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Effect of Food Intake on the Bioavailability of Boswellic Acids from a Herbal Preparation in Healthy Volunteers
Abstract
In this study we investigated the effects of concomitant food intake on the bioavailability of distinct boswellic acids (BAs) from the test preparation BSE-018, a dry extract from Boswellia serrata gum resin. In a randomised, open, single-dose, two-way crossover study, healthy male subjects received three capsules of BSE-018 equivalent to 786 mg dry extract of Boswellia serrata gum resin either in the fasted state or together with a standardised high-fat meal. BA plasma concentrations were analysed for up to 60 h after oral dosing by reversed phase HPLC. As compared to the fasted state (treatment A), the administration of BSE-018 concomitantly with a high-fat meal (treatment B) led to several-fold increased areas under the plasma concentration-time curves as well as peak concentrations of beta-boswellic acid (betaBA), 11-keto-beta-boswellic acid (KbetaBA) and acetyl-11-keto-beta-boswellic acid (AKbetaBA). Plasma levels of both acetyl-alpha-boswellic acid (AalphaBA) and alphaBA became only detectable when administered with treatment B, i.e., the high-fat meal. Accordingly, pharmacokinetic data could be calculated for betaBA, KbetaBA and AKbetaBA (treatment A) and for betaBA, KbetaBA, AKbetaBA, alphaBA, and AalphaBA (treatment B). For the first time these data reveal detailed kinetics of BAs after oral dosing of an extract and demonstrate a profound effect of food intake on the pharmacokinetic profile of the BAs. This finding should be very important whenever BAs would be considered for therapeutic use.
... In order not to exceed the framework of this review, the focus was set on the pharmacokinetic studies carried out in at least six humans determining more than one boswellic acid. Two studies of Gerbeth et al. [20] and Sterk et al. [21] fulfilled these requirements, the results of which are summarized in Table 1. In the study of Gerbeth et al. the subjects included in a prospective, randomized, placebo-controlled double-blind pilot clinical trial on the effect of Boswellia on cerebral edema were asked to take the Boswellia medication at home [22]. ...
... The blood samples were taken during weekly routine medical check-ups, irrespective of the time of medication intake [20]. The randomized, open, single-dose two-way cross over study of Sterk et al. was devoted to investigate the effect of concomitant standardized high-fat meal intake on the bioavailability of boswellic acids [21]. Compared to the high doses of Boswellia gum resin extracts that have been orally administered in the above studies, boswellic acids, especially KBA and AKBA, revealed very low bioavailability associated with a very high pharmacokinetic variability. ...
... Therefore several attempts were made to enhance the bioavailability of boswellic acids. As shown by Sterk et al. the bioavailability of boswellic acids could be significantly enhanced by concomitant intake of a fat-meal due to the solubilizing effect of bile acids [21]. Also the plasma concentration of KBA but not AKBA could be increased in 15 male volunteers who were administered a single dose of 800 mg Boswellia extract in fed conditions compared to the plasma levels obtained under fasted conditions. ...
Medicinal plants represent a big reservoir for discovering new drugs against all kinds of diseases including inflammation. In spite the large number of promising anti-inflammatory plant extracts and isolated components, research on medicinal plants proves to be very difficult. Based on that background this review aims to provide a summarized insight into the hitherto known pharmacologically active concentrations, bioavailability, and clinical efficacy of boswellic acids, curcumin, quercetin and resveratrol. These examples have in common that the achieved plasma concentrations were found to be often far below the determined IC50 values in vitro. On the other hand demonstrated therapeutic effects suggest a necessity of rethinking our pharmacokinetic understanding. In this light this review discusses the value of plasma levels as pharmacokinetic surrogates in comparison to the more informative value of tissue concentrations. Furthermore the need for new methodological approaches is addressed like the application of combinatorial approaches for identifying and pharmacokinetic investigations of active multi-components. Also the physiological relevance of exemplary in vitro assays and absorption studies in cell-line based models is discussed. All these topics should be ideally considered to avoid inaccurate predictions for the efficacy of herbal components in vivo and to unlock the “black box” of herbal mixtures.
... It is known that boswellic acids are absorbed from oral administration since circulating levels of several of these constituents have been documented in human plasma (Table 1). [1][2][3][4][5][6][7][8][9] To date, much focus has been on the activity of 11-keto-b-boswellic acid (KBA) and acetyl-11keto-b-boswellic acid; however, b-boswellic acid (BBA) levels have been shown to be 100-fold higher in human plasma. 1 Over 50% of adults in the United States use various types of supplements and recent reports indicate herbal supplement sales continue to grow each year. 10,11 B. serrata extract (BSE)-containing products have gained popularity with sales skyrocketing to a 674% increase, as reported in 2014 based on the American Botanical Council's annual report on herbal supplement sales in the United States. ...
