New Approaches in the Treatment of Inflammatory
Bowel Disease
Roshni
Solanki*, Dhaval Madat, Khushbu Chauhan and Lalkrushn Parmar
Dept. of Pharmacology, Faculty of Pharmacy,
DDU, Nadiad-387001.
ABSTRACT:
Inflammatory
bowel disease (IBD) commonly refers to ulcerative colitis (UC) and Crohn
disease (CD), which are chronic inflammatory diseases of the GI tract of
unknown etiology. This
inflammatory response is most likely made possible by defects in both the
mucosal immune system and the barrier function of the intestinal epithelium.
Many conventional treatments are used to inhibit inflammation and suppress the
immunological response like 5-amino salicylic acid, Corticosteroids,
antibiotics etc. Recently biological therapy involving specific molecular
players which are specialized proteins interfering with the body's inflammatory
response are targeted for treatment of IBD Promising targets include tumor
necrosis factor TNF-alpha, interleukins, adhesion molecules, colony-stimulating
factors, and others. Elevation of cAMP by PDE4 inhibition and selective COX-2
inhibition is a new option to treat inflammatory bowel disease.
KEYWORDS: Inflammatory bowel disease, TNF-alpha.
INTRODUCTION
Inflammatory bowel disease is a chronic
inflammatory disease of gastrointestinal tract. It comprises the two
conditions, Crohn's disease and ulcerative colitis, characterized by chronic recurrent
ulceration of the bowel and of unknown etiology. The pathogenesis likely
involves genetic, environmental, and immunologic factors.1
UC is a condition in which the inflammatory
response and morphologic changes remain confined to the colon. The rectum is
involved in 95% of patients, with variable degrees of proximal extension. Inflammation
is limited primarily to the mucosa and consists of continuous involvement of
variable severity with ulceration, edema, and hemorrhage along the length of
the colon. The characteristic histological findings are acute and chronic
inflammation of the mucosa by polymorphonuclear leukocytes and mononuclear
cells, crypt abscesses, distortion of the mucosal glands, and goblet
cell depletion.2
Crohn’s disease:
CD in contrast to UC, can involve any part of the
gastrointestinal tract from the oropharynx to the perennial area.
Diseased segments frequently are separated by intervening normal
bowel, leading to the term "skip areas." Inflammation can
be transmural, often extending through to the serosa, resulting in
sinus tracts or fistula formation. Histologic findings include small
superficial ulcerations over a Peyer’s patch (aphthoid ulcer) and
focal chronic inflammation extending to the submucosa, sometimes accompanied
by noncaseating granuloma formation.
The most common location is the ileocecal
region, followed by the terminal ileum alone, diffuse small bowel,
or isolated colonic disease in decreasing order of frequency.2
Incidence and Prevalence:
The annual incidence of ulcerative
colitis and Crohn's disease ranges from 1 to 10 cases per 100,000 people
annually depending on the region studied.3-4 The peak age-specific incidence
occurs near 20 years of age, and a second, smaller peak occurs near age 50.
The prevalence of ulcerative
colitis and Crohn's disease ranges from 10 to 70 per 100,000 people, but recent
studies in Manitoba, Canada, and Rochester,
have shown prevalence as high as 200 per 100,000 people.5,6 In the United States, males
and females are equally affected.
At present no direct therapy is
available for the treatment of IBD, here some of factors are focused to be
target as a novel therapy for the IBD.
At the present time, there are five basic
categories of medications used in the treatment of IBD
Biologic therapies represent a new class of drugs. These genetically engineered medications are
made from living organisms and their products, such as proteins, genes, and
antibodies. Biologics interfere with the body's inflammatory response in IBD by
targeting specific molecular players in the process such as cytokines—specialized
proteins that play a role in increasing or decreasing inflammation. Promising
targets include tumor necrosis factor (TNF)-alpha, interleukins, adhesion
molecules, colony-stimulating factors, and others.
Biologic therapies offer a distinct advantage in IBD treatment. Their mechanism
of action is targeted. Unlike corticosteroids, which tend to suppress the
entire immune system and thereby produce major side effects, biologic agents
act selectively. Therapies are targeted to particular enzymes and
proteins that have already been proven defective, deficient, or excessive in
people with IBD and in animal models of colitis.
