PHARMACOLOGY OF COMBINED MESALZINE AND RIFAXIMIN THERAPY TO INFLAMMATORY BOWEL DISEASE

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ABOUT AUTHORS
Prajapati Krishna V*, Raj Hasumati A, Jain Vinit C, Prajapati Neelam S.
Department of Quality Assurance,
Shree Dhanvantary Pharmacy College, Kim, Surat, Gujarat, India
*krish1112k@gmail.com

ABSTRACT
This review article presents the pharmacology of combined Mesalazine and Rifaximin therapy especially in inflammatory bowel disease. Mesalazine is used as in anti-inflammatory agent, Non-Steroidal. Rifaximin is used in Gastrointestinal Agents, Anti-infective agent. The use of Rifaximin in combination with Mesalazine has been proved to provide beneficial effect in inflammatory bowel disease. The mechanism of Mesalazine and Rifaximin is quite different. Mesalamine and Rifaximin are two different types of drugs offering some symptomatic relief to the IBD patients. Mesalamine treats inflammation, whereas, Rifaximin reduces bio burden.
Patent for combination of both drugs were approved by WIPO. The main objective of this review article is to provide pharmacological information of combined therapy of Mesalazine and Rifaximin to researcher in development of combined dosage form of this.

REFERENCE ID: PHARMATUTOR-ART-2412

PharmaTutor (Print-ISSN: 2394 - 6679; e-ISSN: 2347 - 7881)

Volume 4, Issue 5

Received On: 04/01/2016; Accepted On: 21/01/2016; Published On: 01/05/2016

How to cite this article: Prajapati KV, Raj HA, Jain VC, Prajapati NS; Pharmacology of Combined Mesalzine and Rifaximin Therapy for Inflammatory Bowel Disease; PharmaTutor; 2016; 4(5); 41-45

INTRODUCTION [1-5]
Inflammatory bowel disease (IBD)
is a spectrum of chronic idiopathic inflammatory intestinal conditions. IBD is a group of inflammatory conditions of the colon and small intestine. IBD causes significant gastrointestinal symptoms that include diarrhea, abdominal pain, bleeding, anemia, and weight loss. IBD also is associated with a spectrum of extra intestinal manifestations, including arthritis, ankylosing spondylitis, sclerosing cholangitis, uveitis, iritis, pyoderma gangrenosum, and erythema nodosum.

Figure 1: Inflammatory bowel disease [2]

Major types of IBD:
[1] Crohn's disease (CD):

CD is a condition of chronic inflammation potentially involving any location of the GIT from mouth to anus. CD is nonspecific inflammatory bowel disease that may affect any segment of the gastrointestinal tract. Crohn's disease, by contrast, is characterized by Trans mural inflammation of any part of the gastrointestinal tract but most commonly the area adjacent to the ileocecal valve. The inflammation in Crohn's disease is not necessarily confluent, frequently leaving "skip areas" of relatively normal mucosa. The Trans mural nature of the inflammation may lead to fibrosis and strictures or, alternatively, fistula formation.

[2] Ulcerative colitis (UC)
UC is an inflammatory disorder that affects the rectum and extends proximally to affect variable extent of the colon. Ulcerative Colitis nonspecific inflammatory bowel disease of unknown etiology that affects the mucosa of the colon and rectum. Ulcerative colitis is characterized by confluent mucosal inflammation of the colon starting at the anal verge and extending proximally for a variable extent [e.g., proctitis, left-sided colitis, or pan colitis].

Figure 2: Type of IBD [3]: (a) Crohn’s disease (b) Ulcerative Colitis

Other forms of IBD:

  • Collagenous colitis
  • Lymphocytic colitis
  • Ischemic colitis
  • Behçet’s disease
  • Infective colitis
  • Indeterminate colitis

MECHANISM OF INFLAMMATORY BOWEL DISEASE [4]

Figure 3: Mechanism of inflammatory bowel disease [5] 

Crohn's disease and ulcerative colitis are chronic idiopathic inflammatory disorders  of the GI tract; a summary of proposed pathogenic events and potential sites of therapeutic intervention. While Crohn's disease and ulcerative colitis share a number of gastrointestinal and extra intestinal manifestations and can respond to a similar array of drugs, emerging evidence suggests that they result from fundamentally distinct pathogenetic mechanisms. Histologically, the transmural lesions in Crohn's disease exhibit marked infiltration of lymphocytes and macrophages, granuloma formation, and sub mucosal fibrosis, whereas the superficial lesions in ulcerative colitis have lymphocytic and neutrophilic infiltrates. Within the diseased bowel in Crohn's disease, the cytokine profile includes increased levels of interleukin-12 (IL-12), interferon-g, and tumor necrosis factor-a (TNF-a), findings characteristic of T-helper 1 (TH1)-mediated inflammatory processes. In contrast, the inflammatory response in ulcerative colitis resembles more closely that mediated by the TH2 pathway.

