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I, Kusahami, an ulcerative colitis patient, collect the latest news articles about Ulcerative Colitis and Crohn’s Disease from various sources written in English, French, German, Italian, Spanish, Portuguese, Dutch, Chinese and Japanese, then digest them into easy-to-read expression without jargon as far as possible, and present them to Japanese patients. I'll continue to pile up my articles on this blog until we humankind overcome UC and CD.
Since Oct. 2005.
All Rights Reserved.
(An antibiotic combination therapy against Fusobacterium varium)
(Original article was written in Japanese by Kusahami on Oct. 6, 2006.)
“ATM Therapy” is a new treatment for ulcerative colitis (UC), developed by Dr. Toshifumi Ohkusa, MD, PhD, Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan, and his colleagues. After his long years of study, Dr. Ohkusa set up a hypothesis that Fusobacterium varium, a bacterium living in mucosa of UC patient and producing high concentration of butyric acid, is involved in the onset or worsening of UC. Then the research team tried giving patients three antibiotics that have very high bacterium-killing ability against F. varium, and as a result, a large percentage of UC patients achieved remissions.
Names of antibiotics, daily doses, terms of dosages have been already opened to public.
Amoxicillin 500mg three times a day, that is, 1500mg per day.
Tetracycline 500mg three times a day, that is, 1500mg per day.
Metronidazole 250mg three times a day, that is, 750mg per day.
All three antibiotics should be co-administered simultaneously, for 2 weeks.
Dr. Ohkusa named this treatment “ATM Therapy”. “ATM” is an acronym of these three antibiotics.
Amoxicillin is a frequently prescribed antibiotic in case of a cold. Also, Metronidazole is a frequently used antibiotic when diagnosed with trichomonas vaginitis. Tetracycline hydrochloride is an antibiotic frequently used in the past, but not frequently today because tetracycline-resistant bacteria become predominant.
These three antibiotics have been used in clinical practice for a long time, and there are already ample accumulations of information as to adverse effects. However, ATM therapy requires a little more dosage amount and dosing period than usual. Therefore, long-term safety evaluation task is needed for this new therapy.
Below, I have summarized the developmental process of “ATM therapy,” also known as “Fusobacterium varium eradication therapy,” referring their published study papers, media reports, and so on. I hope this information helps you.
Developmental history of ATM Therapy:
When Dr. Ohkusa and his colleagues thoroughly investigated affected mucosa on biopsy-specimens obtained from 16 ulcerative colitis patients who had undergone colon removal surgery, they found, in all 16 patients, some unknown bacteria adhered to mucosa at the affected areas. Furthermore, the bacteria invaded into mucosa at ulcerated areas, and also it was found that, in healthy control, no bacterial invasion was seen, though adhesions were seen in some patients.
Because, at that time, Dr. Ohkusa was studying eradication therapy for Helicobacter pylori which is primary cause of gastric and duodenal ulcer, he inferred that ulcerative colitis is also a chronic inflammatory disease caused by some sort of bacterium, and then tried identifying the culprit bacterium.
The team isolated 20 distinct bacterial species from mucosas of ulcerative colitis patients. Only one of those bacteria, Fusobacterium varium, showed a high detection rate in UC patients.
They measured concentrations of antibody (IgG+IgA+IgM) against Fusobacterium varium in blood serums by ELISA method. The mean concentration of the antibody in blood serums collected from 31 active ulcerative colitis patients was 0.716 OD (optical density), and that of from 31 Crohn’s disease patient was 0.117 OD, from 31 healthy controls (HC) was 0.108 OD. The mean concentration in active UC was significantly higher than others.
The team searched biopsy-specimens for Fusobacterium varium by immuno-histo-chemical method. F. varium was detected in 84 percent (26/31) of mucosa of active ulcerative colitis patients, 13 percent (4/31) of that of non-active UC, 16 percent (5/31) of Crohn’s disease, 13 percent (4/31) of active ischemic colitis, and 3 percent (1/31) of colon adenoma. Only UC had a significantly high detection-rate.