Within the last decade, a class of biologics
known as anti-TNF was introduced for use in Crohn's disease. More
recently, anti-TNF has been used in ulcerative colitis. These drugs
suppress part of the immune system by binding to and inactivating tumor
necrosis factor alpha (TNF-alpha). TNF-alpha is a cytokine, a specialized
protein that promotes inflammation in the intestine in other organs and
tissues.
Infliximab (Remicade®) is the first FDA-approved biologic therapy
for Crohn's disease and fistulizing Crohn's disease, as well as
for ulcerative colitis. It is given as a drip via intravenous
infusion. It is used for people with moderately-to-severely active
disease who have not responded well to other therapies.
Adalimumab (Humira®) was recently approved for use in
Crohn's disease. It binds to and inactivates tumor necrosis factor
alpha. It is given by injection. It is used for people with
moderately to severely active disease who have not responded well to other
therapies, and who have lost response or are unable to tolerate
infliximab.
Another anti-TNF, Certolizumab pegol
(currently known as Cimzia®), is currently being investigated for people
with Crohn's disease.
(b)Adhesion
Molecule Inhibitors:
A recent development in biologic therapy is
the development of adhesion molecule inhibitors. Their mechanism of
action is different from the anti-TNF agents. Adhesion molecule
inhibitors work by binding to particular cells in the bloodstream that are
key players in inflammation. Natalizumab (currently known as Tysabri®),
already approved for multiple sclerosis, is one such therapy currently
under investigation for the treatment of Crohn's disease.
Side
Effects:
The most common side effects with the
anti-TNF agents include infusion or injection site reactions (redness,
swelling, itching, bruising, rash), upper respiratory infections, headaches,
rash, and nausea.
v There have been some reports of serious
infections associated with anti-TNF agent use, including tuberculosis
(TB) and sepsis, a life-threatening blood infection. You should always have a
TB skin test before you use infliximab or adalimumab as the drug can increase
the risk of active TB for those who have been exposed. It's not that you will
"catch" TB when taking infliximab, but if you have latent (inactive)
TB, the drug can reactivate the infection. In this case, your doctor should
begin TB treatment before you start these medications. The same precaution
should be taken before beginning treatment with corticosteroids.
v Infliximab or adalimumab may reduce the
body's ability to fight other infections as well. If you are prone to
infections or develop any signs of infection while taking these drugs such
as fever, fatigue, cough, or the flu, inform your doctor immediately.
v It may be inadvisable for people with heart
failure to take anti-TNF agents, so tell your doctor if you have any heart
condition before starting this medication. Inform your doctor at once if you
develop new or worsening symptoms of heart failure—namely shortness of breath
or swelling of the ankles or feet.
Table: 1 Medications used in
the treatment of IBD
|
Medication |
Colon activity |
Small-bowel activity |
Dosage range |
Relative side effect risk |
|
Prednisone (generic) |
+++ |
+++ |
10 to 50 mg per day |
Very high |
|
Corticosteroid enema(Cortenema) |
+++ |
|
One enema (100 mg) per day |
Low (but avoid long-term use) |
|
Mercaptopurine (Purinethol) |
+++ |
+++ |
50 to 100 mg per day |
High |
|
Methotrexate (Rheumatrex) |
+++ |
+++ |
15 to 25 mg per week |
High |
|
5-Acetylsalicylic
acid compounds |
||||
|
Sulfasalazine (Azulfidine) |
+++ |
+ |
2 to 4 g per day |
Intermediate |
|
Olsalazine (Dipentum) |
+++ |
+ |
1 to 3 g per day |
Low to intermediate |
|
Mesalamine (Pentasa) |
++ |
++ |
2 to 4 g per day |
Low |
|
Mesalamine (Asacol) |
+++ |
+ |
1.6 to 4.8 g per day |
Low |
|
Mesalamine enema (Rowasa) |
+++ |
|
4 g per day |
Very low |
|
Metronidazole (generic) |
++ |
++ |
750 to 1,500 mg per day |
Intermediate |
Table: 2 Herbal agents used for treatment of IBD.
