Boswellia 90™ and Boswellia 3K™ Science & Research

Review of recent clinical Studies with Boswellic acids

Multiple studies (see references at the end) show the benefits in arthritis, cancer, asthma/allergies and inflammatory bowel disease. More recently, surprising benefits in the treatment of the prostate has also been shown.

Arthritis
The first scientific reports on the pain relieving properties of Boswellic acids came out more then 35 years ago. Animal studies demonstrated the anti-inflammatory activity of Boswellic acids and the prevention of progressive joint collagen destruction due to the finding of decreased levels of connective tissue metabolites. More recent animal studies demonstrated reduced carrageenan or dextran induced edema, reduced papaya latex- induced rat paw inflammation, reduced intermittent lameness, local pain and stiff gait in osteoarthritic dogs, etc. A very recent study proved that strong anti-arthritic changes were accompanied by significantly suppressed TNFα and IL-1β.

In human studies the result s were equally encouraging. 42 patients with osteoarthritis recorded increased walking distance, less knee stiffness, etc.

General conclusions:
- Boswellic acids lessened severity of pain in joints;
- Boswellic acids diminished knee swelling and knee flexion;
- Boswellic acids increased duration of walking distance.

Inflammatory bowel disease

Animal studies showed protective effects specifically of AKBA in toxin induced hepatitis and ileitis. AKBA also significantly blunted experimental mouse colitis and prevented typical inflammatory cell reactions like recruitment of adherent leukocytes and platelets into inflamed colonic venules. AKBA also largely prevented the P-selectin up-regulation. These effects were similar to those in mice treated with corticosteroids.

Recently, Boswellic acids were shown to prevent experimental diarrhea and to normalize intestinal motility without slowing down the rate of transit when given to control animals.

In another study 14 Boswellic acids treated patients, out of a total of 20 patients, went into remission, as opposed to 4 out of 10 patients in the control sulfasalazine group. 

General conclusions:

Cancer

Topical application of Boswellic acids prevented or slowed tumor cell promotion when animals were fed a diet containing 0.2% by weight AKBA, clearly showing anti- neoplastic qualities of Boswellic acids. 

Another study showed that Boswellic acids influenced glioma cell growth. AKBA could still be detected in the brain 3 hours after oral administration of a 240mg/kg of Boswellic acids to rats. 

In a human study, 19 children with intra-cranial tumors received palliative therapy with Boswellic acids.  Although no anti-neoplastic effects were seen, 8/19 children experienced some significant clinical improvement.

In 2002, the European Agency for the Evaluation of Medicinal products (EMEA) released a positive opinion for orphan designation of Boswellic acids for the treatment of peritumoral edema derived from brain tumors. 

General conclusions:
- Boswellic acids improved general health status, muscular strength, weight gain in   cancer patients;
- Boswellic acids decreased neurological symptoms in patients with intra-cranial tumors;
- Boswellic acids decreased edema of brain tumor patients.

Allergy and Asthma

In several studies animal passive paw anaphylaxis reaction and mast cell degranulation was reduced.

A human clinical double blind study was done on forty patients with chronic asthma. They were given 300 mg three times daily of boswellia for 6 weeks. 70% of patients showed improvement by the lowering of attack frequency, lowered eosinophilic counts, disappearance of dyspnea, rhonchi and an increase in pulmonary function, such as increase of FEV 1 and FVC. In the control group only 27% of patients showed improvement. 

General conclusions:
- Boswellic acids improved general status in chronic asthma patients;

Inhibition of the 5-Lipoxygenase will be increasingly seen as part of complete medical treatment. The necessity of appropriately suppressing the 5-Lipoxygenase originating inflammation has been tackled largely unsuccessfully by the pharmaceutical industry up to now. Besides Boswellic acids there is currently no other comparably potent and risk free natural 5-Lipoxygenase inhibitor on the market. Boswellic acids are 5-Lipoxygenase inhibitors but the use of unpurified boswellia extracts with a low 1-3% AKBA concentration have proven to have limitations and in some conditions are even not desired at all.

