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Summary

The pro-inflammatory leukotrienes (LT’s), lipid mediators generated by the 5-lipoxygenase (5-LO) enzyme, are heavily involved in the pathogenesis of inflammatory bowel disease (IBD) and other intestinal conditions.1, 2  No FDA approved drugs that target the pathological events induced by LT’s are currently approved for digestive diseases.3 The few synthetic LT antagonists that might be given as an off label medicine have significant potential side effects.

From the gum resin boswellia, the AKBA fraction, acetyl-11-keto-beta-boswellic acid, a very potent, natural 5-LO and leukotriene inhibitor can be extracted.4, 5 Studies show its usefulness in intestinal concerns of various kinds, specifically IBD.6, 7

Recently, a novel boswellia extract, std. to 90% AKBA has become available.* It shows increased clinical effectiveness over the older lesser purified preparations and avoids some of their pitfalls. The new phyto supplement AKBA Plus ™ is rapidly becoming a Gold Standard boswellia product with wide applicability in nutritional programs for both digestive and also other conditions where LT’s are involved, including asthma, allergies, arthritis, several forms of cancers, and more.   

5-Lipoxygenase and Leukotrienes in IBD

The 5-LO enzyme works on the arachidonate substrate to produce the “misery” of the leukotrienes.8, 9 The disease activity of IBD is known to correlate with the 5-lipoxygnenase activity and colonic concentrations of LT’s. 10 LTB4, as an example, has been known for decades to be over-expressed in colitis.11 Inhibiting eicosanoid biosynthesis was soon proven to be a therapeutic strategy in reducing the inflammation of IBD. 12, 13 A variety of conventional drug modalities- corticosteroids, sulphasalazine, as well as selective 5-LO inhibitors (zileuton)- were shown to both block 5-LO activity as well as its chemotactic and chemokinetic metabolites. An improvement in both histologic and symptom scores were recorded with leukotriene inhibition. 14 More recently, additional details have emerged elucidating the pathway by which increased 5-LO activity ultimately leads to neutrophil influx and mucosal injury through the expression of adhesion molecules.15, 16
       

The natural inhibition of 5-LO and LT’s by Boswellic acids (BA’s), especially the AKBA fraction
       
Sadly, it is little known that a potent natural inhibitor of the 5-lipoxygenase enzyme is available.17, 18

Principally among the many extractive fractions of the gum resin frankincense, Boswellia serrata, is the 5-LO inhibitor fraction AKBA, acetyl-11-keto-beta-boswellia acid. 19 Boswellia as such has been known for centuries to be a potent anti-inflammatory agent. Studies have proven its efficacy not only in colitis but also in asthma, allergies and environmental sensitivities, arthritis and various forms of cancers.20 (Of particular interest also are the newer findings regarding the anti-neoplastic properties of AKBA in prostate, pancreas, bladder and breast cancers). 21, 22

AKBA was found to specifically inhibit production of LTB4 in a dose dependent manner and with a very low IC50 of 1.5 μM. AKBA was proven to have a three times more potent inhibition of LT’s synthesis then the unpurified boswellic acids. 23

Significantly, AKBA exerts its anti-inflammatory effects by a multitude of mechanisms: non-redox inhibition of the 5-LO;  impairing leukocyte infiltration; nearly complete suppression of the complement pathway; inhibition of mast cell degranulation, NFκB pathway, matrix metalloproteinases and adhesion receptors, IL-2 and IL-1β,  human leukocyte elastase,  topoisomerase I and II and  the activity of P-glycoprotein in leukemia cell lines; suppression of macrophage NO production thus lessening the risk of anaphylaxis and suppression of TNFα induction as well as suppression of the P-selectin up-regulation; and more. 6, 24-27

The role of AKBA in IBD

Both experimental and human clinical studies have confirmed the salutary role of AKBA in reducing the inflammation of digestive diseases. Krieglstein et. al. 28 induced ileitis in an animal model by subcutaneous injection of indomethacin. High dose AKBA reduced significantly the tissue injury score, microcirculatory inflammatory features and lowered the leukocyte adhesion by up to 98%.

In a similar study AKBA was shown to blunt experimental murine colitis activity in DSS challenged mice. AKBA treatment was comparable in its effects with those effects of standard medications of ulcerative colitis like dexamethasone steroids. Significantly, AKBA prevented the P-selectin up-regulation normally associated with colitis. Recruitment of leukocytes and platelets into the inflamed colonic microvasculature was found to be lowered. Leukocyte-endothelial cell adhesion was shown to be a major target of action for AKBA. 29

Since both controlled clinical studies and anecdotal evidence suggest that boswellia extracts lower the incidence of diarrhea in patients with IBD, the effects of AKBA on intestinal motility and diarrhea were studied in animal models.30    Specifically, in animals with patho-physiologic states, AKBA inhibited electrically-, acetylcholine- and barium chloride induced contractions in guinea pig ileum via a mechanism involving L-type Ca 2+ channels. AKBA did not affect intestinal motility and rate of transit in both the large and small intestine in the healthy control mice.

In a human study 31 the effect of boswellia extracts on ulcerative colitis was compared to controls treated with sulfasalazine. Stool properties, the histopathology and scan microscopy of rectal biopsies, blood parameters including hemoglobin, serum iron, calcium, iron, proteins, total leukocytes and eosinophils were studied. All parameters improved after treatment with boswellia. (The dosage was 350 mg three times daily. Unfortunately the standardization of the boswellia extract was not noted.) In fact the outcome in the boswellia group was better with 82% improvement then the outcome in the sulfasalazine control group with 73% improvement.