... 11 Furthermore, B. serrata contin-ues to move up the list of 40 top-selling herbal supplements in the United States, and is currently positioned at number 19. 11 A Search of the U.S. National Institutes of Health (NIH) Dietary Supplement Label Database (DSLD) for B. serrata resulted in 460 products found containing B. serrata in the label. 13 The majority of BSE-containing products in commerce are marketed toward providing joint health (46%), flexibility (18%), and 4 2.453 (Fed) 7.471 6 10.1 7 6.35 8 4 3.551 6 3.5 7 Acetyl-a-boswellic acid 0.238 (Fed) 4 0.894 6 4.0 7 Acetyl-b-boswellic acid 1.724 6 2.4 7 4.90 8 BBA, b-boswellic acid; KBA, 11-keto-b-boswellic acid. ...
... 11 Furthermore, B. serrata contin-ues to move up the list of 40 top-selling herbal supplements in the United States, and is currently positioned at number 19. 11 A Search of the U.S. National Institutes of Health (NIH) Dietary Supplement Label Database (DSLD) for B. serrata resulted in 460 products found containing B. serrata in the label. 13 The majority of BSE-containing products in commerce are marketed toward providing joint health (46%), flexibility (18%), and 4 2.453 (Fed) 7.471 6 10.1 7 6.35 8 4 3.551 6 3.5 7 Acetyl-a-boswellic acid 0.238 (Fed) 4 0.894 6 4.0 7 Acetyl-b-boswellic acid 1.724 6 2.4 7 4.90 8 BBA, b-boswellic acid; KBA, 11-keto-b-boswellic acid. ...
Introduction: As the use of dietary supplements increases, botanical-drug interaction (BDI) potentials should be evaluated. Boswellia serrata extract (BSE) is traditionally used as an anti-inflammatory supplement. In the scientific literature, BSE has been shown to reduce the activity (55% to ≥65%) across major CYP450 enzymes, including CYP3A4/5 and CYP2C9, using baculovirus-infected insect cells. These reported results, contrasted with a seemingly history of safe use of BSE, led us to question the relevance of the results using pooled human liver microsomes (PHLM), when compared to a more physiologically relevant model such as primary human hepatocytes. Methods: This study compared PHLM and sandwich-cultured human hepatocytes (SCHH) by evaluating BSE potential inhibitory effects on CYP3A4/5 and CYP2C9 enzymatic activity. Results: In SCHH, inhibition of CYP3A4/5 by BSE was observed resulting in an IC 50 = 17.4 μg/mL with maximum inhibition effect of >70% at 75 μg/mL versus IC 50 = 1.4 μg/mL with a maximum inhibition effect of 98% at 50 μg/mL in PHLM. IC 50 values for CYP2C9 inhibition by BSE were >75 μg/mL with a maximum inhibition effect of <30% versus 11 μg/mL with a maximum inhibition effect of 84% at 50 μg/mL using SCHH and PHLM, respectively. Discussion and Conclusions: Potent CYP3A4/5 and CYP2C9 inhibition observed for BSE in microsomal systems was not observed in SCHH. SCHH are particularly useful for studying complex mixtures such as botanicals. Although our data would suggest that BDI with BSE is low for most drugs, narrow therapeutic drugs such as warfarin should still be used with caution when combined with BSE.
... The results showed some major differences between the samples. The total percentage of PTA varies from 0% (<LOD/LOQ) in B. frereana (samples # [38][39][40] and >35% in B. sacra (sample # 5) and B. carterii (sample # 26) (see Table S1). Further, the results of the HPLC-MS/MS analysis of the extracts were corrected by the extraction yield to obtain the PTA concentrations in the corresponding oleogum resins. ...
... As a result, solubility of the nonpolar PTA and thereby the availability for the cells could be decreased. In line with that, the bioavailability of boswellic acids in vivo depended critically on the presence of bile acids and was therefore significantly increased by a concomitant high-fat meal [38]. Likewise, bioavailability of boswellic acids in a formulation with lecithin, a natural emulsifier, was greatly enhanced [39]. ...
Pentacyclic triterpenic acids from oleogum resins of Boswellia species are of considerable therapeutic interest. Yet, their pharmaceutical development is hampered by uncertainties regarding botanical identification and the complexity of triterpenic acid mixtures. Here, a highly sensitive, selective, and accurate method for the simultaneous quantification of eight boswellic and lupeolic acids by high-performance liquid chromatography with tandem mass spectrometry detection (HPLC-MS/MS) was developed. The method was applied to the comparative analysis of 41 oleogum resins of the species B. sacra, B. dalzielli, B. papyrifera, B. serrata, B. carterii, B. neglecta, B. rivae, B. frereana, and B. occulta. Multivariate statistical analysis of the data revealed differences in the triterpenic acid composition that could be assigned to distinct Boswellia species and to their geographic growth location. Extracts of the oleogum resins exhibited cytotoxicity against the human, treatment-resistant, metastatic breast cancer cell line MDA-MB-231. Extracts from B. sacra were the most potent ones with an average IC 50 of 8.3 ± 0.6 µg/mL. The oleogum resin of the B. sacra was further fractionated to enrich different groups of substances. The cytotoxic efficacy against the cancer cells correlates positively with the contents of pentacyclic triterpenic acids in Boswellia extracts.
https://www.mdpi.com/1420-3049/24/11/2153
... urs-12-ene-3b,24-diol is present as an isomeric diol (Aktionen, 1967). Boswellia serrata extractions consist o gum resins containing around 0 0 o -and -boswellic acids. of the total extracts are mostly bioactive AKBA fractions (Sterk et al., 2004). ...