This newly available Boswellia 90™ standardized to 90% pure pharmaceutical grade AKBA avoids the previous pitfalls and increases the benefits.

Nutritional supplementation with pharmaceutical grade Boswellia 90™, containing a high percentage of the AKBA fraction, avoids the necessity of simultaneous exposure to high levels other undesirable boswellic acids.

Specific Inhibition of the 5-Lipoxygenase by AKBA

The Inflammatory Cascade
In answer to specific external stimuli, arachidonic acid is formed which leads to inflammatory processes. Of main interest here is the 5-lipoxygenase enzyme whose products, leukotrienes, lead to vascular permeability, chemotaxis and white blood cell stickiness, as well as Bronchospasm, platelet clotting and more. Leukotrienes are several orders of magnitude more potent than histamine in increasing vascular permeability and causing bronchospasm.

When a variety of White Blood Cells are activated, (principally among them macrophages and lymphocytes, but also endothelium, epithelium and connective tissue cells), cytokine proteins (such as TNFα, IL-1, etc) are produced and lead to the augmentation of the inflammatory reactions (fever, loss of appetite, etc.) A further consequence of the activation of inflammatory cells is the enhanced production of NO, a potent vasodilator with multiple pro-inflammatory activities. (Robbins and Cotran, Pathologic Basis of Disease, 2005, 7th Edition)

How is 5-Lipoxygenase bio-regulated?
The enzyme is mainly restricted to white blood cells but can also be expressed in human skin keratinocytes, Langerhans cells or brain cells. Stress results in a higher level of 5-Lipoxygenase activation. Of great interest should be the fact that ‘priming’ agents such as Epstein-Barr virus (!) and others do not in themselves lead to activation of 5-Lipoxygenase but subsequent stimulation of the white blood cells with pro-inflammatory stressors leads to a strongly increased inflammation.

5-Lipoxygenase Inhibition

AKBA was confirmed as the most active boswellic acid fraction to inhibit the 5-Lipoxygenase .

AKBA belongs to a group of so called non-redox inhibitors of 5-Lipoxygenase. It has a unique mechanism of action that is gradually being better understood. It acts directly on 5-Lipoxygenase.  Its lack of any significant side effects, its high safety level and favorable toxicological studies, as well as the extensive traditional and modern clinical use across many divergent pathologies makes this an ideal 5-Lipoxygenase inhibitor.   

It is becoming increasingly clear that the interference of Boswellic acids with the inflammatory cascade and the 5-Lipoxygenase is strongly dependent on the biological situation involved and the structure of the Boswellic acids. The so called “keto” ones are the most active , while the other boswellic acids are less desirable.

The 5-Lipoxygenase in Health and Illness

General observations
5-Lipoxygenase is the key enzyme in the biosynthesis of Leukotrienes. These pro-inflammatory mediators are potent chemotactic and chemokinetic mediators stimulating the immigration and activation of granulocytes, leading to adherence of granulocytes to the vessel walls, degranulation of mast cells, and the release of superoxide. They are connected to increased interleukin production and neutrophil dependent hyperalgesia, cause vascular permeability and smooth muscle contraction. Cys-Leukotrienes lead to smooth muscle contraction, plasma extravasation, recruitment of neutrophils, and vasoconstriction. They are up to 1000-fold more potent than histamine.

Animal studies with genetically disrupted 5-Lipoxygenase genes showed significantly reduced inflammatory responses to a number of noxious stimuli especially arachidonic acid caused inflammation. In view of the high AA containing modern Western diets, these results are epidemiologically very significant.   

Multiple other studies have established a significant role for Leukotrienes in inflammatory diseases such as arthritis, inflammatory bowel diseases, asthma and in severe exercise  and aspirin induced forms of asthma, COPD, allergic rhinitis, idiopathic pulmonary fibrosis, ischemia related organ injury, and atopic dermatitis.