They separately incubated each bacterium isolated from mucosas of ulcerative colitis patients. Supernatant fluids of each culture were added to Vero cell cultures to test for cytotoxicity. Vero cell is a cell frequently used in laboratory tests. Only the supernatant of culture of Fusobacterium varium killed Vero cells. They proved that it was not Verotoxin ( 70k Da) that had killed Vero cells, by denying presence of verotoxin-DNA using PCR method.
The team, led by Dr. Ohkusa, found that it was high concentration (32mmol/L) butyric acid (ＣＨ3ＣＨ2ＣＨ2ＣＯＯＨ) produced by Fusobacterium varium that killed Vero cells. Afterward, using human colonic epithelial cell line, they tested butyric acid for cytotoxicity to the cell line and they found that butyric acid in concentration not less than 5.0mmol/L induces apoptotic cell-death.
After they infused Fusobacterium varium culture-supernatant fluid into intestines of laboratory mice, they found development of UC-like pathological lesion.
After they infused 32mmol/L butyric acid solution, which is the same concentration to the supernatant of Fusobacterium varium culture, into intestines of lab mice, they also found development of UC-like lesion.
At that point, Dr. Ohkusa had become confident that Fusobacterium varium deeply concerns development or worsening of ulcerative colitis, and he decided to conduct clinical trial of getting rid of F. varium entirely from ulcerative colitis patients.
He decided to use three antibiotics simultaneously to eradicate Fusobacterium varium avoiding emergence of multi-antibiotics-resistant strains, referring to his experience in study for eradication therapy for Helicobacter pylori and also upon relevant papers.
He chose Amoxicillin, Tetracycline, and Metronidazole that fulfill all the following conditions:
1) It should prove to have relatively high potential to kill the Fusobacterium varium strains isolated from ulcerative colitis patients, in the laboratory test.
2) It should be orally-intakable medicine because patients have to go to the hospital every day for 2 weeks if injection medicines are selected.
3) It should not be expensive so as not burden patients. (The expense for a 2 week prescription would be about 4 thousand yen at national definite price.)
4) It should have been used in clinical practice for a long time, and already have ample accumulations of information as to adverse effects. In Japan, Amoxicillin has been used for about 30 years, Tetracycline about 50 years, Metranidazole about 40 years.
Dr. Ohkusa and his colleagues conducted a clinical trial in 20 chronic ulcerative colitis patients. Patients included in the trial should have high concentrations of antibodies against Fusobacterium varium in blood serums, should have lesions in mucosa of rectum from the histopathological viewpoints, and should be mild and moderate in disease severity. Of the 20 participants, 14 were pan-colitis, 5 were left-sided colitis, and 1 was proctitis as to extent of lesion. Of the 20 participants, 18 were salazosulfapyridine users, 2 were mesalazine users as to 5-ASA drugs selection. Clinical activity, endoscopic, and histological scores in the treatment group decreased significantly at both 3-5 and 12-14 months after the end of treatment. Concentrations of antibodies against F. varium in the serums also decreased at 12-14 months after treatment.
The team conducted another clinical trial in 22 ulcerative colitis patients. Of the 22 participants, 15 were steroid-dependant and 7 were steroid-resistant. Of the 22 participants, 11 were pan-colitis, 9 were left-sided colitis, and 2 were proctitis as to extent of lesion. Of the 22 participants, 5 were severe, 16 were moderate, and 1 was mild as to disease severity. Symptom-severities were evaluated according to Lichitiger's symptom score. Results of endoscopic and histological observations were evaluated according to Matts' grading score. For each participant, this therapy was judged to be effective in leading to remission if disappearance of mucous bloody stool, decreased diarrhea frequency, disappearance of abdominal pain and tenderness, and normalization of CRP level were all observed. If discontinuation of steroids and continuation of remission were both observed for more than 3 months, the participant was judged as a case of success of withdrawal of steroids. The efficacy rate (remission rate) for the therapy was 86 percent (19/22). The success rate of withdrawal of steroids was 80 percent (16/20), though two patients, who could not discontinue steroids because of other disease, were excluded from the count. Three patients, for whom this therapy was ineffective, had relatively low concentrations of antibodies against Fusobacterium varium in blood serums before treatment, and the concentrations didn’t decrease after treatment.
