Re: 세포장례식(efferocytosis)를 유도하는 커큐민(강황).. 궤양성 대장염 치료

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Curcumin Maintenance Therapy for Ulcerative Colitis:

Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial

Hiroyuki Hanai⁎,‡ ∙ Takayuki Iida‡ ∙ Ken Takeuchi‡ ∙ … ∙ Masato Uchijima§§ ∙ Toshi Nagata§§ ∙ Yukio Koide§§ koidelb@hama-med.ac.jp … Show more

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Abstract

Background & Aims: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC). Methods: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. Results: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P = .040). Recurrence rates eval‎uated on the basis of intention to treat showed significant difference between curcumin and placebo (P = .049). Furthermore, curcumin improved both CAI (P = .038) and EI (P = .0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed. Conclusions: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

초록

배경 및 목적: 커큐민은 강황에 함유된 생물학적 활성 식물성 화합물로, 궤양성 대장염(UC) 환자에게 유익할 수 있는 약리학적 작용을 가지고 있습니다. 본 연구의 목적은 휴지기 단계의 궤양성 대장염(UC) 환자에서 커큐민의 유지 요법으로서의 효능을 평가하는 것입니다.

방법: UC가 활동성 없는 89명의 환자를 대상으로 커큐민의 재발 예방을 위한 무작위 이중맹검 다기관 임상시험에 모집했습니다.

45명의 환자는

아침 식사 후 1g, 저녁 식사 후 1g의 커큐민과 설파살라진(SZ) 또는 메사라민을 투여받았으며,

44명의 환자는 위약과 SZ 또는 메사라민을 6개월 동안 투여받았습니다.

임상 활동 지수(CAI)와 내시경 지수(EI)는

연구 시작 시점,

2개월마다(CAI),

6개월 연구 종료 시점,

6개월 추적 관찰 종료 시점에 측정되었습니다.

결과: 7명의 환자가 프로토콜 위반자였습니다.

커큐민을 투여받은 43명 중 2명(4.65%)이 6개월 치료 기간 동안 재발했으며,

위약 그룹의 39명 중 8명(20.51%)이 재발했습니다(P = .040).

의도된 치료에 따라 평가된 재발률은 커큐민과 위약 그룹 간 유의미한 차이를 보였습니다(P = 0.049).

또한 커큐민은 CAI(P = 0.038)와 EI(P = 0.0001)를 모두 개선하여

UC와 관련된 morbidities를 억제했습니다.

6개월간의 추적 관찰 기간 동안 두 그룹의 환자들은 SZ 또는 메살라민을 투여받았습니다.

커큐민 그룹에서 8명의 추가 환자가, 위약 그룹에서 6명의 환자가 재발했습니다.

결론:

커큐민은 휴지기 UC 환자의 관해 유지를 위한 유망하고 안전한 약물로 보입니다.

커큐민에 대한 추가 연구가 본 연구 결과를 강화할 것입니다.

Abbreviations used in this paper

1. CAI (clinical activity index)
2. EI (endoscopic index)
3. MAPK (mitogen-activated protein kinase)
4. NF-κB (nuclear factor-κB)
5. NOS (nitric oxide synthase)
6. SZ (sulfasalazine)
7. TNBS (trinitrobenzene sulfonic acid)
8. UC (ulcerative colitis)

Ulcerative colitis (UC) is a debilitating, chronic, relapsing-remitting IBD that afflicts millions of individuals throughout the world and produces symptoms that impair quality of life and ability to function.1 Although factors like smoking cessation,2 use of nonsteroidal anti-inflammatory drugs,3 and stress4 are known to provoke an exacerbation, clinical relapses are often unpredictable.

Currently, several drugs including sulfasalazine (SZ), mesalamine, corticosteroids, immunomodulators, and remicade are used to treat patients with active IBD.5–12 However, these medications are associated with side effects that add to the disease complications when used either to induce remission or to prevent a recurrence.9–15 Furthermore, given that the majority of patients with UC (approximately 70%) have a clinical course that is either relapsing-remitting or chronic continuous, there is a need for novel safe medications to maintain remission in patients with UC in whom the disease has reverted to a quiescent state.

Curcumin is a natural substance present in turmeric, the spice that gives food an exotic yellow color. Curcumin seems to have a broad spectrum of pharmacologic actions including antitumor, anti-inflammatory, and antioxidant effects.16–20 The pleiotropic effects of curcumin are attributable in part to the inhibition of the transcriptional nuclear factor–κB (NF-κB).21–23 In line with this background, recently we demonstrated that treatment with curcumin can prevent murine experimental colitis by inhibiting N∼F-κB activation and CD4+ T-cell infiltration into the colonic mucosa.24 This study aimed to assess the efficacy of curcumin as a maintenance therapy in patients with quiescent UC.

궤양성 대장염(UC)은

전 세계 수백만 명의 환자에게 영향을 미치는 만성 재발성 염증성 장 질환으로,

삶의 질과 기능에 심각한 장애를 초래합니다.1

흡연 중단,2 비스테로이드성 항염증제 사용,3 스트레스4 등 요인이

증상 악화를 유발할 수 있지만,

임상적 재발은 종종 예측하기 어렵습니다.

현재 활동성 IBD 환자를 치료하기 위해

설파살라진(SZ), 메사라민, 코르티코스테로이드, 면역조절제, 리미케이드 등

여러 약물이 사용되고 있습니다.5–12

그러나 이러한 약물은

완화 유도나 재발 예방을 위해 사용될 때 질병 합병증을

악화시키는 부작용과 연관되어 있습니다.9–15

또한

UC 환자의 대부분(약 70%)이

재발-완화형 또는 만성 지속형 임상 경과를 보이기 때문에,

질병이 휴면 상태로 돌아간 UC 환자에서 완화를 유지하기 위한 새로운 안전한 약물이 필요합니다.

커큐민은

강황에 함유된 천연 물질로,

음식에 이국적인 노란색을 부여합니다.

커큐민은

항종양, 항염증, 항산화 효과를 포함한

광범위한 약리학적 작용을 보이는 것으로 알려져 있습니다.16–20

커큐민의 다중 작용은

부분적으로 전사 인자-κB(NF-κB)의 억제에 기인합니다.21–23

이러한 배경에 따라 최근 우리는 커큐민 치료가

N∼F-κB 활성화와 CD4+ T 세포의 대장 점막 침투를 억제함으로써

실험적 대장염을 예방할 수 있음을 입증했습니다.24

이 연구는 휴면 상태의 UC 환자에서

커큐민의 유지 요법으로서의 효능을 평가하는 것을 목적으로 했습니다.

