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

  • Hamamatsu South Hoapital, Hamamatsu, Japan

Abstract and Figures

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). 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. 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. 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.
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Curcumin Maintenance Therapy for Ulcerative Colitis: Randomized,
Multicenter, Double-Blind, Placebo-Controlled Trial
*Department of Endoscopic and Photodynamic Medicine and
Department of Microbiology and Immunology, Hamamatsu University School of Medicine,
Center for Gastroenterology, Hamamatsu South Hospital, Hamamatsu;
Department of Gastroenterology, Fujieda Municipal General Hospital,
Department of Internal Medicine, Shiga University of Medical Science, Shiga;
Second Department of Medicine, Kurume University School of Medicine,
Department of Gastroenterology, Hamamatsu Medical Center, Hamamatsu; **Department of Gastroenterology, Dokkyo University School of Medicine,
Department of Surgery, Hamamatsu Social Insurance Hospital, Hamamatsu; and
Hamamatsu Mikatahara Seirei Hospital, Hamamatsu, Japan
Background & Aims: Curcumin is a biologically active
phytochemical substance present in turmeric and has pharma-
cologic actions that might benefit patients with ulcerative co-
litis (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 conclu-
sion 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 addi-
tional 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.
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.
Although factors like
smoking cessation,
use of nonsteroidal anti-inflammatory
and stress
are known to provoke an exacerbation,
clinical relapses are often unpredictable.
Currently, several drugs including sulfasalazine (SZ), me-
salamine, corticosteroids, immunomodulators, and remicade
are used to treat patients with active IBD.
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.
Furthermore, given that the major-
ity 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.
The pleiotropic effects of curcumin are attributable in part
to the inhibition of the transcriptional nuclear factor–
In line with this background, recently we demon-
strated that treatment with curcumin can prevent murine ex-
perimental colitis by inhibiting N
B activation and CD4
T-cell infiltration into the colonic mucosa.
This study aimed
to assess the efficacy of curcumin as a maintenance therapy in
patients with quiescent UC.
Patients and Methods
Between April 2004–July 2005, 8 centers in Japan en-
rolled 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 med-
ication 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 aza-
Abbreviations used in this paper: CAI, clinical activity index; EI,
endoscopic index; MAPK, mitogen-activated protein kinase; NF-B,
nuclear factor-B; NOS, nitric oxide synthase; SZ, sulfasalazine; TNBS,
trinitrobenzene sulfonic acid; UC, ulcerative colitis.
©2006 by the AGA Institute
thioprine, 6-mercaptopurine, or cyclosporine; (2) patients with
severe cardiovascular diseases; (3) patients with laboratory ab-
normalities indicating anemia (hemoglobin 9 g/dL), leukope-
nia, thrombocytopenia, or abnormal coagulation; (4) patients
with renal or liver disease, chronic pancreatitis, diabetes melli-
tus, or gallstone; (5) patients with infection, sepsis, or pneumo-
nia; 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.
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; me-
dian, 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.
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.
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
2test. Pvalue .05 was considered
significant in all statistical evaluations.
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
Figure 1. Summary of the study design, randomization, and clinical
outcomes of the 6 months of treatment.
Table 1. Compositions of Medications (%)
Curcumin Placebo
Curcumin 50.0 Microcrystalline cellulose 25.0
42.5 Dextrin 29.6
Malitol 7.5 Cornstarch 10.0
Malitol 35.0
FD & C Yellow No. 5 0.15
FD & C Yellow No. 6 0.04
Caramel color 0.2
Total 100 100
Table 2. Demography of Patients at Baseline
Demography Curcumin Placebo Pvalue
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 continuousa10 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)
Mean standard deviation values and (ranges) are presented.
aPatients 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.
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).
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-
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
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
guanosine triphosphate level. The elevated
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 hyper-
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 me-
salamine had significantly better clinical efficacy in the preven-
tion 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, nephri-
tis, agranulocytosis, and male infertility are reported in approx-
imately 30% of patients who take SZ.
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
Table 4. Recurrence Status at 6 Months
Curcumin Placebo Pvalue
No. of patients treated 43 39
No. of patients with
% with recurrence 4.65 20.51 .040
95% confidence interval 0.56–15.47 9.30–36.46
Analysis is based on the number of eligible patients who completed
the study, excluding the 7 patients who became protocol violators
during the study.