Recent studies have implicated Leukotrienes and other 5-Lipoxygenase products in unexpected pathophysiological illnesses such as the bone resorptive metabolism of osteoporosis, the atherogenic processes of the cardiovascular system, atopic and hyperproliferative skin diseases such as dermatitis and psoriasis, the proliferation as well as survival of tumor cells, and multiple other conditions. Studies confirm the role of 5-Lipoxygenase products in ear inflammation and peritonitis. 

Interestingly, the global inhibition of 5-Lipoxygenase has proven to be more efficacious than the partial inhibition of the 5-Lipoxygenase pathway through either Leukotriene antagonists, Leukotriene receptor antagonists or Leukotriene competitors.

Cardio-vascular Diseases
The role of the 5-Lipoxygenase in atherosclerosis is particularly interesting. 

Atherosclerosis, a major cause of morbidity and mortality, is now seen as an inflammatory fibro-proliferative disease. Leukotriene receptors are abundantly expressed in atherosclerotic lesions in the aorta, heart and carotid artery. In fact the presence of high expression of 5-Lipoxygenase, correlates well with high plaque instability.

Review of animal and human data suggest that 5-Lipoxygenase and its metabolites are up regulated in vessel walls, macrophages, dendritic cells, foam cells, mast cells, and neutrophils. Recent studies clearly have identified the 5-Lipoxygenase gene as a risk factor in such cardio vascular diseases as stroke and myocardial infarction.  

A survey of 470 subjects identified to have a gene variant leading to an increased expression of 5-Lipoxygenase demonstrated a significant increase in carotid artery intima-media thickness. Dietary intake of fish oils, which reduce the production of Leukotrienes, blunted the genotype effect. Another recent survey of subjects from Britain and Iceland, with higher than normal 5-Lipoxygenase expression, showed, double the usual rate of heart attacks. Mice genetically lacking the 5-Lipoxygenase gene showed a dramatic 26 fold reduction in aortic lesions.

These studies suggest that 5-Lipoxygenase inhibition would be a valuable preventative measure in CV disease.

Significantly increased urinary Leukotriene levels were found in patients following admission for acute myocardial infarction. Elevated levels of Leukotrienes were also found in patients with unstable angina.

Leukotrienes are also involved in sickle cell disease and septic shock. Taken together these studies demonstrate that there is a significant benefit to treat patients suffering from ischemic injuries and the resulting organ damage by eliminating inflammatory events through 5-Lipoxygenase control. 

Recently, LT receptors have been shown to be expressed in the intimal hyperplasia of early atherosclerosis and in restenotic lesions after angioplasty. These findings emphasize the role that a 5-Lipoxygenase target could play in preventing restenosis after coronary interventions. 

Hypertension
The 5-Lipoxygenase derived products cystLT and 12-HETE are vasomotor mediators with increased biosynthesis in various models of hypertension. Leukotrienes are involved in glomerular inflammatory injury. In addition it has been suggested that they might contribute to the vasoconstrictor, hypertrophic and mitogenic effects of angiotensin II. This might explain at least in part the vascular inflammatory complications associated with hypertension.
 
Cancers
Aberrant functioning and over-expression of 5-Lipoxygenase pathway products may contribute to cell proliferation, evoke angiogenesis and effect survival of particularly prostate and pancreatic cancers. Making these cellular signals part of the therapeutic targets, either alone or better in combination with other modalities has been shown to slow tumor progression, reduce tumor cell invasiveness and tumor cell motility and decrease tumor angiogenesis.

Cigarette smoke is known to cause an inflammatory response in the colon that can lead to colon adeno-carcinoma. The mechanism seems to be via an up-regulation of 5-Lipoxygenase induced protein expression accompanied by up-regulation of mettaloproteinases-2 and vascular endothelial growth factor. 5-Lipoxygenase inhibitors reduced the incidence of adenomas, angiogenesis and MMP-2 activity and VEGF.  Studies strongly suggest that cigarette smoke induced 5-Lipoxygenase expression leading to colon adenoma formation can be reduced by 5-Lipoxygenase inhibitors. 