Patients and Methods

Patients

Between April 2004–July 2005, 8 centers in Japan enrolled a total of 89 patients. The study protocol was reviewed and approved by the Committees on Ethics of clinical trials involving human subjects at each institution, and the trial was conducted in accord with the Declaration of Helsinki. Inclusion criteria were (1) patient had a diagnosis of UC as confirmed by radiologic, endoscopic, or histologic criteria that are established by the Research Committee of Inflammatory Bowel Disease, the Japan Ministry of Health; (2) age between 13–65 years; (3) patient’s UC had a clinical activity index (CAI) ≤4, stable for the previous 4 weeks; (4) patient had achieved remission with a corticosteroid ≥20 mg/day prednisolone or an alternative medication and had successfully ceased steroid therapy; and (5) patient had a hemoglobin of ≥10 g/dL. Exclusion criteria were (1) patient was receiving an immunomodulator like azathioprine, 6-mercaptopurine, or cyclosporine; (2) patients with severe cardiovascular diseases; (3) patients with laboratory abnormalities indicating anemia (hemoglobin <9 g/dL), leukopenia, thrombocytopenia, or abnormal coagulation; (4) patients with renal or liver disease, chronic pancreatitis, diabetes mellitus, or gallstone; (5) patients with infection, sepsis, or pneumonia; and (6) pregnant or nursing women. Dropout criteria were (1) patient exhibits complications during the study; (2) patient decides to withdraw from the trial at will; and (3) patient requires additional drug therapy that violates the inclusion criteria. Any adverse symptom was recorded in the diary kept by patients during the study. Laboratory investigations including a complete blood count and blood chemistry were performed 3 times, at baseline, at 3 months, and at the end of the treatment.

2004년 4월부터 2005년 7월까지 일본 내 8개 기관에서 총 89명의 환자가 등록되었습니다. 연구 프로토콜은 각 기관의 인간 대상 임상 시험 윤리위원회에서 검토 및 승인되었으며, 연구는 헬싱키 선언에 따라 진행되었습니다. 포함 기준은 다음과 같습니다:

(1) 일본 보건복지부 염증성 장질환 연구위원회가 정한 방사선학적, 내시경적, 또는 조직학적 기준에 따라 UC로 진단된 환자;

(2) 연령 13–65세;

(3) 환자의 UC가 지난 4주간 임상 활동 지수(CAI) ≤4로 안정된 상태;

(4) 코르티코스테로이드(프레드니솔론 ≥20 mg/일) 또는 대체 약물로 완화 상태를 달성하고 스테로이드 치료를 성공적으로 중단한 환자; 

(5) 헤모글로빈 ≥10 g/dL인 환자.

배제 기준은

(1) 아자티오프린, 6-메르카aptop린, 사이클로스포린과 같은 면역조절제를 투여 중인 환자;

(2) 중증 심혈관 질환을 가진 환자;

(3) 빈혈(헤모글로빈 <9 g/dL), 백혈구 감소증, 혈소판 감소증, 또는 이상 혈액 응고 소견을 보이는 실험실 검사 이상이 있는 환자;

(4) 신장 질환, 간 질환, 만성 췌장염, 당뇨병, 또는 담석이 있는 환자;

(5) 감염, 패혈증, 또는 폐렴이 있는 환자; 및

(6) 임신 중이거나 수유 중인 여성.

중도 탈락 기준은 (1) 연구 기간 중 합병증이 발생한 환자; (2) 환자가 자발적으로 연구에서 탈퇴한 경우; 및 (3) 포함 기준을 위반하는 추가 약물 치료가 필요한 환자입니다. 연구 기간 중 환자가 기록한 일지에 모든 부작용이 기록되었습니다. 혈액 검사(완전 혈구 계수 및 혈액 화학 검사)는 기저선, 3개월 후, 치료 종료 시점의 3회에 걸쳐 수행되었습니다.

Methods

This study was to be a randomized, multicenter (8 hospital institutions), double-blind, and placebo-controlled clinical trial. Assignment to curcumin or placebo was according to a computer-generated randomization scheme done by the clinical pharmacist. Patients were given SZ (1.0–3.0 g/day; median, 2.0 g/day) or mesalamine (1.5–3.0 g/day; median, 2.25 g/day) plus 2 g curcumin, 1 g taken after breakfast and 1 g after the evening meal, or placebo for 6 months (Figure 1). Patients were then followed for an additional 6 months, during which either SZ or mesalamine was continued. All medications except SZ or mesalamine were discontinued 4 weeks before starting this study. All study personnel and participants were blinded to treatment assignment for the duration of the study. Only the study statisticians and the data monitoring committee could see unblinded data, but none had any contact with the study patients. Curcumin and placebo were made to have identical appearance (yellow), prepared by API Co, Ltd (Gifu, Japan). The compositions of curcumin and placebo are shown in Table 1.

방법

이 연구는 무작위 배정, 다기관(8개 병원 기관), 이중 맹검, 위약 대조 임상 시험으로 진행되었습니다.

커큐민 또는 위약 배정은 임상 약사가 컴퓨터 생성 무작위 배정 방안에 따라 진행되었습니다.

환자들은 SZ (1.0–3.0 g/일; 중간값, 2.0 g/일) 또는 메사라민 (1.5–3.0 g/일; 중간값, 2.25 g/일)에 추가로 커큐민 2g (아침 식사 후 1g, 저녁 식사 후 1g) 또는 위약을 6개월 동안 투여받았습니다 (그림 1).

환자들은 추가로 6개월 동안 추적 관찰되었으며, 이 기간 동안 SZ 또는 메사라민 투여가 계속되었습니다. 이 연구 시작 4주 전까지 SZ 또는 메사라민을 제외한 모든 약물은 중단되었습니다. 연구 기간 동안 모든 연구 인력과 참가자는 치료 배정에 대해 눈가림 상태였습니다. 연구 통계학자와 데이터 모니터링 위원회만 눈가림이 해제된 데이터를 확인할 수 있었으나, 이들은 연구 환자와의 접촉이 없었습니다. 커큐민과 위약은 동일한 외관(노란색)으로 제조되었으며, API Co, Ltd (일본 기후)에서 제조되었습니다. 커큐민과 위약의 성분은 표 1에 표시되어 있습니다.

Figure viewer

Figure 1 Summary of the study design, randomization, and clinical outcomes of the 6 months of treatment.

CurcuminPlacebo

Table 1

Compositions of Medications (%)

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Clinical Assessment

CAI was measured at entry (within 2 weeks before randomization), every 2 months, and then at the conclusion of the clinical trial, whereas endoscopic index (EI) was determined at entry and at the conclusion of the trial. Both CAI and EI were according to Rachmilewitz.25 Patients who had a CAI ≤4 were considered to be in clinical remission, whereas relapse was defined as CAI ≥5.

Statistical Analysis

Data are presented as the mean ± standard deviation values and ranges unless indicated otherwise. For determining statistical significance, comparisons were made by using the Fisher exact test or the χ2 test. P value <.05 was considered significant in all statistical eval‎uations.

임상 평가

CAI는 무작위 배정 전 2주 이내에 측정되었으며, 2개월마다 측정된 후 임상 시험 종료 시점에 측정되었습니다. 반면 내시경 지수(EI)는 시험 시작 시점과 시험 종료 시점에 측정되었습니다. CAI와 EI는 모두 Rachmilewitz에 따라 측정되었습니다.25 CAI가 4 이하인 환자는 임상적 완화 상태로 간주되었으며, 재발은 CAI가 5 이상인 경우로 정의되었습니다.