Table 3. Recurrence Rates at 6 and 12 Months Based on
Intention to Treat
Curcumin Placebo Pvalue
No. of patients randomized 45 44
No. of patients with
recurrence at 6 mo
% with recurrence at 6 mo 4.44 15.15 .049
95% confidence interval (%) 0.54–15.15 8.19–32.71
No. of patients with
recurrence at 12 mo
10 14
% with recurrence at 12 mo 22.2 31.8 .433
95% confidence interval (%) 11.2–37.1 18.6–47.6
Figure 2. The Kaplan-Meier curves showing the efficacy outcomes during the 6 months of therapy and 6 months of follow-up.
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 medic-
inal 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-
B and I
B kinase.
B is suspected to promote the expression of human
Consistent with this assertion, recently we demon-
strated that curcumin can suppress colonic inflammation in-
duced by trinitrobenzene sulfonic acid (TNBS) in a mice model
of colitis.
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.
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.
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
However, curcumin has broader effects on the NF-
signal transduction pathways. In addition, curcumin inhibits
mitogen-activated protein kinase (MAPK),
c-Fos, and nitric
oxide synthase (NOS) activity,
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. Espe-
cially the endoscopic score was substantially improved com-
pared 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 me-
salamine 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.
Therefore, we conclude that
curcumin therapy is both effective and safe in maintaining UC
In conclusion, the results of this study indicate that the
turmeric component, curcumin, is potentially a promising med-
ication 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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Entry 6 Mo Entry 6 Mo
CAI 1.3 1.1 1.0 2.0 1.0 1.1 2.2 2.3
Pvalue .038 .0003
EI 1.3 0.8 0.8 0.6 1.3 1.0 1.6 1.6
Pvalue .0001 .0728
Pvalues by the 2test.
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Address requests for reprints to: Yukio Koide, MD, PhD, Department
of Microbiology and Immunology, Hamamatsu University School of
Medicine, 1-20-1 Handayama, Hamamatsu 431-3192, Japan. e-mail:; fax: 81-53-435-2335.
Supported by the Broad Medical Research Program (IBD-0069) from
The Eli and Edythe L. Broad Foundation.
... Analysis showed that curcumin acted by inhibiting the hydrolysis of SREBP-2 precursor protein to modulate the expression of NPC1L1 in cells of the small intestine. Hanai et al. (Hanai et al., 2006) evaluated the therapeutic effect of curcumin on ulcerative colitis (UC) in clinical trials and found that curcumin combined with mesalamine had significantly better clinical efficacy than placebo + mesalamine in preventing recurrence, significantly relieving the clinical symptoms of UC and reducing the recurrence rate. Sugimoto et al. (Sugimoto et al., 2002) investigated the effect and mechanism of curcumin on a trinitrobenzene sulfonic acid-induced mouse model of colitis; 0.5%, 2.0%, and 5.0% curcumin was added to the feed of mice in the curcumin intervention group. ...
... Significant improvement in clinical activity index (CAI) and endoscopic index (EI) Hanai et al. (2006) curcumin Mouse colitis model (7-8 week old male C57BL/ 6 and BALB/c mice, 21-23 g) ...
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... Indeed, even high doses (up to 12 g/day) are well tolerated, and only minor side effects have been reported, for example, diarrhea. Hanai et al. [184] reported that the most common side effects of curcumin were related to gastrointestinal problems, such as nausea and the sensation of abdominal distension; they were usually mild and transient, and no subjects in the studies dropped out because curcumin's side effects [185,186]. Other side effects include temporary tongue staining and a mild yellowish discoloration of the teeth that disappeared with brushing [187,188]. ...
