the agents are administered sepa istered separately in any order. rately in any order, 23. The method of claim 9, wherein the agents are admin wherein the gastrointestinal disorder is a pseudoobstruc istered separately in any order. tion. 24. The method of claim 10, wherein the agents are admin 14. A method of treating or substantially ameliorating a 60 istered separately in any order. gastrointestinal disorder comprising administering to an indi 25. The method of claim 11, wherein the agents are admin vidual in need thereof: istered separately in any order. (a) a Vancomycin, a chlorobiphenyl Vancomycin, a multi 26. The method of claim 12, wherein the agents are admin Valent polymer of Vancomycin, a carbohydrate-modified istered separately in any order. Vancomycin, a Vancomycin-disulfide, a lipidated Vanco :k k k k k