... Boswellia serrata extractions consist of gum resins containing around 50-60% of α-and β-boswellic acids. 1-3% of the total extracts are mostly bioactive AKBA fractions (Sterk et al., 2004). ...
... urs-12-ene-3b,24-diol is present as an isomeric diol (Aktionen, 1967). Boswellia serrata extractions consist o gum resins containing around 0 0 o -and -boswellic acids. of the total extracts are mostly bioactive AKBA fractions (Sterk et al., 2004). ...
... Sterket al., reported very low plasma concentration in human volunteers, while the study of Sharma et al. showed that AKBA was not detected in plasma. 8,9 In order to circumvent this problem, Solid lipid boswelliaserrataparticle having phosphatidylcomplexation of BSE was developed for better bioavailability of BAs. Metabolic stability studies evaluate the susceptibility of compounds to biotransformation or intrinsic clearance; it also helps in the prediction of pharmacokinetic parameters. ...
Boswellic acids (BAs) including 11-keto-β-boswellic acid (KBA) and 3-acetyl-11-keto-β-boswellic acid (AKBA) are the active principles of Boswelliaserrata extract (BSE) which is used in traditional Indian medicine for the treatment of inflammatory conditions. BAs are characterized by low oral bioavailability. In order to circumvent this problem, solid lipid boswelliaserrata particles (SLBSP) were developed which is essentially a complexation of BAs with phospholipids such as phosphatidyl choline. The objective of this study was to compare the metabolic stability of SLBSP versus plain BSE using HHL-17, a Human telomere inactivated hepatocyte cell line. The two
formulations were incubated in HHL-17 for time points ranging from 30 minutes to 480 minutes. At the end of incubation period, cells were lysed and concentration of KBA and AKBA in the cell lysates was estimated using a validated LC-MS/MS technique. It was observed that KBA from plain BSE was cleared by the hepatocytes with a half-life of 5.8 hours, whereas, KBA from SLBSP exhibited lesser accumulation in hepatocytes and lowmetabolic clearance. No difference was observed in the rate of metabolism of AKBA from the two formulations. It can be concluded that phospholipid complexation confers metabolic stability to KBA by rendering it less permeable into human hepatocytes.
... Despite the beneficial biological effects of boswellic acids, their poor pharmacokinetic properties lead to a modest (Sharma et al. 2004;Sterk et al. 2004). The mean elimination half-life time for 11-keto β-boswellic acid is about 6 h (Sharma et al. 2004). ...
Boswellic acids, the main active compound found in the oleo-gum resin of Boswellia serrata Roxb., Burseraceae, have been used in traditional and modern medicine due to their strong therapeutic effects. These pentacyclic triterpene structures exhibit a wide range of biological activities, including anti-inflammatory, anti-tumor, antiviral, hepatoprotective, gastroprotective, antidiabetic, antimicrobial, hemolytic, antipruritic, spasmolytic, and antithrombotic properties. However, despite their beneficial effects against chronic diseases through multi-targeting properties such as inhibition of leukotriene and prostaglandin synthesis, the poor pharmacokinetic properties of boswellic acids lead to poor pharmacological performance. To address this issue, this review focuses on different strategies for boswellic acid nanoparticle formation and their therapeutic effects. Novel drug delivery systems such as polymeric micelles, metallic nanoparticles (ZnO and Ag), polymeric nanoparticles (chitosan and lactic-co-glycolic acid), nano metal organic frameworks (zeolitic imidazolate framework-8), phytosome, liposome, and nanogel are used for boswellic acid nanoparticle formation to increase oral bioavailability and pharmacokinetic properties. Overall, these novel drug delivery systems enhance the biological effects and pharmacokinetics properties of boswellic acids. Therefore, nanoparticle formation represents an important approach to improve the valuable therapeutic effects of boswellic acids.Graphical Abstract
... However, concentrations of 11-keto-β-boswellic acid were highest among the patient with the highest measured reduction in edema [93]. Results found by another randomized control trial looking more broadly at serum levels of BA constituents suggested that β-boswellic acids may be the primary active component of the extract as it was measured at steady serum levels [94]. The variability seen in these studies may result from the influence of participant diet, as the oral bioavailability of BA has been shown to increase when combined with dietary fat compared to when taken in a fasted state [95]. ...
Steroid use is a widely accepted practice for both the treatment and prevention of tumor-induced edema, but there are many unknowns regarding their current clinical utility with modern anti-tumor therapies. This decreases edema and relieves the symptomatic mass effect. There are clearly understood benefits and commonly accepted complications of methylprednisolone (MP) use, but the topic is recently controversial. With immunotherapy advancing, a robust immune response is crucial for full therapeutic efficacy. The immunosuppression of MP may interfere with future and current therapeutics relying on the integrity of the patient’s immune system. This further emphasizes the need for alternative agents to effectively treat tumor-induced cerebral edema. This review highlights the current clinical utility of steroids to treat brain tumor-related edema and the underlying pathophysiology. It also reviews details regarding different steroid formulations and dosing. Research available regarding concurrent steroid use with immunotherapy is detailed next, followed by alternatives to steroids and barriers to their adoption. Finally, this paper discusses pre-clinical findings and emerging treatments aimed to augment or replace steroid use.