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The growing popularity of the use of nutraceuticals in the prevention and alleviation of symptoms of many diseases in humans and dogs means that they are increasingly the subject of research. A representative of the nutraceutical that deserves special attention is turmeric. Turmeric belongs to the family Zingiberaceae and is grown extensively in Asia. It is a plant used as a spice and food coloring, and it is also used in traditional medicine. The biologically active factors that give turmeric its unusual properties and color are curcuminoids. It is a group of substances that includes curcumin, de-methoxycurcumin, and bis-demethoxycurcumin. Curcumin is used as a yellow-orange food coloring. The most important pro-health effects observed after taking curcuminoids include anti-inflammatory, anticancer, and antioxidant effects. The aim of this study was to characterize turmeric and its main substance, curcumin, in terms of their properties, advantages, and disadvantages, based on literature data.
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Introducción: la colitis ulcerativa pediátrica (CUP), la enfermedad de Crohn pediátrica (ECP) y la enfermedad inflamatoria intestinal pediátrica no clasificable (EIIPNC) tienen particularidades clínicas y psicosociales que las diferencian de las del adulto y pueden condicionar enfoques terapéuticos distintos por las posibles repercusiones nutricionales, crecimiento y desarrollo, lo que representa un desafío para el pediatra y el gastroenterólogo. Objetivo: desarrollar recomendaciones basadas en la evidencia por consenso de expertos para el diagnóstico y el tratamiento oportunos y seguros de la enfermedad inflamatoria intestinal pediátrica (EIIP) en menores de 18 años, para los profesionales que atienden estos pacientes y los pagadores en salud. Metodología: a través de un panel de expertos del Colegio Colombiano de Gastroenterología, Hepatología y Nutrición Pediátrica (COLGAHNP) y un grupo multidisciplinario se formularon 35 preguntas en relación con el cuadro clínico, el diagnóstico y el tratamiento de la EIIP. A través de una revisión y un análisis crítico de la literatura, con especial énfasis en las principales guías de práctica clínica (GPC), estudios clínicos aleatorizados (ECA) y metaanálisis de los últimos 10 años, los expertos plantearon 77 recomendaciones que respondían a cada una de las preguntas de investigación con sus respectivos puntos prácticos. Posteriormente, cada una de las afirmaciones se sometieron a votación dentro del grupo desarrollador, incluyendo las afirmaciones que alcanzaron > 80 %. Resultados: todas las afirmaciones alcanzaron una votación > 80 %. La EIIP tiene mayor extensión, severidad y evolución hacia la estenosis, enfermedad perianal, manifestaciones extraintestinales y retraso en el crecimiento en comparación con los pacientes adultos, por lo que su manejo debe ser realizado por grupos multidisciplinarios liderados por gastroenterólogos pediatras y prepararlos para una transición a la edad adulta. Los criterios de Porto permiten una clasificación práctica de la EIIP. En la ECP, debemos usar la clasificación de París y debemos realizar ileocolonoscopia y esofagogastroduodenoscopia, ya que el 50 % tienen un compromiso superior, usando el SES-CD (UCEIS/Mayo en CUP) y tomando múltiples biopsias. Los laboratorios iniciales deben incluir marcadores de inflamación, calprotectina fecal y descartar infecciones intestinales. El tratamiento, la inducción y el mantenimiento de la EIIP deben ser individualizados y decididos según la estratificación de riesgo. En el seguimiento se debe usar el Pediatric Crohn Disease Activity Index (PCDAI) y Pediatric Ulcerative Colitis Activity Index (PUCAI) de las últimas 48 horas. Los pacientes con EIIP temprana e infantil, deben ser valorados por inmunólogos y genetistas. Conclusión: se proporciona una guía de consenso con recomendaciones basadas en la evidencia sobre el diagnóstico y los tratamientos oportunos y seguros en los pacientes con EIIP.
Introduction: Acute gastrointestinal cramping pain (GICP) is a debilitating condition that affects many people worldwide, significantly reducing their quality of life. As such, prompt treatment is crucial. Areas covered: This article will explore relevant literature from databases such as PubMed, Scopus, Google Scholar, Cochrane Library, and Web of Science. Additionally, we searched and the WHO ICTRP database for the latest clinical trials. Expert opinion: Consensus dictates that antispasmodics such as hyoscine-N-butyl bromide and mebeverine should be the primary treatment for GICP. If these prove ineffective, patients can switch to an antispasmodic with a different mode of action or add acetaminophen/NSAIDs for more severe cases. Currently, several antispasmodics are undergoing clinical trials, including drotaverine, alverine, pinaverium, otilonium bromide, fenoverine, tiropramide, otilonium bromide, trimebutine, and peppermint oil. Well-designed head-to-head studies are necessary to evaluate current antispasmodics' safety, efficacy, pharmacokinetic, and pharmacoeconomics profiles. Recent studies have shown that fixed-dose combinations of antispasmodics + NSAIDs or two different antispasmodics can improve patient compliance and synergistically reduce GICP. Therefore, it is recommended that the global availability and accessibility of these products be enhanced.
