Enteric combination therapy

Abstract

There is disclosed herein a composition for treating gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinsons disease, MS, Alzheimers Disease, Motor Neurone Disease or autism, the composition comprising: (i) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, am inoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (ii) at least one anti-clostridial agent selected from the above combined with an opioid blocking agent. There is also disclosed herein a method of treating various gastrointestinal or neurological disorders, constipation, functional constipation, irritable bowel syndrome, diverticulitis, travelers diarrhoea, chronic idiopathic nausea, IBD-associated constipation and diarrhoea, pseudo-obstruction, diabetic gastroparesis, cyclic vomiting, reflux oesophagitis, autism enteropathy, flatulence, halitosis, chronic fatigue, bloating, proctalgia fugax, Parkinsons disease, MS, Alzheimers Disease, Motor Neurone Disease or autism, the method comprising administering orally, via enema or by suppository: (i) a composition of the invention; (ii) at least two anti-clostridial agents selected from the group consisting of: vancomycin, vancomycin derivatives, a multi-valent polymer of vancomycin, am inoglycosides, nitroimidazoles, ansamysins, nifuroxazide, colchicine, prucalopride, prokinetic agent and 5-aminosalicylic acid; or (iii) at least one anti-clostridial agent selected from the above and an opioid blocking agent to a patient in need of such treatment.

Claims

1. A pharmaceutical composition comprising: colchicine, a nitroimidazole and a vancomycin, a vancomycin derivative, or a multi-valent polymer of vancomycin, wherein the vancomycin derivative comprises a carbohydrate-modified vancomycin, a vancomycin-disulfide derivative, a lipidated vancomycin, a chlorobiphenyl-desleucyl-vancomycin, an oritavancin, a telavancin or a chlorobiphenyl vancomycin.

2. The pharmaceutical composition of claim 1, wherein the nitroimidazole is selected from the group consisting of metronidazole, tinidazole, nimorazole, secnidazole, ordinazole and mixtures thereof.

3. The pharmaceutical composition of claim 1, wherein the nitroimidazole is dosaged for administration in doses ranging from 0.01 mg per day to 5000 mg per day.

4. The pharmaceutical composition of claim 3, wherein the nitroimidazole is dosaged for administration in doses ranging from 50 mg per day to 500 mg per day.

5. The pharmaceutical composition of claim 1, wherein the vancomycin, vancomycin derivative or multi-valent polymer of vancomycin is dosaged for administration in doses ranging from 0.01 mg per day to 5000 mg per day.

6. The pharmaceutical composition of claim 5, wherein the vancomycin, vancomycin derivative or multi-valent polymer of vancomycin is dosaged for administration in doses ranging from 50 mg per day to 500 mg per day.

7. The pharmaceutical composition of claim 1, wherein the colchicine is dosaged for administration in doses ranging from 0.005 mg to 5 mg per day.

8. The pharmaceutical composition of claim 1, wherein the colchicine, the nitroimidazole and the vancomycin, vancomycin derivative, or multi-valent polymer of vancomycin are formulated in a single capsule or tablet.

9. The pharmaceutical composition of claim 8, wherein the capsule or tablet is enteric coated.

10. The pharmaceutical composition of claim 1, wherein the colchicine, the nitroimidazole and the vancomycin, vancomycin derivative, or multi-valent polymer of vancomycin are formulated together as an enema formulation.

11. The pharmaceutical composition of claim 1, wherein the colchicine, the nitroimidazole and the vancomycin, vancomycin derivative, or multi-valent polymer of vancomycin are formulated together as a suppository formulation.

12. The pharmaceutical composition of claim 1, wherein the colchicine, the nitroimidazole and the vancomycin, vancomycin derivative, or multi-valent polymer of vancomycin are formulated together as an orally administered formulation.

13. A pharmaceutical composition comprising: colchicine, a nitroimidazole and a vancomycin.

14. The pharmaceutical composition of claim 13, wherein the nitroimidazole is selected from the group consisting of metronidazole, tinidazole, nimorazole, secnidazole, ordinazole and mixtures thereof.

15. The pharmaceutical composition of claim 13, wherein the colchicine, the nitroimidazole and the vancomycin are formulated in a single capsule or tablet.

16. The pharmaceutical composition of claim 13, wherein the colchicine, the nitroimidazole and the vancomycin are formulated together as an enema formulation, a suppository formulation or as an orally administered formulation.

17. A pharmaceutical composition comprising: colchicine, a nitroimidazole and a multi-valent polymer of vancomycin.

18. The pharmaceutical composition of claim 17, wherein the nitroimidazole is selected from the group consisting of metronidazole, tinidazole, nimorazole, secnidazole, ordinazole and mixtures thereof.