They examined long-term clinical courses of participants from the viewpoint of improvement of quality of life(QOL). They analyzed the data from 61 participants, consisting of 12 steroid-resistant patients, 32 steroid-dependant patients, and 17 mesalazine or salazosulfapyridine-user patients. The efficacy rate (remission rate) for the ATM therapy was 100 percent (12/12) for steroid-resistant patients, 88 percent (28/32) for steroid-dependant, and 94 percent (16/17) for mesalazine or salazosulfapyridine users. Even for patients who had used more than 10,000mg of steroids, 92 percent (12/13) of them succeeded in withdrawal of steroids. The success rate of maintaining remission 3 months after the treatment was 92 percent for steroids-resistant patients, 86 percent for steroids-dependent, 100 percent for mesalazine or salazosulfapyridine users, and furthermore, 1 year after the treatment, 86 percent for steroids-resistant patients, 73 percent for steroids-dependent, and 89 percent for mesalazine or salazosulfapyridine users.
The research team had already conducted another randomized, double-blind, placebo-controlled, multi-center clinical trial in 210 active ulcerative colitis patients. The resultant data is now under analysis. The results of the data will be published sometime soon.
Additional clinical trials are in the planning stages.
◆Commensal bacteria can enter colonic epithelial cells and induce proinflammatory cytokine secretion: a possible pathogenic mechanism of ulcerative colitis.
Ohkusa T, Yoshida T, Sato N, Watanabe S, Tajiri H, Okayasu I.
J Med Microbiol. 2009 May;58(Pt 5):535-45.
◆Effectiveness of antibiotic combination therapy in patients with active ulcerative colitis: a randomized, controlled pilot trial with long-term follow-up.
Ohkusa T, Nomura T, Terai T, Miwa H, Kobayashi O, Hojo M, Takei Y, Ogihara T, Hirai S, Okayasu I, Sato N.
Scand J Gastroenterol. 2005 Nov;40(11):1334-42.
◆Cytotoxicity of organic acids produced by anaerobic intestinal bacteria on cultured epithelial cells.
Sakurazawa T, Ohkusa T.
J Gastroenterol. 2005 Jun;40(6):600-9.
◆Mucosa-associated bacteria in ulcerative colitis before and after antibiotic combination therapy.
Nomura T, Ohkusa T, Okayasu I, Yoshida T, Sakamoto M, Hayashi H, Benno Y, Hirai S, Hojo M, Kobayashi O, Terai T, Miwa H, Takei Y, Ogihara T, Sato N.
Aliment Pharmacol Ther. 2005 Apr 15;21(8):1017-27.
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◆Antibacterial and antimycobacterial treatment for inflammatory bowel disease.
Ohkusa T, Sato N.
J Gastroenterol Hepatol. 2005 Mar;20(3):340-51.
◆The role of bacterial infection in the pathogenesis of inflammatory bowel disease.
Ohkusa T, Nomura T, Sato N.
Intern Med. 2004 Jul;43(7):534-9.
[ Abstract] [Free full text in pdf]
◆Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis.
Ohkusa T, Okayasu I, Ogihara T, Morita K, Ogawa M, Sato N.
Gut. 2003 Jan;52(1):79-83.
[Free full text in html]
◆Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody.
Ohkusa T, Sato N, Ogihara T, Morita K, Ogawa M, Okayasu I.
J Gastroenterol Hepatol. 2002 Aug;17(8):849-53.
◆Bacterial invasion into the colonic mucosa in ulcerative colitis.
Ohkusa T, Okayasu I, Tokoi S, Ozaki Y.
J Gastroenterol Hepatol. 1993 Jan-Feb;8(1):116-8.
Special thanks to Mesa and her English-native husband, for their proof-reading of this English version.
Commented by 草はみ at 2009-11-18 00:11 x