통계 분석

데이터는 달리 명시되지 않는 한 평균 ± 표준 편차 값과 범위로 제시되었습니다. 통계적 유의성을 판단하기 위해 Fisher 정확도 검정 또는 χ² 검정을 사용했습니다. 모든 통계적 평가에서 P 값 <0.05는 유의미한 것으로 간주되었습니다.

Results

Clinical Outcomes

Seven patients (2 in the curcumin group and 5 in the placebo group) were excluded in line with patients’ wishes. Hence, 43 patients in the curcumin group and 39 patients in the placebo group completed the study. Study groups were well-matched with respect to gender, age, duration of UC, recurrences during the past 2 years, clinical course, CAI, and EI (Table 2). Recurrent rates eval‎uated in all patients (intention to treat) also showed significant differences between the curcumin and the placebo groups (P = .049, Table 3). Relapses in the 2 groups during the 6-month study period together with the follow-up data are presented in Figures 1 and 2. Of the 43 patients who received curcumin, 2 patients (4.55%) relapsed during 6 months, whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P = .040) (Table 4).

결과

임상 결과

환자의 요청에 따라 7명(커큐민 그룹 2명, 플라시보 그룹 5명)이 연구에서 제외되었습니다. 따라서 커큐민 그룹 43명과 플라시보 그룹 39명이 연구를 완료했습니다. 연구 그룹은 성별, 연령, UC 지속 기간, 지난 2년간의 재발 횟수, 임상 경과, CAI, EI(표 2) 측면에서 잘 일치했습니다. 모든 환자(의도된 치료)에서 평가된 재발률은 커큐민 그룹과 플라시보 그룹 간 유의미한 차이를 보였습니다(P = .049, 표 3). 6개월 연구 기간 동안 두 그룹의 재발 사례와 추적 관찰 데이터는 그림 1과 2에 제시되어 있습니다. 커큐민을 투여받은 43명 중 2명(4.55%)이 6개월 동안 재발했으며, 위약 그룹의 39명 중 8명(20.51%)이 재발했습니다(P = .040) (표 4).

Figure viewer

Figure 2 The Kaplan-Meier curves showing the efficacy outcomes during the 6 months of therapy and 6 months of follow-up.

DemographyCurcuminPlaceboP value

Male/female	23/22	26/18	.52
Age, mean (y)	45.2±15.8	39.7±14.2	.11
Range	(18–75)	(21–68)
Duration of UC (mo)	98.6±74.2	93.5±74.2	.77
Range	(11–305)	(5–336)
No. of recurrences during past 2 y	1.6±1.2	1.5±1.0	.78
Range	(0–5)	(0–4)
Clinical course (cases)
First attack	5	4
Relapsing-remitting	29	28
Chronic continuousa	10	8	.89
CAI before study	1.3±1.1	1.0±1.1	.23
Range	(0–4)	(0–4)
EI before study	1.3±0.8	1.3±1.0	.60
Range	(0–3.0)	(0–3.6)

Table 2

Demography of Patients at Baseline

Mean ± standard deviation values and (ranges) are presented.

a

Patients with chronic continuous UC had a CAI ≤4 for at least 4 weeks before entry. “Chronic continuous” is commonly used in Japan to indicate a CAI that oscillates between fully quiescent (0–1) and clinical remission (4) in some patients.

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CurcuminPlaceboP value

Table 3

Recurrence Rates at 6 and 12 Months Based on Intention to Treat

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CurcuminPlaceboP value

Table 4

Recurrence Status at 6 Months

Analysis is based on the number of eligible patients who completed the study, excluding the 7 patients who became protocol violators during the study.

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We also determined the mean CAI and EI values before and after the treatment (Table 5). The mean CAI in the curcumin group was improved from 1.3 ± 1.1 at baseline to 1.0 ± 2.0 at 6 months (P = .038). In contrast, CAI in the placebo group showed significant deterioration; mean CAI increased from 1.0 ± 1.1 to 2.2 ± 2.3 (P = .0003). Furthermore, patients in the curcumin group had significantly improved EI, 1.3 ± 0.8 vs 0.8 ± 0.6 (P = .0001). The EI values in the placebo group showed no significant difference between baseline and post-treatment.

CurcuminPlaceboEntry6 MoEntry6 Mo

Table 5

Changes in CAI and EI During the 6 Months of Treatment

P values by the χ2 test.

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Follow-up Observations

A 6-month follow-up was done after the end of the 6-month study period. As shown in Figure 2, 8 additional patients in the curcumin group and 6 patients in the placebo group relapsed during the 6-month follow-up while being on SZ or mesalamine. There was no significant difference between the 2 groups with respect to relapse rates during the 6-month follow-up.

Safety Eval‎uation

A total of 9 mild and transient side effects in 7 of 89 patients were observed during curcumin maintenance therapy. Some patients experienced more than 1 event. The side effects included sensation of abdominal bulging, nausea, transient hypertension, transient increase in the number of stools, and elevated γ–guanosine triphosphate level. The elevated γ–guanosine triphosphate was observed in a patient who was a regular alcohol drinker. No patient discontinued curcumin therapy as a result of side effects, except 1 patient with hypertension.

Discussion

The clinical outcomes of this double-blind, placebo-controlled trial of curcumin therapy to sustain remission in patients with quiescent UC might be briefly summarized as follows: (1) 2 g/day curcumin in combination with SZ or mesalamine had significantly better clinical efficacy in the prevention of relapse compared with placebo plus SZ or mesalamine; (2) curcumin significantly improved both CAI and EI; and (3) curcumin was well-tolerated and was not associated with any serious side effect.

Most currently available conventional drugs used to treat UC are associated with unpleasant side effects. For example, nausea, vomiting, headaches, rash, fever, hepatitis, pancreatitis, nephritis, agranulocytosis, and male infertility are reported in approximately 30% of patients who take SZ.1 The sulfa moiety of the drug is known to interfere with folic acid absorption. Even the mesalamine derivatives that lack the sulfa moiety are associated with fever, diarrhea, and abdominal discomfort. In contrast, none of these side effects were observed when patients were given curcumin. Curcumin is a diferulolymethane, a natural plant product extracted from the root of Curcuma longa Linn. It is a common food additive popular for its pleasant mild aroma and exotic yellow color, not likely to cause side effects. In India and China, for centuries curcumin has been known as a medicinal plant. It is very likely that curcumin has several biochemical actions that are not yet elucidated. Recently, curcumin was reported to block the upstream of NF-κB and IκB kinase.26 NF-κB is suspected to promote the expression‎ of human IBD.26–28 Consistent with this assertion, recently we demonstrated that curcumin can suppress colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS) in a mice model of colitis.24

In the present study, only 2 of 43 patients treated with curcumin in combination with SZ or mesalamine relapsed during the 6 months of therapy, whereas 8 of 39 patients who received placebo with SZ or mesalamine relapsed during the same period. It is appropriate to mention that mesalamine alone when used as maintenance therapy during a 6-month period has an efficacy similar to that of SZ, which is equal to the placebo group in our study.29,30 In addition, in this study, we added a 6-month follow-up to the 6-month treatment time during which patients received SZ or mesalamine only. Clinical assessment at the end of the follow-up showed no significant difference between the 2 groups. This supported our impression that curcumin, in fact, does suppress relapse.