... In previous clinical studies the major toxic effects of B. serrata that limited dose were gastrointestinal [32,33]. Patients were instructed to contact the study team if they experienced any intolerable side effect, and the dose was withheld for up to three days until the adverse event improved or resolved. ...
Background
Boswellic acids, the active components of frankincense, have been shown to suppress tumor proliferation and apoptosis in vitro with a strong clinical trial safety profile in patients with inflammatory diseases. We performed a Phase Ia window of opportunity trial of Boswellia serrata (B. serrata), the plant that produces frankincense, in patients with breast cancer to evaluate its biologic activity and safety.
Methods
This was a Phase Ia window of opportunity trial invasive breast cancer patients treated pre-operatively with B. Serrata (2400 mg/day PO) until the night before surgery. Paraffin-embedded sections from pretreatment diagnostic core biopsies were evaluated using a tunnel assay and immunohistochemistry staining with Ki-67 antibodies. A non-intervention control arm consisted of core and surgical tissue specimens from untreated patients was used to compare to patients treated with B. Serrata. The change in proliferation and apoptosis between diagnostic core specimens and specimens obtained at surgery was compared between the control and treatment groups using a two-tailed paired t-test.
Results
There was an increase in percent change in proliferation from core biopsy to surgical excision in the control group (n = 18) of 54.6 ± 21.4%. In the B. serrata-treated group there was a reduction in proliferation between core biopsy and excision (n = 18) of 13.8 ± 11.7%. The difference between core and surgical specimens was statistically significant between the control and B. serrata-treated groups (p = 0.008). There was no difference in change in apoptosis. There were no serious adverse events related to the drug.
Conclusion
Boswellia serrata inhibited breast cancer proliferation in vivo in a clinically well-tolerated Phase Ia window of opportunity trial.
Trial registration: ClinicalTrials.gov. Identifier NCT03149081, date of registration May 11, 2017
... Research conducted by Sami et al. (2019) demonstrated the existence of an antioxidant effect that acts as a nephroprotective in doxorubicin-induced nephrotoxicity. Research conducted by Sterk et al. (2004) regarding the pharmacokinetics of boswellic acid revealed that the concentration of boswellic acid in plasma after administration of Boswellia serrate extract was very low. The results of further studies revealed that about 80% of the initial concentration of boswellic acid is metabolized after 15 minutes and less than 1% of the initial concentration remains in plasma after 120 minutes (Kruger et al. 2008). ...
Cyclophosphamide (CP) is a chemotherapeutic agent that belongs to the alkylating agent group that is widely used in the treatment of cancer. Cardiotoxicity is often a side effect of using CP in medical therapy. In this study, 24 Sprague Dawley rats were randomly divided into 4 groups. Group 1 (K1) was given injection with aqua pro injection intraperitoneally (IP) once a week for 21 days. Group 2 (K2) was given IP CP with a dose of 50 mg/kg BW, once a week for 21 days. Group 3 (K3) was given boswellic acid extract at a dose of 250 mg/kg BW orally, every day for 21 days. Group 4 (K4) was given boswellic acid nanoparticles at a dose of 250 mg/kg BW orally, every day for 21 days. During the treatment the body weight of the rats was weighed every day. At the end of the treatment, the rats were euthanized and blood samples were taken for blood biochemical evaluation, namely CPK, LDH, AST, and ALT. The results showed that the levels of CPK, LDH, AST, and ALT in K2 were significantly higher (p<0.05) than K1, K3 and K4. Statistically, the results of CPK, LDH, AST and ALT in K3 and K4 were not significantly different (p<0.05) compared to K1. The two groups (K3 and K4) were not significantly different (p<0.05) but on average the CPK, LDH, AST, and ALT results in K4 had lower scores than K3. This can indicate the protective effect of boswellic acid and boswellic acid nanoparticles on the heart against cyclophosphamide-induced cardiotoxicity.
... Hence, the research study was aimed at synthesizing boswellic acid silver nanoparticles with a small particle size that can act as novel structures [19] to enhance the solubility and therapeutic activity. The trial was also extended to understand the in vitro drug release kinetics. ...
The Boswellic acids are pentacyclic triterpenoids obtained from the plant Boswellia serrata gum resin proven to be effective as anti-inflammatory agents in the treatment of inflammatory bowel disease, rheumatoid arthritis, and gout. The Boswellic acids were isolated from the gum resin of the plant B. serrata and characterized by UV-HPLC, TLC, and FTIR studies and further converted into silver nanoparticles using concentration variation method. The green synthesized boswellic acid silver nanoparticles were novel structures with 277.3 ± 0.5 nm size, stable without agglomeration characterized by UV-HPLC, DLS, SEM, XRD, and FTIR spectral studies. The green synthesized boswellic acid silver nanoparticles were evaluated for in vivo anti-inflammatory activity using the carrageenan-induced rat paw edema method and also compared with native boswellic acid and standard diclofenac. The Boswellic acid silver nanoparticles were found to show high inhibitory activity at 500 mg/kg and 2000 mg/kg body weight dose when compared to the native boswellic acid and standard diclofenac at the same doses. The novel Boswellic acid silver nanoparticles were studied for in vitro drug release kinetics using USP dissolution apparatus I (Basket type) which resulted in sustained release characteristics when compared with native boswellic acid. The invivo and invitro correlation for bioavailability and size modulation impact are needed to establish safety of Boswellic acid silver nanoparticles as novel dosage forms.