|
Mucilaginous herbs |
Astringents(antibacterial,
anti-viral and anti-inflammatory) |
Demulcents |
Mucosal tonics and
regeneratives |
|
Chamomilla recutita (Chamomile) |
Agrimonia eupatoria (Agrimony) |
Symphytum off. (Comfrey) |
Gotu kola (Centella asiatica) |
|
Calendula officinalis (Marigold) |
Quercus alba / rubra (White / Red Oak) |
Althea off. (Marshmallow) |
Plantain (Plantago lanceolata / major) |
|
Salix nigra/alba (Black/White Willow) |
Geranium maculatum (Cranesbill) |
Ulmus fulvus (Slippery Elm) |
Goldenseal (Hydrastis canadensis) |
|
Filipendula ulmaris (Meadowsweet) |
Geranium robertianum (Herb robert) |
|
|
|
Dioscorea villosa (Wild Yam) |
Potentilla spp. (Tormentil) |
|
|
|
Glycyrrhiza glabra (Licorice) |
Capsella bursa-pastoris (Shepherd’s Purse) |
|
|
|
Harpagophytum procumbens (Devil’s Claw) |
Rubus ideaus (Red raspberry) |
|
|
|
Althea officinalis (Marshmallow) |
Geum urbanum (Avens) |
|
|
|
|
Curcuma longa (Turmeric) |
|
|
v On rare occasions, blood disorders have been
noted with anti-TNF agents. Inform your doctor if you develop possible signs
such as persistent fever, bruising, bleeding, or paleness while taking
infliximab or adalimumab. Nervous system disorders also have been reported
occasionally. Let your doctor know if you have or have had a disease that
affects the nervous system, or if you experience any numbness, weakness,
tingling, or visual disturbances while taking these medications.
v Although reports of lymphoma (a cancer of
the lymphatic system) in patients taking anti-TNF agents are rare, they do
occur more often than in the general population.
Surgical Treatment:8
Ø There are different approaches to the
surgical management of CD and UC. Because UC only involves the rectum and
colon, proctocolectomy is curative. In UC, there are 2 primary reasons for
colectomy: malignancy (or dysplasia) and disease that is not controlled by medical
treatment (including massive hemorrhage, perforation, toxic megacolon, and
fulminant colitis).9
Years ago, total proctocolectomy with ileostomy was the
surgery of choice. Although this surgical option is curative, these patients
are faced with the inconvenience and comorbidities associated with ileostomy
care. Another option is colectomy with ileorectal anastomosis.
However, because rectal mucosa is still
present, these patients are at increased risk of developing proctitis, and they
need continued screening for rectal carcinoma. The most common and popular
option is ileal pouch–anal anastomosis. In this surgery, the ileum is formed
into a pouch to maintain continence and attached to the anus.
Ø Pouchitis, inflammation of the ileal pouch,
occurs in 20% to 50% of patients with an ileal pouch.10 Antibiotics
and probiotics are effective treatment options for this complication.
Pharmacotherapy in Pregnancy:
Ø Women with inflammatory
bowel disease are no longer advised not to have children. Pregnancy is usually
uneventful in patients with quiescent inflammatory bowel disease. Patients with
active disease are more likely to have a miscarriage, to deliver prematurely or
to have an infant with below-normal birth weight. However, medical management
results in a satisfactory outcome in most of these pregnancies.11
Ø For obvious reasons,
radiologic studies should be avoided in pregnant women. If possible, flexible
sigmoidoscopy should also be avoided, because it may stimulate premature labor.
Ø In most patients, the
risks to the newborn from untreated disease are much greater than the risks
associated with medical therapy. For many years, corticosteroids and
sulfasalazine have been used safely in pregnant women with active inflammatory
bowel disease. The sulfapyridine moiety of sulfasalazine is tightly bound to
serum proteins and therefore does not appear to increase the risk of
kernicterus. A recent review12 of 5-ASA compounds in pregnancy
suggests that they are also safe.
Ø Metronidazole has been
shown to be potentially teratogenic in animal studies. However, a recent
meta-analysis of short-term metronidazole therapy (seven to 10 days) in
pregnant women with Trichomonas infection suggested that the drug can be used
in the first trimester without an increased risk of teratogenicity13 because information on long-term
effects is lacking, it is prudent to avoid prolonged metronidazole therapy in
pregnancy.