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Inflammatory bowel disease (IBD) is a chronic and progressive inflammatory disorder affecting the gastrointestinal tract (GT) caused by a wide range of genetic, microbial, and environmental factors. IBD is characterized by chronic inflammation and decreased gut microbial diversity, dysbiosis, with a lower number of beneficial bacteria and a concomitant increase in pathogenic species. It is well known that dysbiosis is closely related to the induction of inflammation and oxidative stress, the latter caused by an imbalance between reactive oxygen species (ROS) production and cellular antioxidant capacity, leading to cellular ROS accumulation. ROS are responsible for intestinal epithelium oxidative damage and the increased intestinal permeability found in IBD patients, and their reduction could represent a potential therapeutic strategy to limit IBD progression and alleviate its symptoms. Recent evidence has highlighted that dietary polyphenols, the natural antioxidants, can maintain redox equilibrium in the GT, preventing gut dysbiosis, intestinal epithelium damage, and radical inflammatory responses. Here, we suggest that the relatively new foodomics approaches, together with new technologies for promoting the antioxidative properties of dietary polyphenols, including novel delivery systems, chemical modifications, and combination strategies, may provide critical insights to determine the clinical value of polyphenols for IBD therapy and a comprehensive perspective for implementing natural antioxidants as potential IBD candidate treatment.
Curcumin is frequently used to treat inflammatory conditions such as ulcerative colitis (UC), characterized by irritation and ulceration within the intestinal colon. Nevertheless, its limited solubility in aqueous solutions and challenges in terms of bioavailability often impact the efficacy of treatments. UC is known to have multifactorial pathogenesis, with genetic, infectious, immunological, and dietary factors contributing to its occurrence. Its manifestations include bloody diarrhea, cramps, and abdominal tenderness. The objective of this study was to conduct an exploratory and qualitative literature review concerning the utilization of curcumin for managing UC. Upon analyzing the gathered literature, it becomes evident that curcumin exhibits exceptional anti-inflammatory properties. Notably, the most favorable outcomes are observed when employing nanostructured curcumin, which enhances permeability, bioavailability, and aqueous solubility. In cases of UC, the pronounced inflammatory processes can even result in the development of neoplasms. In the reviewed studies on colitis, curcumin proves to be a therapeutic option by reducing the inflammatory process. Moreover, when combined with medications used for colitis treatment, curcumin enhances the effects of these drugs, making them more effective than when used alone to treat this disease.
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Transcription factors of the nuclear factor kappaB (NF-kappaB) family play an important role in the regulation of genes involved in inflammation. In inflammatory bowel diseases, proinflammatory cytokines known to be regulated by NF-kappaB are involved. The aim of this study was to investigate the role of NF-kappaB activation during mucosal inflammation in situ. A monoclonal antibody, alpha-p65mAb, was applied for immunofluorescence and immunohistochemical analysis that recognizes activated NF-kappaB. Electrophoretic mobility shift assay was used to directly demonstrate the presence of active DNA-binding NF-kappaB. Using the alpha-p65mAb antibody, activated NF-kappaB could be found in biopsy specimens from inflamed mucosa but was almost absent in uninflamed mucosa. The number of cells showing NF-kappaB activation correlated with the degree of mucosal inflammation but was not significantly different between inflamed mucosa from patients with Crohn's disease, ulcerative colitis, and nonspecific colitis or diverticulitis. NF-kappaB activation was localized in macrophages and in epithelial cells as identified by double-labeling techniques. Electrophoretic mobility shift assay with isolated lamina propria mononuclear cells and epithelial cells confirmed these results. This study shows for the first time the activation of NF-kappaB during human mucosal inflammation in situ. In addition to macrophages, epithelial cells contained activated NF-kappaB, indicating an involvement in the inflammatory process.