... Among all the Boswellic acids of Boswellia species, the two BAs that are highly potent and have great anti-inflammatory properties are keto boswellic acid and acetyl keto boswellic acid. [21,22] ...
“Boswellia serrata” is a herb used for ages in the Indian system of medicine and other systems of medicines across the world. It comes under the family “Burseraceae”. The Boswellia serrata is called by various local names in different regions, out of which “Kundur” “salai” “guggul” “Shallaki” are very prominently used. “Shallaki” is a widely used active ingredient in the “Unani” “Siddha” and “Ayurvedic” medicines oriented for the treatment of inflammation and pain. It is also used as a component to add fragrance to the products. Boswellia serrata plant contains oleo-gum resins and the ASU drug manufacturer mostly use this resin to prepare Boswellia-oriented drugs and this practice of using resin as the key component of drugs is very old and effective. In ancient ayurvedic texts, particular methods describe the extraction, purification, and usage of this oleo gum resin. Now in the modern era, when a lot of research has been done on this plant and its parts, this plant has come out to be even more important as it is found to be showing specific characteristics beneficial for treating illnesses such as dysentery, urinary tract disorders, hemorrhoids, ulcers, and dyspepsia. The present review provides an overview of some pharmacological activities and the importance of “Salaiguggal” or “ Boswellia serrata “. “Salai guggal” is rich in essential oils, and therefore, it becomes important for the perfume industries as its essential oils are soothing to smell and show therapeutic effects. The essential oils of Boswellia serrata are a mixture of different boswellic acids such as “mono-terpenes”, “di-tepenes” and “sesqui-terpenes”. Whereas the oleo gum resin of “ Boswellia serrata “ comprises monosaccharides such as pentose and hexose sugars. The oleo gum resin of this plant is highly recommended by almost every medical practitioner who deals in herbal medicines as it has shown a huge range of effective characteristics in asthma, cancer, microbial/fungal infections, inflammation, arthritis, diarrhea, and also as an analgesic. A proper systematic literature review was done using different databases that were available online like Google Scholar, PubMed, and ScienceDirect.
... The concomitant administration of the extract with a high-fat meal led to a several-fold increase in AUC as well as peak concentrations of βBA, KβBA, and AKβ-BA when compared to the fasted state. Plasma levels of both AαBA and αBA could only be detected when administered together with the high-fat meal (Sterk et al., 2004). ...
... Henkel et al. suggested that βBA acts as a direct LPS inhibitor and may contribute to anti-inflammatory effects by inhibiting LPS activity in a range of blood plasma levels (6.4-10.1 µM) after oral administration of standard doses of BA extract [22,27,28]. The neutralization mechanism of LPS by βBA may be a key part of the molecular actions responsible for valuable BA effects and might be one of the significant BA derivatives in LPS-induced inflammatory diseases. ...
Osteoporosis is a systemic metabolic bone disorder that is caused by an imbalance in the functions of osteoclasts and osteoblasts and is characterized by excessive bone resorption by osteoclasts. Targeting osteoclast differentiation and bone resorption is considered a good fundamental solution for overcoming bone diseases. β-boswellic acid (βBA) is a natural compound found in Boswellia serrata, which is an active ingredient with anti-inflammatory, anti-rheumatic, and anti-cancer effects. Here, we explored the anti-resorptive effect of βBA on osteoclastogenesis. βBA significantly inhibited the formation of tartrate-resistant acid phosphatase-positive osteoclasts induced by receptor activator of nuclear factor-B ligand (RANKL) and suppressed bone resorption without any cytotoxicity. Interestingly, βBA significantly inhibited the phosphorylation of IκB, Btk, and PLCγ2 and the degradation of IκB. Additionally, βBA strongly inhibited the mRNA and protein expression of c-Fos and NFATc1 induced by RANKL and subsequently attenuated the expression of osteoclast marker genes, such as OC-STAMP, DC-STAMP, β3-integrin, MMP9, ATP6v0d2, and CtsK. These results suggest that βBA is a potential therapeutic candidate for the treatment of excessive osteoclast-induced bone diseases such as osteoporosis.
... Accordingly, in vitro study in Caco-2 cells, a well-accepted model to simulate human intestinal absorption, revealed only moderate to poor permeability for boswellic acids and low permeability for AKBA [32]. This outcome can be explained on the basis of their high hydrophobicity and in turn very low water solubility, justifying the negligible quantity orally absorbed [33]. Therefore, such poor bioavailability is a major limitation to the efficacy of this herbal product. ...