5-Lipoxygenase and its metabolites have been found to have an increased expression in lung cancers and to inhibit apoptosis as well as contribute to cell proliferation. These advances in the understanding of the molecular biology of lung cancer have led to the conclusion that 5-Lipoxygenase pathway inhibitors should be part of the chemoprevention armamentarium in these illnesses.

Respiratory illness
Pulmonary damage in cystic fibrosis is mediated largely by 5-Lipoxygenase pathway generated eicosanoids and leukotrienes. A reduction in pro-inflammatory mediators was deemed to substantially lessen the damaging tissue inflammation.

RSV infection causes significant morbidity both in the adult but especially in the pediatric population. By the age of three, most children have been infected at least once. The typical symptoms of runny nose, copious mucous discharge, cough, progression to wheezing and potential respiratory distress can lead to hospitalization in 1-2% of all cases. The illness can last for weeks and can exacerbate asthma.

The mechanism for viral damage is not well understood and no specific therapy is indicated. Interestingly, however, the 5-Lipoxygenase and the Leukotrienes discharged from mast cells are significantly increased in the inflammatory discharge and a potential role for 5-Lipoxygenase inhibition is thus given.

Pneumoccocal otitis media is associated with the production of high levels of Leukotrienes. The presumptive mechanism seems to be that the pneumoccocus bacteria activates the 5-Lipoxygenase pathway by up-regulating the expression of the cPLA2 and 5-LipoxygenaseX genes. This in turn may stimulate the production of proteins leading to the formation of fluid in the middle ear.  This may explain the anecdotally observed benefit of supplementation with Boswellic acids in children with various upper and lower respiratory illnesses.

Rhinovirus infections can cause cough, wheezing and bronchial hyper-responsiveness, in otherwise normal individuals. Bronchial aspirations in these patients demonstrated marked inflammation characterized by markedly enhanced expression of 5-Lipoxygenase pathway proteins.

The Leukotrienes involvement in severe asthma, especially Aspirin induced asthma and Exercise induced asthma is becoming well established.

5-Lipoxygenase inhibition has been demonstrated to significantly increase forced expiratory volume and morning and evening peak expiratory flow rate. Because inhibition of the 5-Lipoxygenase pathway is so highly effective in both AIA and EIA their use has been recommended as meriting a primary therapy status in both disorders.

Patients with severe asthma and frequent asthma exacerbations may also be good candidates since there is a common association with neutrophil predominance and there is pronounced airway remodeling. An additional highly significant advantage to 5-Lipoxygenase inhibition is that it fills the gap in anti-inflammatory coverage of inhaled glucocorticoids.

Trials of 5-Lipoxygenase inhibitors in allergic rhinitis and sinusitis showed that 72% of participants had a positive response of symptom reduction and 50% experienced reduction of nasal polyps.

Osteoporosis, Bone Metabolism and Joint Diseases
A connection between 5-Lipoxygenase, LTB4, other arachidonic acid derived eicosanoids and osteoporosis is becoming more apparent.

Bone resorption requires cooperation between osteoclasts and mononuclear accessory cells. 5-Lipoxygenase metabolites have been shown to stimulate this process.  Among the 5-Lipoxygenase generated Leukotrienes especially LTB4 seems to activate osteoclasts and cause surface erosion.

Various animal models using experimental inhibition of 5-Lipoxygenase have prevented loss of bone mass in rodents, with a concomitant increase of femur and humerus volume and density, femur calcium levels and ash weight.

Skin Diseases
5-Lipoxygenase and its lipid metabolites, the Leukotrienes, have been increasingly recognized as having a pivotal role in dermatologic disorders like psoriasis, acne and atopic dermatitis. In all three conditions reducing the levels of Leukotrienes resulted in significant lessening of swelling , itching , redness and reduced responses to antigens.