In a later study by the same authors 32 20 patients suffering of chronic colitis were treated with boswellia extracts and compared to 10 sulfasalazine treated patients acting as controls. Of the 20 boswellia treated patients 18 showed an improvement in one or more parameters while in the control group only 6 out of 10 patients showed similar results. Moreover, in the experimental group 14 out of 20 patients went into remission while in the control group the remission rate was only 4 out of 10.

In a randomized, double blind, parallel group comparison, the efficacy of boswellia extracts in active Crohn’s disease was evaluated. 44 patients in the experimental group did better than the 39 patients in the control group treated with mesalazine. The Crohn’s Disease Activity Index at the end of the study period was reduced by 90 in the experimental group and only by 53 in the control group. 33 In terms of a benefit risk evaluation boswellia clearly appeared to be superior to the mesalazine.

In a very recent double blind, multi center, randomized and placebo controlled study boswellia extracts were shown to be beneficial in collagenous colitis.7

The role of AKBA in colon cancer and gastric ulcers

There is increasing evidence that AKBA is a considerable anti-cancer agent.21, 34

In a colon cancer cell lines study, AKBA was shown to inhibit cellular growth in several cell lines. Cells were arrested at the G1 phase. Further analysis demonstrated that cyclin D1 and E, CDK 2 and 4 and phosphorylated Rb were decreased in AKBA treated cells while p21 expression was increased.35

The 5-LO pathway has been found to create pivotal mediators in Helicobacter pylori-induced inflammatory response. H. pylori stimulated the translocation of cPLA2 from cytoplasm to nucleus and increased the biosynthesis of HETEs in the gastric epithelium. The administration of 5-LO inhibitors resulted in down-regulation of pro-inflammatory mediators such as IL-8 and TNFα in both H. pylori-infected gastric epithelial cells and macrophage cells. Thus 5-LO inhibition could be of significance in the management of ulcer disease.  39, 40

A study evaluated the anti-ulcer efficacy of the boswellic acids. Boswellic acids are not only devoid of ulcer production but protective also. Ulcerations were induced by several methods in rat models. Results of the present study revealed that BA possesses a dose dependent antiulcer effect against different experimental models. It showed different degrees of inhibition of the ulcer score towards different ulcerogenic agents. The ulcer score against various ulcer inducing agents such as pyloric ligation, ethanol/HCl, acetylsalicylic acid (acute and chronic), indomethacin and cold restraint stress, was inhibited by 39%, 38%, 51%, 31%, 37% and 42% respectively at 250 mg/kg. From the data it is concluded that BA inhibited ulcer production non-specifically in all the experimental models. It is possible that BA might be acting by increasing the gastric mucosal resistance and local synthesis of cytoprotective prostaglandins and inhibiting the leukotriene synthesis. 41

Dosage and Administration:
       
The most convincing therapeutic successes were seen, both in individual doctors’ practices and in controlled studies, when sufficiently high dosages were administered such that adequate plasma levels could be reached. The success of boswellia extracts up to now is all the more surprising since only poorly standardized products have been available on the general market. The component AKBA is recognized as the active anti- inflammatory principle in the boswellia and yet by far most of the formulas have only 1-3% AKBA concentration.

However, a novel AKBA Plus™ supplement is now available with a boswellia concentration of over 90% AKBA! The enhanced efficacy of this new formula is considerable.

AKBA Plus™ now allows for the first time that the necessary effective plasma levels can be reached to ensure an even higher success rate then previously thought possible. Since for most adults the start up dosage is 150mg daily, 1 capsule of approx. 50 mg given as 3 caps daily should be adequate for most patients. These calculations are based among others on the latest pharmacokinetic studies on AKBA.36, 37 (To achieve the plasma levels of 3 AKBA Plus™ capsules approx. 15-20 caps of common preparations would be needed). Even more, recent experimental findings suggest that to achieve equivalence to steroids up to 500 mg of pure AKBA must be administered. 29 This would be the equivalent of 9 capsules daily of AKBA Plus™. One patient has reported complete resolution of all symptoms only after taking 12 AKBA Plus™ capsules daily for several weeks.

Ideally, in order to enhance effectiveness, AKBA Plus™ should be administered every 8 hours.

The absorption of AKBA Plus™ is enhanced in this professional formula through the addition of Fenugreek and Bioperine®. Giving the supplement with a meal will further improve absorption.
In nearly 2 million dosages dispensed clinical successes could be seen where previously therapeutic failure had been noted.

Safety and toxicology;
       
AKBA Plus™ is virtually side effects free. This conclusion can be ascertained after clinical review of tolerability of nearly two million doses administered. Isolated cases of headache after AKBA Plus™ have been noted with intake of even one single capsule. There has been no dose dependent intolerance observed. There have not been any reports of the intestinal distress seen with other boswellia preparations. Toxicological studies also attest to the safety of this formula. These positive findings distinguish AKBA Plus™ from non purified boswellia extracts where ineffectiveness in colitis was concluded and some hepatotoxicity was seen.38

AKBA Plus™ is manufactured in a GMP approved facility. The supplement is third party tested and certified.

Conclusion

There is convincing evidence that the inhibition of the 5-LO enzyme and the inhibition of the leukotriene synthesis play a major role in reducing the inflammation of IBD.
       
AKBA Plus™ can significantly contribute to controlling the 5-LO generated pathology. Without it the needed nutritional program is essentially incomplete. Due to the relatively high doses that need to be administered only a purified highly concentrated AKBA containing boswellia extract is ultimately adequate in ensuring therapeutic plasma levels and ultimately patient compliance.  AKBA Plus™ is positioned to become the Gold Standard in its class.  **             

*For more information:
The monograph: “Therapeutic Advantages of a New Pharmaceutical Grade Boswellia Extract  is available to licensed physicians.

Please contact the company and request other professional AKBA reports, a professional catalog, and  educational materials on other products.

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