The 3-O-acetyl-11-keto-β-boswellic acid (AKBA) is the most active compound of Boswellia serrata proposed for treating neurodegenerative disorders, including Alzheimer's disease (AD), characterized in its early phase by alteration in mood. Accordingly, we have previously demonstrated that an intracerebroventricular injection of soluble amyloid beta 1-42 (Aβ) peptide evokes a depressive-like phenotype in rats. We tested the protective effects of AKBA in the mouse model of an Aβ-induced depressive-like phenotype. We evaluated the depressive-like behavior by using the tail suspension test (TST) and the splash test (ST). Behavioral analyses were accompanied by neurochemical quantifications, such as glutamate (GLU), kynurenine (KYN) and monoamines, and by biochemical measurements, such as glial fibrillary acid protein (GFAP), CD11b and nuclear factor kappa B (NF-kB), in mice prefrontal cortex (PFC) and hippocampus (HIPP). AKBA prevented the depressive-like behaviors induced by Aβ administration, since we recorded a reduction in latency to initiate self-care and total time spent to perform self-care in the ST and reduced time of immobility in the TST. Likewise, the increase in GLU and KYN levels in PFC and HIPP induced by the peptide injection were reverted by AKBA administration, as well as the displayed increase in levels of GFAP and NF-kB in both PFC and HIPP, but not in CD11b. Therefore, AKBA might represent a food supplement suitable as an adjuvant for therapy of depression in early-stage AD.
... Corosolic acid Reviews healthy volunteers, produced by a single oral dose of Boswellia extract (AKBA 20-30 mg), was attributable to increased absorbance following a high-fat meal [C max : 6 ng/mL (fasted) vs. 28.8 ng/mL (fed)] [67,68]. After repeated oral administration of a Boswellia extract (800 mg, three times daily for 4 weeks), the steady-state concentration was 0.04 µM (~20.5 ng/mL) [69]. ...
Retinal diseases are a leading cause of impaired vision and blindness but some lack effective treatments. New therapies are required urgently to better manage retinal diseases. Natural pentacyclic triterpenoids and their derivatives have a wide range of activities, including antioxidative, anti-inflammatory, cytoprotective, neuroprotective, and antiangiogenic properties. Pentacyclic triterpenoids have great potential in preventing and/or treating retinal pathologies. The pharmacological effects of pentacyclic triterpenoids are often mediated through the modulation of signalling pathways, including nuclear factor erythroid-2 related factor 2, high-mobility group box protein 1, 11β-hydroxysteroid dehydrogenase type 1, and Src homology region 2 domain-containing phosphatase-1. This review summarizes recent in vitro and in vivo evidence for the pharmacological potential of pentacyclic triterpenoids in the prevention and treatment of retinal diseases. The present literature supports the further development of pentacyclic triterpenoids. Future research should now attempt to improve the efficacy and pharmacokinetic behaviour of the agents, possibly by the use of medicinal chemistry and targeted drug delivery strategies.
... Boswellic acids are targeted by CYP-3A4-mediated intestinal metabolism, buildup in enterocytes, gastrointestinal instability, and saturation kinetics, all adding up to poor gastric absorption [26]. All these factors contribute to poor oral bioavailability of boswellic acids [27]. ...
PurposeMacromolecules are important in polymer-based drug delivery systems as they help in specific targeting. This study explores the use of guggul gum (GG) and chitosan (Ch) in encapsulating boswellic acid (BA) which has high first-pass metabolism and low aqueous solubility for possible uses in inflammatory conditions.Methods
Ionic complexation was used for nanoparticle formulation. The contents of guggul gum, chitosan, and boswellic acid were taken as independent variables, and their influence on encapsulation, particle size, and polydispersity were optimized by using Box-Behnken design. The developed formulation was assessed for drug release (in vitro) and release kinetics, stability, and preclinical pharmacokinetics. The formulation was also evaluated for inhibition of carrageenan-induced hind paw inflammation in rats.ResultsThe nanoparticles were successfully prepared by ionic complexation method. The runs suggested by the design yielded a quadratic model for predicting the relationship between independent variables and responses. The optimum condition suggested by point prediction tool yielded spherical nanoparticles with 81.7% encapsulation, drug loading 21.2%, 377.19 nm size, and 0.201 PDI. The nanoparticles showed zero-order kinetics demonstrating an amalgamation of drug diffusion through matrix and erosion of polymeric medium.Conclusion
Ionic complexation is a suitable method for nanopartile formulation. GG-Ch nanoparticles are beneficial for specific delivery and anti-inflammation of boswellic acid. The bioavailability of boswellic acid was increased by 11.38 times when given as a GG-Ch nanoparticle. The nanoparticles were stable at 25 °C for 6 months.
... Conversely, pharmacokinetic studies of boswellic acids only revealed poor bioavailability, especially with regards to the two boswellic acids contents namely KBA and AKBA. Several studies have shown that despite the use of high doses of boswellic acid derivatives in oral administration, little or none detectable levels of these active derivatives can be found in human biological blood or fluids (Sterk et al., 2004;Krüger et al., 2008;Sharma et al., 2010) . The current scientific hypothesis is that poor absorption and high metabolism of boswellic acids may be responsible for the low bioavailability. ...