In atopic dermatitis (eczema) changes related to Leukotrienes, like an elevation of eosinophils and increased production of cytokines IL-4, IL-5, IL-13, can be controlled with means that suppress Leukotrienes. Circulating leukocytes in atopic dermatitis show an increase in LTB4 and LTC4. The characteristic erythema is probably mediated via cyst-Leukotrienes. Skin cell production of Leukotrienes was increased almost 5-fold with antigen challenge. In 5 of 7 clinical studies a significant reduction in disease activity and symptom severity was noted with the use of 5-Lipoxygenase inhibitors.

Considering that acne is a complex inflammatory disease, it is not surprising that Leukotrienes play an important pathological role here too. LTB4 and LTC4 have been shown to have a mitogenic effect on keratinocytes. Sebocytes also express both 5-Lipoxygenase and Leukotrienes. Pharmacologic studies also support the idea that 5-Lipoxygenase and its eicosanoid metabolites have a significant role in acne. 5-Lipoxygenase inhibitors have been shown to be therapeutically beneficial by reducing the severity and frequency of acne lesions, and reducing sebum production and the total output of sebum lipids and sebum free fatty acids.

Neurological Diseases
Clinical observations have shown that patients with migraine taking LT receptor antagonists due to concomitant asthma have a lower migraine frequency. These observations are further enhanced by reports that these patients also become less sensitive to environmental triggers such as perfumes and other noxious stimuli. In an open label study the effect of LT antagonists on migraine sufferers was tested with the following results: 53% of subjects showed a greater than 50% reduction in the frequency of severe attacks; 41% showed a reduction of more than 60% in attack frequency. This was considered to be a clear indication that the 5-Lipoxygenase pathway was involved in the pathogenesis of migraine. 

More recently the postulate was examined that cognitive decline in aged brains is due to inflammatory CNS changes. Aging rats with significant cognitive defects in comparison to younger ones were examined by observing vascular leakage into the retina. Cognitive decline paralleled the Leukotrienes mediated retinal damage.

Food Allergies
Food allergies in both adults and children have seen an explosive increase in the last several years. As an example, in recent media news an Australian study is mentioned reporting a 12-fold (!) increase in food allergies since 1995 alone. Yet few new therapeutic methods have been developed to effectively deal with these problems.  Are 5-Lipoxygenase mediators involved in food allergies?

Hyper-responsiveness to histamine is a key feature of a variety of pathological conditions, including food allergies and other intestinal conditions. Cysteinyl Leukotrienes have been implicated as mediators of increased histamine responses. Cyst Leukotrienes mediate histamine hyper-responsiveness by increasing histamine receptors in immunologically relevant cell types.

In a study of 40 patients with adverse reactions after food intake Leukotrienes were shown to be significantly higher after antigen stimulation in the food sensitive group than in the control group. Patients with chronic urticaria challenged with aspirin showed a significantly higher urinary excretion rate of Leukotrienes as compared to controls.

Considering these novel insights into the role of 5-Lipoxygenase and Leukotrienes in the pathophysiology of these conditions one can expect to see an increased role for Boswellic acids in the first line therapy of these common complaints.

Venous Stasis
The formation of varicose veins is more than a cosmetic disease. Venous blood stasis, vessel wall injury and a hyper-coagulable plasma state can lead to deep vein thrombosis and thromboembolism. Neutrophils are known to promote vascular injury and thrombosis following venous stasis. Leukotrienes are potent mediators of vascular injury and neutrophil chemotaxis. Animal studies demonstrated that 5-Lipoxygenase inhibition reduces deleterious neutrophil/vessel wall interactions. 

Gastric Diseases
AA metabolites via the 5-Lipoxygenase pathway have been found to be 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 LOX 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. 5-Lipoxygenase inhibition could impose significant anti-inflammatory responses after H. pylori infection, based on the fact that H. pylori infection provoked gastric inflammation through metabolizing arachidonic acid by the 5-Lipoxygenase pathway.

Some of the Conditions in which 5-Lipoxygenase and leukotrienes can be excessively high and need to be suppressed.

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