The 2-g curcumin per day in this study is similar to the dose reported to have antitumor effect.31 However, we admit that the dose of curcumin used in this study might not be the optimum and the most effective regimen. This could be viewed as one major limitation of our data. With this in mind, we believe that future studies in larger cohorts of patients should use multiple doses of curcumin, because a dose higher than 2 g/day might appear superior to 2 g/day.

Aminosalicylates have been reported to be inhibitors of NF-κB.4 However, curcumin has broader effects on the NF-κB signal transduction pathways. In addition, curcumin inhibits mitogen-activated protein kinase (MAPK),32 c-Fos, and nitric oxide synthase (NOS) activity,33 thus potentially having a broader spectrum of anti-inflammatory effects compared with aminosalicylates (not to mention its safety).

In our study, both the clinical and endoscopic eval‎uation scores were significantly improved by curcumin therapy. Especially the endoscopic score was substantially improved compared with the placebo. Nine of the curcumin-treated patients reported some mild side effects such as abdominal bloating and nausea. Because the patients were also receiving SZ or mesalamine as well, we could not with certainty attribute these complaints to curcumin. A phase I human trial with 25 subjects using up to 8 g curcumin per day found no toxicity or serious side effects related to curcumin.34 Therefore, we conclude that curcumin therapy is both effective and safe in maintaining UC remission.

In conclusion, the results of this study indicate that the turmeric component, curcumin, is potentially a promising medication for the treatment of IBD. In the near future, we plan to undertake a multiple-dose (including a high-dose) curcumin trial without an aminosalicylate as maintenance therapy in patients with quiescent UC.

논의

이 이중 맹검, 위약 대조 임상 시험에서 휴지기 UC 환자의 완화 유지에 대한 커큐민 치료의 임상적 결과는 다음과 같이 요약될 수 있습니다:

(1) 2g/일 커큐민과 SZ 또는 메사라민 병용 요법은 위약과 SZ 또는 메사라민 병용 요법보다 재발 예방에 있어 임상적 효능이 유의미하게 우수했습니다;

(2) 커큐민은 CAI와 EI 모두에서 유의미하게 개선되었습니다;

(3) 커큐민은 잘 견디었으며 심각한 부작용과 연관되지 않았습니다.

현재 UC 치료에 사용되는 대부분의 전통적 약물은 불쾌한 부작용과 연관되어 있습니다.

예를 들어, SZ를 복용하는 환자의 약 30%에서 메스꺼움, 구토, 두통, 발진, 발열, 간염, 췌장염, 신염, 무과립구증, 남성 불임 등이 보고되었습니다.1 이 약물의 설파 성분은 엽산 흡수를 방해하는 것으로 알려져 있습니다. 설파 성분을 포함하지 않은 메사라민 유도체도 발열, 설사, 복부 불편감과 연관되어 있습니다. 반면, 커큐민을 투여받은 환자에서는 이러한 부작용이 관찰되지 않았습니다. 커큐민은 Curcuma longa Linn의 뿌리에서 추출된 자연 식물 성분인 디페룰올리메탄입니다. 이는 즐거운 부드러운 향기와 이국적인 노란색으로 인해 부작용을 일으키지 않는 일반적인 식품 첨가물로 널리 사용됩니다.

인도 및 중국에서는 수세기 동안 커큐민이 약용 식물로 알려져 왔습니다.

커큐민은 아직 밝혀지지 않은 여러 생화학적 작용을 가질 가능성이 매우 높습니다.

최근 커큐민이 NF-κB와 IκB 키나제의 상류 경로를 차단한다는 보고가 있었습니다.26

NF-κB는 인간 IBD의 발현을 촉진하는 것으로 의심됩니다.26–28

이 주장과 일치하게, 최근 우리는 커큐민이 트리니트로벤젠 설폰산(TNBS)에 의해 유발된 대장염 마우스 모델에서 대장 염증을 억제한다는 것을 입증했습니다.24

본 연구에서 커큐민과 SZ 또는 메사라민을 병용 투여받은 43명 중 2명만이 6개월 치료 기간 동안 재발했으며, 반면 SZ 또는 메사라민과 플라시보를 투여받은 39명 중 8명이 같은 기간 동안 재발했습니다. 메사라민을 단독으로 6개월간 유지 요법으로 사용했을 때의 효능은 SZ와 유사하며, 이는 본 연구에서 플라시보 그룹과 동일했습니다.29,30 또한 본 연구에서는 SZ 또는 메사라민만을 투여받은 환자의 6개월 치료 기간에 6개월의 추적 관찰 기간을 추가했습니다. 추적 관찰 종료 시 임상 평가 결과 두 그룹 간 유의미한 차이는 관찰되지 않았습니다. 이는 커큐민이 실제로 재발을 억제한다는 우리의 인상을 뒷받침합니다.

본 연구에서 사용된 하루 2g의 커큐민 용량은 항종양 효과를 보고된 용량과 유사합니다.31 그러나 본 연구에서 사용된 커큐민 용량이 최적 또는 가장 효과적인 투여 요법이 아닐 수 있음을 인정합니다. 이는 우리 데이터의 주요 한계 중 하나로 볼 수 있습니다. 이를 고려할 때, 향후 대규모 환자 집단에서 진행될 연구에서는 커큐민의 다중 용량을 사용해야 한다고 믿습니다. 2g/일보다 높은 용량이 2g/일보다 우수할 수 있기 때문입니다.

아미노살리실산염은 NF-κB 억제제로 보고되었습니다.4 그러나 커큐민은 NF-κB 신호 전달 경로에 더 광범위한 영향을 미칩니다. 또한 커큐민은 미토겐 활성화 단백질 키나제(MAPK),32 c-Fos, 및 질산산화효소(NOS) 활성을 억제하며,33 따라서 아미노살리실산염보다 더 넓은 범위의 항염증 효과를 가질 수 있습니다(안전성 측면에서도 마찬가지입니다).

본 연구에서 커큐민 치료는 임상적 및 내시경 평가 점수 모두에서 유의미하게 개선되었습니다. 특히 내시경 점수는 위약 대비 크게 개선되었습니다. 커큐민 치료를 받은 환자 9명에서 복부 팽만과 메스꺼움과 같은 경미한 부작용이 보고되었습니다. 그러나 환자들이 SZ 또는 메사라민을 병용 투여받고 있었기 때문에, 이러한 증상을 커큐민에 직접적으로 귀인할 수는 없었습니다. 25명의 대상자를 대상으로 하루 최대 8g의 커큐민을 투여한 제1상 인간 임상 시험에서 커큐민과 관련된 독성이나 심각한 부작용은 발견되지 않았습니다.34 따라서 우리는 커큐민 치료가 UC의 완화 유지에 효과적이고 안전하다고 결론지입니다.

결론적으로,

이 연구 결과는 강황의 성분인 커큐민이

IBD 치료를 위한 유망한 약물 후보로 잠재력을 가지고 있음을 보여줍니다.