Chronic inflammation is a key culprit factor in the onset and progression of several diseases. Novel and pharmacologically effective therapeutic approaches are needed for new treatment remedy or improved pharmacokinetics and pharmacodynamics for existing synthetic drugs, in particular natural products. Boswellic acids are well-known natural products, with capacity to effectively retard inflammation without severe adverse effects. However, the therapeutic use of Boswellic acids are greatly hindered by its poor pharmacokinetic properties. Co-administration strategies that facilitate the oral absorption and distribution of Boswellic acids should lead to a safe and more effective use of this product prophylactically and therapeutically in inflammatory disorders. In this study, we examined the effect of Piper longum extract on the absorption and bioavailability of Boswellic acid in rabbits. In addition, we further explored computational pharmacodynamic interactions between Piper longum and Boswellic acid. Piper longum extract at 2.5 and 10 mg/kg, increased the bioavailability of Boswellic acid (p < 0.05). Based on our drug-based computational modeling, cytochrome P450 (CYP450)-mediated mechanism was involved in increased bioavailability. These findings confirmed that Piper longum with Boswellic acid may be administered orally together for effective therapeutic efficacy. Thus, our studies support the application of Piper longum with Boswellic acid as a novel therapeutic avenue in diseases associated with inflammation.
... Previous studies on KBA and AKBA have suggested their low bioavailability and reported very low plasma concentration in human volunteers, while another study showed that AKBA was not detected in plasma [6,23]. In order to circumvent this, Solid lipid Boswellia serrata particle having phosphatidyl complexation of BSE was developed for better bioavailability of BAs [24]. ...
Objectives
The present study was planned to investigate the efficacy of SLBSP vs. standardized BSE for symptomatic knee osteoarthritis (OA) treatment.
Methods
It was a prospective, randomized, double-blind, double-dummy, placebo-controlled, and single-centre clinical trial for symptomatic osteoarthritis of knee. Subjects were randomized to receive SLBSP capsule+BSE Placebo or BSE tablet+SLBSP placebo for two months. Patients were allowed to take rescue analgesics (Acelofenac 100 mg). Improvement in pain and function was assessed utilizing WOMAC, VAS. Level of CTX-II in urine and serum levels of inflammatory cytokines including IL-2, IL-4, IL-6, TNF- α , and IFN-γ was measured initially and at end of treatment.
Results and conclusions
Western Ontario and McMaster Universities osteoarthritis index (WOMAC) and Visual Analog Scale score improved markedly in SLBSP as well as in BSE arm (p < 0.05). Difference in VAS and WOMAC scores between the two arms was not statistically significant. Most significant effect was observed in the need for rescue analgesics. SLBSP caused marked lowering of pro-inflammatory cytokines levels whereas a several fold increase was noted in the BSE arm (p < 0.05). Both groups showed marked improvement in pain, SLBSP being superior to BSE with respect to reducing the need for rescue analgesics in addition to modulating inflammatory cytokines.
... Despite the significant anti-inflammatory and anticancer potential of BAs, their hydrophobic nature decreases their absorption, which renders them poorly bioavailable, especially for oral administration. Early studies revealed that the bioavailability of BAs can be enhanced after the administration of fatty meal [27,28]. Subsequently, the enhancement of the absorption of BAs was investigated using the lecithin delivery system known as phytosomes [29]. ...
The biological activities of four aromatic plants, namely frankincense, myrrh, ginger, and turmeric, were reviewed in the current study. The volatile fraction (essential oil) as well as the nonvolatile fraction of these four plants showed different promising biological activities that are displayed in detail. These activities can include protection from and/or alleviation of some ailment, which is supported with different proposed mechanisms of action. This review aimed to finally help researchers to get a handle on the importance of considering these selected aromatic plants, which have not been thoroughly reviewed before, as a potential adjuvant to classical synthetic drugs to enhance their efficiency. Moreover, the results elicited in this review encourage the consumption of these medicinal plants as an integrated part of the diet to boost the body's overall health based on scientific evidence.
... Abdel-Tawab et al. (2011) indicated that many pharmacokinetic studies had confirmed the fact that the bioavailability of BAs, especially KBA and AKBA, is low due to the hindered systemic absorption, both in animals and in humans. In this context, Sterk et al. (2004) mentioned the beneficial effects of a fatty meal on the bioavailability of BAs combined with the improvement of absorption lately reported for a novel lecithin formulation of curcumin. It encouraged the researchers to compare the bioavailability of BAs in a soy lecithin formulation of the extract of B. Serrata with the unformulated extract. ...
... Pharmacokinetics properties of BA AKBA and KBA are lipotropic fractions of BA responsible for their poor intestinal penetration and high retention [28,29]. Literature reports that the bioavailable plasma levels of various BAs were enhanced many folds by simultaneous administration of a fat-rich food [16]. ...