MESALAZINE [6-9]
Category:
Anti-inflammatory agent, Non-steroidal anti-inflammatory agent
Chemical name:  5-Amino-2-Hydroxybenzoic acid[6]
Characteristics: appearsas off white to gray
Solubility: Slightly soluble in water, alcohol; more soluble in hot water; soluble in hydrochloric acid [6]
Melting point: 275-280 °C [7]
PKa value: pKa: 1.90,   pKb: 5.43[7]
Molecular formula:C7H7NO3.
Molecular weight:153.14 g/mol [8]

The structural formula is shown below:

Figure 4: The chemical structure of Mesalazine

MECHANISM OF ACTION:
Although mesalamine is a salicylate, its therapeutic effect does not appear to be related to cyclooxygenase inhibition; indeed, traditional non-steroidal anti-inflammatory drugs actually may exacerbate IBD. Although the mechanism of action of mesalazine is not fully understood, it appears to be topical rather than systemic. Mucosal production of Arachidonic acid metabolites, both through the cyclooxygenase pathways, i.e., prostanoids, and through the lipoxygenase pathways, i.e., leukotrienes and hydroxyeicosatetraenoic acids, is increased in patients with chronic inflammatory bowel disease, and it is possible that mesalazine diminishes inflammation by blocking cyclooxygenase and inhibiting prostaglandin production in the colon. Mesalamine appears to diminish inflammation by inhibiting cyclooxygenase and lipoxygenase, thereby decreasing the production of prostaglandins, and leukotrienes and hydroxyeicosatetraenoic acids (HETs) respectively. It is also believed acts as a scavenger of oxygen-derived free radicals, which are produced in greater in patients with inflammatory bowel disease.[9]

PHARMACOKINETIC[10]:

(Table 1)

Parameter

Observation

Bioavailability

orally: 20-30% absorbed  rectally: 10-35%

Metabolism

Rapidly & extensively metabolised intestinal mucosal wall and the liver

Biological half-life

5 hours after initial dose. At steady state 7 hours

Excretion

excreted mainly by the kidney as N-acetyl-5-aminosalicylic acid

RIFAXIMIN [11-14]
Category:
Gastrointestinal Agents, Anti-infective Agents
Chemical name: (7S,9E,11S,12R,13S,14R,15R,16R,17S,18S,19E,21Z)-2,15,17,36-tetrahydroxy-11-methoxy-3,7,12,14,16,18,22,30-octamethyl-6,23-dioxo-8,37-dioxa-24,27,33-triazahexacyclo(23.10.1.14,7.055.0²64.0²7,³²)heptatriaconta1,3,5(35),9,19,21,25[36],26[34],28,30,32-undecaen-13-yl acetate[11]
Characteristics:Red Orange Crystalline Powder         
Solubility: Soluble in DMSO (47 mg/ml), water (<1 mg/ml), ethanol (157 mg/ml), alcohols, and chloroform.[12]
Melting point: 218-227°C [13]
PKa value: pKa: 8.06, pKb: 4.42[13]
Molecular formula:C43H51N3O11.
Molecular weight:785.87g/mol [14]

The structural formula is shown below:

Figure 5: The structure of Rifaximin

MECHANISM OF ACTION [11]
Rifaximin is a semisynthetic, rifamycin-based non-systemic antibiotic, meaning that the drug will not pass the gastrointestinal wall into the circulation as is common for other types of orally administered antibiotics. It is used to treat diarrhea caused by E. coli.Rifaximin acts by inhibiting RNA synthesis in susceptible bacteria by binding to the beta-subunit of bacterial deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase enzyme. This results in the blockage of the translocation step that normally follows the formation of the first phosphodiester bond, which occurs in the transcription process.[13]

PHARMACOKINETICS [14]:

(Table 2)

Parameter

Observation

Bioavailability

< 0.4%

Metabolism

Hepatic

Biological half-life

6 hours

Excretion

Fecal [97%]

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