향후에는 아미노살리실산제를 유지 요법으로 사용하지 않는

다용량(고용량 포함) 커큐민 임상 시험을

UC 활동이 없는 환자에서 진행할 계획입니다.

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Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial

Hiroyuki Hanai⁎,‡ ∙ Takayuki Iida‡ ∙ Ken Takeuchi‡ ∙ … ∙ Masato Uchijima§§ ∙ Toshi Nagata§§ ∙ Yukio Koide§§ koidelb@hama-med.ac.jp … Show more

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Abstract

Background & Aims: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC). Methods: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. Results: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P = .040). Recurrence rates eval‎uated on the basis of intention to treat showed significant difference between curcumin and placebo (P = .049). Furthermore, curcumin improved both CAI (P = .038) and EI (P = .0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed. Conclusions: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

Abbreviations used in this paper

1. CAI (clinical activity index)
2. EI (endoscopic index)
3. MAPK (mitogen-activated protein kinase)
4. NF-κB (nuclear factor-κB)
5. NOS (nitric oxide synthase)
6. SZ (sulfasalazine)
7. TNBS (trinitrobenzene sulfonic acid)
8. UC (ulcerative colitis)

Ulcerative colitis (UC) is a debilitating, chronic, relapsing-remitting IBD that afflicts millions of individuals throughout the world and produces symptoms that impair quality of life and ability to function.1 Although factors like smoking cessation,2 use of nonsteroidal anti-inflammatory drugs,3 and stress4 are known to provoke an exacerbation, clinical relapses are often unpredictable.

Currently, several drugs including sulfasalazine (SZ), mesalamine, corticosteroids, immunomodulators, and remicade are used to treat patients with active IBD.5–12 However, these medications are associated with side effects that add to the disease complications when used either to induce remission or to prevent a recurrence.9–15 Furthermore, given that the majority of patients with UC (approximately 70%) have a clinical course that is either relapsing-remitting or chronic continuous, there is a need for novel safe medications to maintain remission in patients with UC in whom the disease has reverted to a quiescent state.

Curcumin is a natural substance present in turmeric, the spice that gives food an exotic yellow color. Curcumin seems to have a broad spectrum of pharmacologic actions including antitumor, anti-inflammatory, and antioxidant effects.16–20 The pleiotropic effects of curcumin are attributable in part to the inhibition of the transcriptional nuclear factor–κB (NF-κB).21–23 In line with this background, recently we demonstrated that treatment with curcumin can prevent murine experimental colitis by inhibiting N∼F-κB activation and CD4+ T-cell infiltration into the colonic mucosa.24 This study aimed to assess the efficacy of curcumin as a maintenance therapy in patients with quiescent UC.

Patients and MethodsPatients

Between April 2004–July 2005, 8 centers in Japan enrolled a total of 89 patients. The study protocol was reviewed and approved by the Committees on Ethics of clinical trials involving human subjects at each institution, and the trial was conducted in accord with the Declaration of Helsinki. Inclusion criteria were (1) patient had a diagnosis of UC as confirmed by radiologic, endoscopic, or histologic criteria that are established by the Research Committee of Inflammatory Bowel Disease, the Japan Ministry of Health; (2) age between 13–65 years; (3) patient’s UC had a clinical activity index (CAI) ≤4, stable for the previous 4 weeks; (4) patient had achieved remission with a corticosteroid ≥20 mg/day prednisolone or an alternative medication and had successfully ceased steroid therapy; and (5) patient had a hemoglobin of ≥10 g/dL. Exclusion criteria were (1) patient was receiving an immunomodulator like azathioprine, 6-mercaptopurine, or cyclosporine; (2) patients with severe cardiovascular diseases; (3) patients with laboratory abnormalities indicating anemia (hemoglobin <9 g/dL), leukopenia, thrombocytopenia, or abnormal coagulation; (4) patients with renal or liver disease, chronic pancreatitis, diabetes mellitus, or gallstone; (5) patients with infection, sepsis, or pneumonia; and (6) pregnant or nursing women. Dropout criteria were (1) patient exhibits complications during the study; (2) patient decides to withdraw from the trial at will; and (3) patient requires additional drug therapy that violates the inclusion criteria. Any adverse symptom was recorded in the diary kept by patients during the study. Laboratory investigations including a complete blood count and blood chemistry were performed 3 times, at baseline, at 3 months, and at the end of the treatment.

Methods

This study was to be a randomized, multicenter (8 hospital institutions), double-blind, and placebo-controlled clinical trial. Assignment to curcumin or placebo was according to a computer-generated randomization scheme done by the clinical pharmacist. Patients were given SZ (1.0–3.0 g/day; median, 2.0 g/day) or mesalamine (1.5–3.0 g/day; median, 2.25 g/day) plus 2 g curcumin, 1 g taken after breakfast and 1 g after the evening meal, or placebo for 6 months (Figure 1). Patients were then followed for an additional 6 months, during which either SZ or mesalamine was continued. All medications except SZ or mesalamine were discontinued 4 weeks before starting this study. All study personnel and participants were blinded to treatment assignment for the duration of the study. Only the study statisticians and the data monitoring committee could see unblinded data, but none had any contact with the study patients. Curcumin and placebo were made to have identical appearance (yellow), prepared by API Co, Ltd (Gifu, Japan). The compositions of curcumin and placebo are shown in Table 1.

Figure viewer

Figure 1 Summary of the study design, randomization, and clinical outcomes of the 6 months of treatment.

CurcuminPlacebo

Table 1

Compositions of Medications (%)

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Clinical Assessment

CAI was measured at entry (within 2 weeks before randomization), every 2 months, and then at the conclusion of the clinical trial, whereas endoscopic index (EI) was determined at entry and at the conclusion of the trial. Both CAI and EI were according to Rachmilewitz.25 Patients who had a CAI ≤4 were considered to be in clinical remission, whereas relapse was defined as CAI ≥5.

Statistical Analysis

Data are presented as the mean ± standard deviation values and ranges unless indicated otherwise. For determining statistical significance, comparisons were made by using the Fisher exact test or the χ2 test. P value <.05 was considered significant in all statistical eval‎uations.

ResultsClinical Outcomes

Seven patients (2 in the curcumin group and 5 in the placebo group) were excluded in line with patients’ wishes. Hence, 43 patients in the curcumin group and 39 patients in the placebo group completed the study. Study groups were well-matched with respect to gender, age, duration of UC, recurrences during the past 2 years, clinical course, CAI, and EI (Table 2). Recurrent rates eval‎uated in all patients (intention to treat) also showed significant differences between the curcumin and the placebo groups (P = .049, Table 3). Relapses in the 2 groups during the 6-month study period together with the follow-up data are presented in Figures 1 and 2. Of the 43 patients who received curcumin, 2 patients (4.55%) relapsed during 6 months, whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P = .040) (Table 4).

Figure viewer

Figure 2 The Kaplan-Meier curves showing the efficacy outcomes during the 6 months of therapy and 6 months of follow-up.