19. The pharmaceutical composition of claim 17, wherein the colchicine, the nitroimidazole and the multi-valent polymer of vancomycin are formulated in a single capsule or tablet.

20. The pharmaceutical composition of claim 17, wherein the colchicine, the nitroimidazole and the multi-valent polymer of vancomycin are formulated together as an enema formulation, a suppository formulation or as an orally administered formulation.

Description

EXAMPLES

Example 1

(1) A 38 year old female patient with life-long constipation, defecating between 0-2 times per week, had multiple investigations carried out and no abnormalities were found with respect to the colon or the bowel flora, and had failed known standard therapies. She was not hypothyroid and had otherwise normal blood tests. She was given a trial of Vancomycin 500 mg bd and Metronidazole 200 mg bd and began defecating by day 3 of the treatment. She was able to continue defecating normally with her constipation completely being reversed while she took the therapy for 4 weeks. After stopping the therapy, within 2 weeks the constipation started recurring. Restarting the treatment again allowed her to defecate normally. Apart from the constipation her bloating was markedly reduced during treatment, and her sensation of fullness was improved and her reflux symptoms also lessened. Her previous tiredness was markedly reduced during treatment.

Example 2

(2) An elderly gentleman with severe constipation requiring 6 coloxyl tablets per day and Parkinson's disease was commenced on Vancomycin 500 mg bd, Metronidazole 400 mg bd and Colchicine 0.5 mg bd. Within 3 days he was defecating normally and was able to stop taking the Coloxyl. Unexpectedly, by week 4 his Parkinson's disease had improved quite dramatically. In spite of still-continuing to take Sinemet in his original dose, he no longer experiences any tremor and over the period of several months his gait improved and Glabellar tap test reversed to normality. Continuing the treatment for over a yearhis constipation remained completely gone, his Parkinson's was virtually undetectable and he was able to reduce his dose of Sinemet, suggesting his Parkinson's disease neurotoxicity may have originated from the bowel flora.

Example 3

(3) A 41 year old female with a 10 year constipation history associated bloating, tiredness and headaches was commenced on 500 mg of Vancomycin twice daily and Rifaximin 200 mg twice daily. After a week's treatment her constipation improved markedly but the Rifaximin had to be increased to 400 mg twice daily for the constipation and other symptoms to be virtually completely undetectable. Progressively her bloating improved and her tiredness and headaches improved. She continued on treatment now for over 3 months and continues well on the therapy not wanting to stop the treatment because she feels so well.

Example 4

(4) An 8 year old male with constipation alternating at times with diarrhea with Autism Spectrum Disorder was commenced on Vancomycin 250 mg twice daily together with Naloxone hydrochloride 10 mg twice daily. After 3 weeks of treatment the constipation was completely resolved but in addition his behavior and lethargy changed. He became affectionate and relatively calm, achieving toilet retraining which he had never previously achieved. His vocabulary began to increase quite rapidly, his on task performance, compliance with parental requests and awareness of surroundings improved quite quickly and he was engaging in positive activities. Repetitive and self stimulatory behaviors were reduced. The improvement lasted for the duration of four months treatment as various parameters kept on improving.

Example 5

(5) Elderly male with severe constipation, bloating and abdominal pain and early Parkinson's disease characterized by stiffness was commenced on Vancomycin 500 mg twice daily together with Rifaximin 500 mg twice daily and Naloxone hydrochloride 10 mg twice daily. Within a week he was defecating normally. I was able to stop the various teas and Normacol together with Movicol which he was using for constipation. By week 6 his stiffness had markedly improved, he had stopped freezing while attempting to initiate walking and his fine tremor, previously present, was no longer detectable. Cogwheel rigidity also improved and he was able to reduce his anti-Parkinsonian treatment by about 30% at this stage. He continued the treatment for 6 months and his Parkinsonian symptoms further regressed although they were not completely undetectable at this stage.

Example 6

(6) A 52 year old female with lifelong constipation associated with marked bloating was commenced on 500 mg Vancomycin twice daily, 500 mg Rifaximin twice daily and Naloxone hydrochloride 10 mg twice daily. After one week of treatment her constipation improved markedly and kept on improving over the next 2-3 weeks. Her bloating took some time to resolve and about 5 weeks she was not able to detect bloating even though she may have eaten a fatty meal. She continued on therapy for 6 months without changing and she was asymptomatic at that time.

(7) Although the invention has been described with reference to specific examples, it will be appreciated to those skilled in the art that the invention may be embodiment in many other forms.