Ø Immunosuppressant drugs
should not be given to pregnant women. However, azathioprine and mercaptopurine
do not appear to increase the risk of congenital malformations in pregnant
patients with severe inflammatory bowel disease. Methotrexate probably should
not be used in pregnant women with inflammatory bowel disease, since little is
known about the effects of the drug in pregnancy.
Herbal agents used for the
treatment of IBD14:
Many herbal agents are used to treat inflammation by
different mechanisms
New paradigms for treatment of
Inflammatory bowel disease:
Ø PDE4 inhibition:18
The role of Phosphodiesterase enzymes is to
regulate intracellular levels of cyclic nucleotides camp and cGMP by catalyzing
their breakdown to inactive 5’AMP and 5’GMP. There are 11 families of PDE
enzymes (PDE1-PDE11), There is increasing evidence to indicate that the
expression of PDE4 in specific compsartments within cells tightly regulates
cyclic nucleotide levels in the vicinity of effector protein, thus implicating
PDE4 regulating cellular function. PDE4A, PDE4B and PDE4D are particularly
abundant in many types of inflammatory and immune cells, including T cells and
B cells, monocytes, macrophages, neutrophils and eosinophils. Phosphidiesterase
4(PDE4) is the predominant enzyme that metabolizes cAMP in inflammatory cells and
the anti-inflammatory and immunomodulatory potential of PDE4 inhibitors in
human leukocytes, endothelium and epithelium is well documented.
Inflammation is a hallmark of IBD, and
elevation of cAMP levels can inhinbit the pro inflammatory and tissue
distructive properties of leukocytes. PDE4A, PDE4B and PDE4D are the
predominant metabolizes cAMP hydrolyzing PDEs in most inflammatory cells and in
general intracellular elevations in metabolizes cAMP are associated with broad
anti-inflammatory effects.19 For example PDE4 inhibitors are
potent supressors of many cytokines(Figure 1), including TNF-a release from
macrophages19, monocytes18 and T cells.20
which indicates that they could be effective in IBD.
Figure 1. Potential anti-inflammatory and immunomodulatory
effects of PDE4 inhibitors.GM-CSF=granulocyte-macrophage colony stimulating
factor, LTB4- LeukotrineB4,
Mechanism of action:PDE4 alter intestinal blood flow and
elevations of camp levels potentially inhibit the release of pro inflammatory
mediators relax gut and vascular smooth muscle and thus provide a broad spectrum
action to inhibit tissue destruction
Figure 2. Abnormalities in IBD and the
potential beneficial effects of PDE4 inhibitors
Ø
Selective cyclooxygenase-2 inhibitors:
NSAIDS are non specifically
inhibit the cyclooxygenase enzymes (COX-1 and COX-2) leading to loss of gastric
mucosal integrity and at the same time producing the desired anti-inflammatory
effect.20 It has been proposed that the selective COX-2
inhibitors (coxibs) are non-toxic to the gastrointestinal tract by sparing
COX-1 while retaining the potential anti-inflammatory effect.21
COX-2 inhibotors maintain Bowel integrity22, role in repairing
damaged tissue23 and having protective role in healing.23,24 It
was on this background that the NSAIDS particularly COX-2 inhibitors were
indicated in IBD.
While IBD can limit quality of life due to
pain, vomiting, diarrhea, and other socially unacceptable symptoms, it is
rarely fatal on its own. Fatalities due to complications such as toxic
megacolon, bowel perforation and surgical complications are also rare.
While patients of IBD do have an increased
risk of colorectal cancer this is usually caught much earlier than the general
population in routine surveillance of the colon by colonoscopy, and therefore
patients are much more likely to survive. After treatment, the patient is
usually switched to a lighter drug with fewer side effects. Every so often an
acute resurgence of the original symptoms may appear: this is known as a
"flare-up". Depending on the circumstances, it may go away on its own
or require medication. The time between flare-ups may be anywhere from weeks to
years, and varies wildly between patients - a few have never experienced a
flare-up.
CONCLUSION:
In light of above evidence
there are new targets like inflammatory mediators, PDE4 inhibition, COX-2
inhibition are the new avenues for better treatment of inflammatory bowel
disease. Future development in these new areas can give better fight against
IBD.
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Received on 16.02.2010
Accepted on 24.03.2010
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Pharmacodynamics. 2(3): May-June 2010, 228-232