DemographyCurcuminPlaceboP value

Male/female	23/22	26/18	.52
Age, mean (y)	45.2±15.8	39.7±14.2	.11
Range	(18–75)	(21–68)
Duration of UC (mo)	98.6±74.2	93.5±74.2	.77
Range	(11–305)	(5–336)
No. of recurrences during past 2 y	1.6±1.2	1.5±1.0	.78
Range	(0–5)	(0–4)
Clinical course (cases)
First attack	5	4
Relapsing-remitting	29	28
Chronic continuousa	10	8	.89
CAI before study	1.3±1.1	1.0±1.1	.23
Range	(0–4)	(0–4)
EI before study	1.3±0.8	1.3±1.0	.60
Range	(0–3.0)	(0–3.6)

Table 2

Demography of Patients at Baseline

Mean ± standard deviation values and (ranges) are presented.

a

Patients with chronic continuous UC had a CAI ≤4 for at least 4 weeks before entry. “Chronic continuous” is commonly used in Japan to indicate a CAI that oscillates between fully quiescent (0–1) and clinical remission (4) in some patients.

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CurcuminPlaceboP value

Table 3

Recurrence Rates at 6 and 12 Months Based on Intention to Treat

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CurcuminPlaceboP value

Table 4

Recurrence Status at 6 Months

Analysis is based on the number of eligible patients who completed the study, excluding the 7 patients who became protocol violators during the study.

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We also determined the mean CAI and EI values before and after the treatment (Table 5). The mean CAI in the curcumin group was improved from 1.3 ± 1.1 at baseline to 1.0 ± 2.0 at 6 months (P = .038). In contrast, CAI in the placebo group showed significant deterioration; mean CAI increased from 1.0 ± 1.1 to 2.2 ± 2.3 (P = .0003). Furthermore, patients in the curcumin group had significantly improved EI, 1.3 ± 0.8 vs 0.8 ± 0.6 (P = .0001). The EI values in the placebo group showed no significant difference between baseline and post-treatment.

CurcuminPlaceboEntry6 MoEntry6 Mo

Table 5

Changes in CAI and EI During the 6 Months of Treatment

P values by the χ2 test.

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Follow-up Observations

A 6-month follow-up was done after the end of the 6-month study period. As shown in Figure 2, 8 additional patients in the curcumin group and 6 patients in the placebo group relapsed during the 6-month follow-up while being on SZ or mesalamine. There was no significant difference between the 2 groups with respect to relapse rates during the 6-month follow-up.

Safety Eval‎uation

A total of 9 mild and transient side effects in 7 of 89 patients were observed during curcumin maintenance therapy. Some patients experienced more than 1 event. The side effects included sensation of abdominal bulging, nausea, transient hypertension, transient increase in the number of stools, and elevated γ–guanosine triphosphate level. The elevated γ–guanosine triphosphate was observed in a patient who was a regular alcohol drinker. No patient discontinued curcumin therapy as a result of side effects, except 1 patient with hypertension.

Discussion

The clinical outcomes of this double-blind, placebo-controlled trial of curcumin therapy to sustain remission in patients with quiescent UC might be briefly summarized as follows: (1) 2 g/day curcumin in combination with SZ or mesalamine had significantly better clinical efficacy in the prevention of relapse compared with placebo plus SZ or mesalamine; (2) curcumin significantly improved both CAI and EI; and (3) curcumin was well-tolerated and was not associated with any serious side effect.

Most currently available conventional drugs used to treat UC are associated with unpleasant side effects. For example, nausea, vomiting, headaches, rash, fever, hepatitis, pancreatitis, nephritis, agranulocytosis, and male infertility are reported in approximately 30% of patients who take SZ.1 The sulfa moiety of the drug is known to interfere with folic acid absorption. Even the mesalamine derivatives that lack the sulfa moiety are associated with fever, diarrhea, and abdominal discomfort. In contrast, none of these side effects were observed when patients were given curcumin. Curcumin is a diferulolymethane, a natural plant product extracted from the root of Curcuma longa Linn. It is a common food additive popular for its pleasant mild aroma and exotic yellow color, not likely to cause side effects. In India and China, for centuries curcumin has been known as a medicinal plant. It is very likely that curcumin has several biochemical actions that are not yet elucidated. Recently, curcumin was reported to block the upstream of NF-κB and IκB kinase.26 NF-κB is suspected to promote the expression‎ of human IBD.26–28 Consistent with this assertion, recently we demonstrated that curcumin can suppress colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS) in a mice model of colitis.24

In the present study, only 2 of 43 patients treated with curcumin in combination with SZ or mesalamine relapsed during the 6 months of therapy, whereas 8 of 39 patients who received placebo with SZ or mesalamine relapsed during the same period. It is appropriate to mention that mesalamine alone when used as maintenance therapy during a 6-month period has an efficacy similar to that of SZ, which is equal to the placebo group in our study.29,30 In addition, in this study, we added a 6-month follow-up to the 6-month treatment time during which patients received SZ or mesalamine only. Clinical assessment at the end of the follow-up showed no significant difference between the 2 groups. This supported our impression that curcumin, in fact, does suppress relapse.

The 2-g curcumin per day in this study is similar to the dose reported to have antitumor effect.31 However, we admit that the dose of curcumin used in this study might not be the optimum and the most effective regimen. This could be viewed as one major limitation of our data. With this in mind, we believe that future studies in larger cohorts of patients should use multiple doses of curcumin, because a dose higher than 2 g/day might appear superior to 2 g/day.

Aminosalicylates have been reported to be inhibitors of NF-κB.4 However, curcumin has broader effects on the NF-κB signal transduction pathways. In addition, curcumin inhibits mitogen-activated protein kinase (MAPK),32 c-Fos, and nitric oxide synthase (NOS) activity,33 thus potentially having a broader spectrum of anti-inflammatory effects compared with aminosalicylates (not to mention its safety).

In our study, both the clinical and endoscopic eval‎uation scores were significantly improved by curcumin therapy. Especially the endoscopic score was substantially improved compared with the placebo. Nine of the curcumin-treated patients reported some mild side effects such as abdominal bloating and nausea. Because the patients were also receiving SZ or mesalamine as well, we could not with certainty attribute these complaints to curcumin. A phase I human trial with 25 subjects using up to 8 g curcumin per day found no toxicity or serious side effects related to curcumin.34 Therefore, we conclude that curcumin therapy is both effective and safe in maintaining UC remission.

In conclusion, the results of this study indicate that the turmeric component, curcumin, is potentially a promising medication for the treatment of IBD. In the near future, we plan to undertake a multiple-dose (including a high-dose) curcumin trial without an aminosalicylate as maintenance therapy in patients with quiescent UC.