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When activated, NF-κB, a ubiquitous transcription factor, binds DNA as a heterodimeric complex composed of members of the Rel/NF-κB family of polypeptides. Because of its intimate involvement in host defense against disease, this transcription factor is an important target for therapeutic intervention. In the present report we demonstrate that curcumin (diferuloylmethane), a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-κB activation. Treatment of human myeloid ML-1a cells with tumor necrosis factor (TNF) rapidly activated NF-κB, which consists of p50 and p65 subunits, and this activation was inhibited by curcumin. AP-1 binding factors were also found to be down-modulated by curcumin, whereas the Sp1 binding factor was unaffected. Besides TNF, curcumin also blocked phorbol ester- and hydrogen peroxide-mediated activation of NF-κB. The TNF-dependent phosphorylation and degradation of IκBα was not observed in curcumin-treated cells; the translocation of p65 subunit to the nucleus was inhibited at the same time. The mechanism of action of curcumin was found to be different from that of protein tyrosine phosphatase inhibitors. Our results indicate that curcumin inhibits NF-κB activation pathway at a step before IκBα phosphorylation but after the convergence of various stimuli.
OBJECTIVES:The salicylate mesalazine is commonly used for the treatment of inflammatory bowel diseases, yet its precise mechanism of action is unknown. Because transcription factor NF-κB plays an important role in inflammatory bowel diseases, we investigated the effects of mesalazine therapy on NF-κB activation in patients with ulcerative colitis.METHODS:A total of 20 patients with moderately active ulcerative colitis received mesalazine for 8 wk. Biopsies were taken before and after drug administration and analyzed for NF-κB activation using an antibody specific for active NF-κB.RESULTS:In biopsies of active ulcerative colitis but not in noninflamed mucosa, activation of NF-κB was detected predominantly in macrophages. Mesalazine therapy resulted in a strong abrogation of NF-κB activation in situ.CONCLUSIONS:Our results suggest that the therapeutic properties of mesalazine rely at least in part on the inhibition of NF-κB activation, resulting in the suppression of proinflammatory gene expression in the inflamed mucosa.
Background & Aims: Activation of NF-κB/Rel has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Various drugs used in the treatment of IBD, such as glucocorticoids, 5-aminosalicylic acid, and sulfasalazine, interfere with NF-κB/Rel signaling. The aim of this study was to define the molecular mechanism by which sulfasalazine inhibits NF-κB activation. Methods: The effects of sulfasalazine and its moieties on NF-κB signaling were evaluated using electromobility shift, transfection, and immune complex kinase assays. The direct effect of sulfasalazine on IκB kinase (IKK) activity was investigated using purified recombinant IKK-α and -β proteins. Results: NF-κB/Rel activity induced by tumor necrosis factor α, 12-O-tetradecanoylphorbol-13-acetate, or overexpression of NF-κB–inducing kinase, IKK-α, IKK-β, or constitutively active IKK-α and IKK-β mutants was inhibited dose dependently by sulfasalazine. Sulfasalazine inhibited tumor necrosis factor α–induced activation of endogenous IKK in Jurkat T cells and SW620 colon cells, as well as the catalytic activity of purified IKK-α and IKK-β in vitro. In contrast, the moieties of sulfasalazine, 5-aminosalicylic acid, and sulfapyridine or 4-aminosalicylic acid had no effect. Activation of extracellular signal-related kinase (ERK) 1 and 2, c-Jun-N-terminal kinase (JNK) 1, and p38 was unaffected by sulfasalazine. The decrease in substrate phosphorylation by IKK-α and -β is associated with a decrease in autophosphorylation of IKKs and can be antagonized by excess adenosine triphosphate. Conclusions: These data identify sulfasalazine as a direct inhibitor of IKK-α and -β by antagonizing adenosine triphosphate binding. The suppression of NF-κB activation by inhibition of the IKKs contributes to the well-known anti-inflammatory and immunosuppressive effects of sulfasalazine.GASTROENTEROLOGY 2000;119:1209-1218
It is clear that sulfasalazine plays a major role in the medical therapy of ulcerative colitis and Crohn's disease. In ulcerative colitis, continued sulfasalazine therapy prevents relapses. It is also apparent that this medication can cause a varied spectrum of adverse effects in 10–45% of the people who are dependent upon it. From this review, we know that the toxic manifestations of sulfasalazine can involve almost any organ system, and more recently described side effects related to the medication such as male infertility are just being recognized. Awareness of the wide spectra of adverse effects of sulfasalazine and prompt appropriate measures might allow the patients to avoid major complications and obtain continued benefit from the drug. Although in some cases this may entail discontinuing the medication permanently, most often side effects can be remedied by temporary discontinuation of the drug and then reintroducing the drug very slowly up to a maintenance level not to exceed 2 g/day. A knowledge of the adverse effects of sulfasalazine as well as the indications for its use will allow physicians to provide better care for patients with inflammatory bowel disease.