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Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized, Multicenter, Double-Blind, Placebo-Controlled Trial

Hiroyuki Hanai⁎,‡ ∙ Takayuki Iida‡ ∙ Ken Takeuchi‡ ∙ … ∙ Masato Uchijima§§ ∙ Toshi Nagata§§ ∙ Yukio Koide§§ koidelb@hama-med.ac.jp … Show more

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Abstract

Background & Aims: Curcumin is a biologically active phytochemical substance present in turmeric and has pharmacologic actions that might benefit patients with ulcerative colitis (UC). The aim in this trial was to assess the efficacy of curcumin as maintenance therapy in patients with quiescent ulcerative colitis (UC). Methods: Eighty-nine patients with quiescent UC were recruited for this randomized, double-blind, multicenter trial of curcumin in the prevention of relapse. Forty-five patients received curcumin, 1g after breakfast and 1g after the evening meal, plus sulfasalazine (SZ) or mesalamine, and 44 patients received placebo plus SZ or mesalamine for 6 months. Clinical activity index (CAI) and endoscopic index (EI) were determined at entry, every 2 months (CAI), at the conclusion of 6-month trial, and at the end of 6-month follow-up. Results: Seven patients were protocol violators. Of 43 patients who received curcumin, 2 relapsed during 6 months of therapy (4.65%), whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P = .040). Recurrence rates eval‎uated on the basis of intention to treat showed significant difference between curcumin and placebo (P = .049). Furthermore, curcumin improved both CAI (P = .038) and EI (P = .0001), thus suppressing the morbidity associated with UC. A 6-month follow-up was done during which patients in both groups were on SZ or mesalamine. Eight additional patients in the curcumin group and 6 patients in the placebo group relapsed. Conclusions: Curcumin seems to be a promising and safe medication for maintaining remission in patients with quiescent UC. Further studies on curcumin should strengthen our findings.

Abbreviations used in this paper

1. CAI (clinical activity index)
2. EI (endoscopic index)
3. MAPK (mitogen-activated protein kinase)
4. NF-κB (nuclear factor-κB)
5. NOS (nitric oxide synthase)
6. SZ (sulfasalazine)
7. TNBS (trinitrobenzene sulfonic acid)
8. UC (ulcerative colitis)

Ulcerative colitis (UC) is a debilitating, chronic, relapsing-remitting IBD that afflicts millions of individuals throughout the world and produces symptoms that impair quality of life and ability to function.1 Although factors like smoking cessation,2 use of nonsteroidal anti-inflammatory drugs,3 and stress4 are known to provoke an exacerbation, clinical relapses are often unpredictable.

Currently, several drugs including sulfasalazine (SZ), mesalamine, corticosteroids, immunomodulators, and remicade are used to treat patients with active IBD.5–12 However, these medications are associated with side effects that add to the disease complications when used either to induce remission or to prevent a recurrence.9–15 Furthermore, given that the majority of patients with UC (approximately 70%) have a clinical course that is either relapsing-remitting or chronic continuous, there is a need for novel safe medications to maintain remission in patients with UC in whom the disease has reverted to a quiescent state.

Curcumin is a natural substance present in turmeric, the spice that gives food an exotic yellow color. Curcumin seems to have a broad spectrum of pharmacologic actions including antitumor, anti-inflammatory, and antioxidant effects.16–20 The pleiotropic effects of curcumin are attributable in part to the inhibition of the transcriptional nuclear factor–κB (NF-κB).21–23 In line with this background, recently we demonstrated that treatment with curcumin can prevent murine experimental colitis by inhibiting N∼F-κB activation and CD4+ T-cell infiltration into the colonic mucosa.24 This study aimed to assess the efficacy of curcumin as a maintenance therapy in patients with quiescent UC.

Patients and MethodsPatients

Between April 2004–July 2005, 8 centers in Japan enrolled a total of 89 patients. The study protocol was reviewed and approved by the Committees on Ethics of clinical trials involving human subjects at each institution, and the trial was conducted in accord with the Declaration of Helsinki. Inclusion criteria were (1) patient had a diagnosis of UC as confirmed by radiologic, endoscopic, or histologic criteria that are established by the Research Committee of Inflammatory Bowel Disease, the Japan Ministry of Health; (2) age between 13–65 years; (3) patient’s UC had a clinical activity index (CAI) ≤4, stable for the previous 4 weeks; (4) patient had achieved remission with a corticosteroid ≥20 mg/day prednisolone or an alternative medication and had successfully ceased steroid therapy; and (5) patient had a hemoglobin of ≥10 g/dL. Exclusion criteria were (1) patient was receiving an immunomodulator like azathioprine, 6-mercaptopurine, or cyclosporine; (2) patients with severe cardiovascular diseases; (3) patients with laboratory abnormalities indicating anemia (hemoglobin <9 g/dL), leukopenia, thrombocytopenia, or abnormal coagulation; (4) patients with renal or liver disease, chronic pancreatitis, diabetes mellitus, or gallstone; (5) patients with infection, sepsis, or pneumonia; and (6) pregnant or nursing women. Dropout criteria were (1) patient exhibits complications during the study; (2) patient decides to withdraw from the trial at will; and (3) patient requires additional drug therapy that violates the inclusion criteria. Any adverse symptom was recorded in the diary kept by patients during the study. Laboratory investigations including a complete blood count and blood chemistry were performed 3 times, at baseline, at 3 months, and at the end of the treatment.

Methods

This study was to be a randomized, multicenter (8 hospital institutions), double-blind, and placebo-controlled clinical trial. Assignment to curcumin or placebo was according to a computer-generated randomization scheme done by the clinical pharmacist. Patients were given SZ (1.0–3.0 g/day; median, 2.0 g/day) or mesalamine (1.5–3.0 g/day; median, 2.25 g/day) plus 2 g curcumin, 1 g taken after breakfast and 1 g after the evening meal, or placebo for 6 months (Figure 1). Patients were then followed for an additional 6 months, during which either SZ or mesalamine was continued. All medications except SZ or mesalamine were discontinued 4 weeks before starting this study. All study personnel and participants were blinded to treatment assignment for the duration of the study. Only the study statisticians and the data monitoring committee could see unblinded data, but none had any contact with the study patients. Curcumin and placebo were made to have identical appearance (yellow), prepared by API Co, Ltd (Gifu, Japan). The compositions of curcumin and placebo are shown in Table 1.

Figure viewer

Figure 1 Summary of the study design, randomization, and clinical outcomes of the 6 months of treatment.

CurcuminPlacebo

Table 1

Compositions of Medications (%)

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Clinical Assessment

CAI was measured at entry (within 2 weeks before randomization), every 2 months, and then at the conclusion of the clinical trial, whereas endoscopic index (EI) was determined at entry and at the conclusion of the trial. Both CAI and EI were according to Rachmilewitz.25 Patients who had a CAI ≤4 were considered to be in clinical remission, whereas relapse was defined as CAI ≥5.

Statistical Analysis

Data are presented as the mean ± standard deviation values and ranges unless indicated otherwise. For determining statistical significance, comparisons were made by using the Fisher exact test or the χ2 test. P value <.05 was considered significant in all statistical eval‎uations.

ResultsClinical Outcomes

Seven patients (2 in the curcumin group and 5 in the placebo group) were excluded in line with patients’ wishes. Hence, 43 patients in the curcumin group and 39 patients in the placebo group completed the study. Study groups were well-matched with respect to gender, age, duration of UC, recurrences during the past 2 years, clinical course, CAI, and EI (Table 2). Recurrent rates eval‎uated in all patients (intention to treat) also showed significant differences between the curcumin and the placebo groups (P = .049, Table 3). Relapses in the 2 groups during the 6-month study period together with the follow-up data are presented in Figures 1 and 2. Of the 43 patients who received curcumin, 2 patients (4.55%) relapsed during 6 months, whereas 8 of 39 patients (20.51%) in the placebo group relapsed (P = .040) (Table 4).

Figure viewer

Figure 2 The Kaplan-Meier curves showing the efficacy outcomes during the 6 months of therapy and 6 months of follow-up.

DemographyCurcuminPlaceboP value

Male/female	23/22	26/18	.52
Age, mean (y)	45.2±15.8	39.7±14.2	.11
Range	(18–75)	(21–68)
Duration of UC (mo)	98.6±74.2	93.5±74.2	.77
Range	(11–305)	(5–336)
No. of recurrences during past 2 y	1.6±1.2	1.5±1.0	.78
Range	(0–5)	(0–4)
Clinical course (cases)
First attack	5	4
Relapsing-remitting	29	28
Chronic continuousa	10	8	.89
CAI before study	1.3±1.1	1.0±1.1	.23
Range	(0–4)	(0–4)
EI before study	1.3±0.8	1.3±1.0	.60
Range	(0–3.0)	(0–3.6)

Table 2

Demography of Patients at Baseline

Mean ± standard deviation values and (ranges) are presented.

a

Patients with chronic continuous UC had a CAI ≤4 for at least 4 weeks before entry. “Chronic continuous” is commonly used in Japan to indicate a CAI that oscillates between fully quiescent (0–1) and clinical remission (4) in some patients.

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CurcuminPlaceboP value

Table 3

Recurrence Rates at 6 and 12 Months Based on Intention to Treat

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CurcuminPlaceboP value

Table 4

Recurrence Status at 6 Months

Analysis is based on the number of eligible patients who completed the study, excluding the 7 patients who became protocol violators during the study.

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We also determined the mean CAI and EI values before and after the treatment (Table 5). The mean CAI in the curcumin group was improved from 1.3 ± 1.1 at baseline to 1.0 ± 2.0 at 6 months (P = .038). In contrast, CAI in the placebo group showed significant deterioration; mean CAI increased from 1.0 ± 1.1 to 2.2 ± 2.3 (P = .0003). Furthermore, patients in the curcumin group had significantly improved EI, 1.3 ± 0.8 vs 0.8 ± 0.6 (P = .0001). The EI values in the placebo group showed no significant difference between baseline and post-treatment.

CurcuminPlaceboEntry6 MoEntry6 Mo

Table 5

Changes in CAI and EI During the 6 Months of Treatment

P values by the χ2 test.

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Follow-up Observations

A 6-month follow-up was done after the end of the 6-month study period. As shown in Figure 2, 8 additional patients in the curcumin group and 6 patients in the placebo group relapsed during the 6-month follow-up while being on SZ or mesalamine. There was no significant difference between the 2 groups with respect to relapse rates during the 6-month follow-up.

Safety Eval‎uation

A total of 9 mild and transient side effects in 7 of 89 patients were observed during curcumin maintenance therapy. Some patients experienced more than 1 event. The side effects included sensation of abdominal bulging, nausea, transient hypertension, transient increase in the number of stools, and elevated γ–guanosine triphosphate level. The elevated γ–guanosine triphosphate was observed in a patient who was a regular alcohol drinker. No patient discontinued curcumin therapy as a result of side effects, except 1 patient with hypertension.

Discussion

The clinical outcomes of this double-blind, placebo-controlled trial of curcumin therapy to sustain remission in patients with quiescent UC might be briefly summarized as follows: (1) 2 g/day curcumin in combination with SZ or mesalamine had significantly better clinical efficacy in the prevention of relapse compared with placebo plus SZ or mesalamine; (2) curcumin significantly improved both CAI and EI; and (3) curcumin was well-tolerated and was not associated with any serious side effect.

Most currently available conventional drugs used to treat UC are associated with unpleasant side effects. For example, nausea, vomiting, headaches, rash, fever, hepatitis, pancreatitis, nephritis, agranulocytosis, and male infertility are reported in approximately 30% of patients who take SZ.1 The sulfa moiety of the drug is known to interfere with folic acid absorption. Even the mesalamine derivatives that lack the sulfa moiety are associated with fever, diarrhea, and abdominal discomfort. In contrast, none of these side effects were observed when patients were given curcumin. Curcumin is a diferulolymethane, a natural plant product extracted from the root of Curcuma longa Linn. It is a common food additive popular for its pleasant mild aroma and exotic yellow color, not likely to cause side effects. In India and China, for centuries curcumin has been known as a medicinal plant. It is very likely that curcumin has several biochemical actions that are not yet elucidated. Recently, curcumin was reported to block the upstream of NF-κB and IκB kinase.26 NF-κB is suspected to promote the expression‎ of human IBD.26–28 Consistent with this assertion, recently we demonstrated that curcumin can suppress colonic inflammation induced by trinitrobenzene sulfonic acid (TNBS) in a mice model of colitis.24

In the present study, only 2 of 43 patients treated with curcumin in combination with SZ or mesalamine relapsed during the 6 months of therapy, whereas 8 of 39 patients who received placebo with SZ or mesalamine relapsed during the same period. It is appropriate to mention that mesalamine alone when used as maintenance therapy during a 6-month period has an efficacy similar to that of SZ, which is equal to the placebo group in our study.29,30 In addition, in this study, we added a 6-month follow-up to the 6-month treatment time during which patients received SZ or mesalamine only. Clinical assessment at the end of the follow-up showed no significant difference between the 2 groups. This supported our impression that curcumin, in fact, does suppress relapse.

The 2-g curcumin per day in this study is similar to the dose reported to have antitumor effect.31 However, we admit that the dose of curcumin used in this study might not be the optimum and the most effective regimen. This could be viewed as one major limitation of our data. With this in mind, we believe that future studies in larger cohorts of patients should use multiple doses of curcumin, because a dose higher than 2 g/day might appear superior to 2 g/day.

Aminosalicylates have been reported to be inhibitors of NF-κB.4 However, curcumin has broader effects on the NF-κB signal transduction pathways. In addition, curcumin inhibits mitogen-activated protein kinase (MAPK),32 c-Fos, and nitric oxide synthase (NOS) activity,33 thus potentially having a broader spectrum of anti-inflammatory effects compared with aminosalicylates (not to mention its safety).

In our study, both the clinical and endoscopic eval‎uation scores were significantly improved by curcumin therapy. Especially the endoscopic score was substantially improved compared with the placebo. Nine of the curcumin-treated patients reported some mild side effects such as abdominal bloating and nausea. Because the patients were also receiving SZ or mesalamine as well, we could not with certainty attribute these complaints to curcumin. A phase I human trial with 25 subjects using up to 8 g curcumin per day found no toxicity or serious side effects related to curcumin.34 Therefore, we conclude that curcumin therapy is both effective and safe in maintaining UC remission.

In conclusion, the results of this study indicate that the turmeric component, curcumin, is potentially a promising medication for the treatment of IBD. In the near future, we plan to undertake a multiple-dose (including a high-dose) curcumin trial without an aminosalicylate as maintenance therapy in patients with quiescent UC.

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