Levels of various serum proteins were found to change in adjuvant induced arthritis. Increased levels of a glycoprotein with an apparent molecular weight of 72 kDa (Gp A72) were observed in the sera of arthritic rats. Gp A72 is an acidic glycoprotein with a pI of 5.1. Gp A72 also showed antitryptic activity. The appearance of Gp A72 in the serum preceded the onset of paw inflammation in arthritic rats and persisted in the chronic phase. Oral administration of the antiinflammatory spice principles-capsaicin (from red pepper) and curcumin (from turmeric) lowered the levels of Gp A72 by 88 and 73% respectively with concomitant lowering of paw inflammation in arthritic rats.
We have studied the effect of curcumin (diferuloylmethane), a major component of the food flavor turmeric, on the proliferation and cell cycle progression of human umbilical vein endothelial cells (HUVEC). Curcumin inhibited the DNA synthesis of HUVEC as revealed by [3H]thymidine incorporation in a dose-dependent manner without significantly affecting the viability of the cells. The growth of HUVEC stimulated with fibroblast growth factor (FGF) and endothelial growth supplement (ECGS) was also inhibited by curcumin. Addition of curcumin to HUVEC resulted in an accumulation of >46% of the cells in early S-phase, as determined by the FACS analysis. Pulse labeling studies with [3H]thymidine demonstrated that curcumin affected cells that were actively undergoing DNA synthesis. The de-novo synthesis of thymidine depends on thymidine kinase (TK) enzyme. Curcumin caused a significant loss of TK activity, which may be one of the possible mechanism(s) for the inhibition of DNA synthesis activity of HUVEC by curcumin. These studies have revealed a unique mode of action of curcumin whereby it effectively blocked the cell cycle progression during S-phase by inhibiting the activity of TK enzyme. The migration, proliferation and differentiation of HUVEC leads to angiogenesis, which facilitates the tumor initiation and promotion. Since curcumin inhibited the proliferation of HUVEC, it could turn out to be a very useful compound for the development of novel anti-cancer therapy.
Recruitment of leukocytes by endothelial cells and their subsequent migration from the vasculature into the tissue play major roles in inflammation. In the present study, we investigated the effect of curcumin, an antiinflammatory agent, on the adhesion of monocytes to human umbilical vein endothelial cells (EC). Treatment of EC with tumor necrosis factor (TNF) for 6 hr augmented the adhesion of monocytes to EC, and this adhesion was due to increased expression of intracellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (ELAM-1). Pretreatment of EC for 1 hr with curcumin completely blocked their adhesion to monocytes, as well as the cell surface expression of ICAM-1, VCAM-1, and ELAM-1 in EC. Although curcumin inhibited adhesion even when administered 1 hr after TNF treatment, maximum inhibition occurred when added either 1 hr before or at the same time as TNF. As the induction of various adhesion molecules by TNF requires activation of the transcription factor NF-κB, the effect of curcumin on the activation of this factor in the EC was also investigated. A 30-min treatment with TNF activated NF-κB; the activation was inhibited in a concentration-dependent manner by pretreatment with curcumin, indicating that NF-κB inhibition may play a role in the suppression of expression of adhesion molecules in EC. Our results demonstrate that the antiinflammatory properties of curcumin may be attributable, in part, to inhibition of leukocyte recruitment.