Boswellia serrata (Burseraceae) is the most ancient and respected herbs in Ayurveda. In Unani system of medicine, oleo-gum resin of Boswellia serrata named Kundur played a prime ingredient role in modern quality perfumes. The gum is used as a remedy for treatment of illness especially skin diseases and rheumatism in Indian system of medicine (Sidha, Ayurvedic and Unani) for last diverse centuries. Salai guggul is one of the accepted drugs for various complaints such as dyspepsia, dysentery, lung diseases, urinary disorder, haemorrhoids and corneal ulcer in Unani system of medicine for the last several decades.The present article is aimed to provide an overview on various pharmacological activities of Boswellia serrata. The resin fraction of salai guggal is rich in boswellic acids and its essential oils that are composed of a mixture of mono, di and sesquiterpenes while gum fraction chiefly contains pentose and hexose sugars. The oleo-gum resin is quite popular among the practitioners of traditional system and possesses wide range of useful biological properties such as antiasthmatic, anticancer, antifungal, anticomplementary, antihyperlipidemic, antiinflammatory, antiarthritic, antirheumatic, antidiarrheal, antimicrobial, antifungal and analgesic.An exhaustive review of literature was performed using various databases on science direct, scopus, pubmed, google scholar and free patents online.This review is a sincere attempt to discuss and present the current status of pharmacological profile of Boswellia serrata.
... Their bioavailability can be improved by increasing the low solubility in the gastrointestinal fluid for better absorption, and, in some cases, by inhibiting their metabolism. It has been shown that high-fat meals enhance triterpene absorption [179]. As a triterpenoid compound, oral administration of OA in rats resulted in low gastrointestinal absorption and hepatic microsomal metabolism [174]. ...
Neuroprotective agents are able to defend the central nervous system against acute or chronic neuronal injuries. Even with the progress made over the last decades, most of the medications prescribed for the management of neurodegenerative diseases can only reduce their symptoms and slow down their progression. Based on natural product research, there are potential effective medicinal plants and phytochemicals for modulating neuronal functions and protecting against neurodegeneration. Plants in the genus Pistacia are also among valuable natural resources for neuroprotection research based on experiences in traditional medicine. Studies have supported the value of bioactive compounds of the genus Pistacia for central nervous system disorders such as Alzheimerʼs, Parkinsonʼs, multiple sclerosis, cerebral ischemia, depression, and anxiety. Related literature has also revealed that most of the evidence on neuroprotection in the genus Pistacia is in the form of preliminary studies, mainly including models of behavior, motor function, and memory impairments in animals, neural toxicity, cerebral ischemia and seizure models, evaluation of their effects on antioxidant and inflammatory biomarkers, amyloid β aggregation, and acetylcholinesterase as well as investigations into some cellular pathways. Along with the phytonutrients in kernels such as pistachios, various phytochemicals, mostly terpenes, and phenolic compounds have also been identified in different plant parts, in particular their oleoresins, of species in the genus Pistacia. In this review, the pharmacology of neurological effects and related molecular mechanisms of the plants belonging to the genus Pistacia and its active constituents, as well as pharmacokinetics aspects, are discussed.
... Such lipids can act as a natural emulsifier for nonpolar compounds like BAs and LAs and increase their bioavailability [44]. Accordingly, the intake of a FN in combination with a high-fat meal improved the bioavailability of BAs in humans [45]. Hence, the intake of pure BAs and LAs in the absence of solubility enhancers might decrease their bioavailability and worsen the therapeutic response. ...
For centuries, frankincense extracts have been commonly used in traditional medicine, and more recently, in complementary medicine. Therefore, frankincense constituents such as boswellic and lupeolic acids are of considerable therapeutic interest. Sixteen frankincense nutraceuticals were characterized by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS), revealing major differences in boswellic and lupeolic acid compositions and total contents, which varied from 0.4% to 35.7%. Frankincense nutraceuticals significantly inhibited the release of proinflammatory cytokines, such as TNF-α, IL-6, and IL-8, by LPS-stimulated peripheral blood mononuclear cells (PBMC) and whole blood. Moreover, boswellic and lupeolic acid contents correlated with TNF-α, IL-1β, IL-6, IL-8, and IL-10 inhibition. The nutraceuticals also exhibited toxicity against the human triple-negative breast cancer cell lines MDA-MB-231, MDA-MB-453, and CAL-51 in vitro. Nutraceuticals with total contents of boswellic and lupeolic acids >30% were the most active ones against MDA-MB-231 with a half maximal inhibitory concentration (IC50) ≤ 7.0 µg/mL. Moreover, a frankincense nutraceutical inhibited tumor growth and induced apoptosis in vivo in breast cancer xenografts grown on the chick chorioallantoic membrane (CAM). Among eight different boswellic and lupeolic acids tested, β-ABA exhibited the highest cytotoxicity against MDA-MB-231 with an IC50 = 5.9 µM, inhibited growth of cancer xenografts in vivo, and released proinflammatory cytokines. Its content in nutraceuticals correlated strongly with TNF-alpha, IL-6, and IL-8 release inhibition.
... Both KBA and AKBA are extremely lipophilic drugs, which result in reduced absorption through the GIT, but they also exhibit high retention time. Preliminary pharmacokinetic studies have shown minimal concentrations of both AKBA and KBA in human plasma after administration of BSE [41, [219][220][221][222][223]. Moreover, the incidence of AKBA in plasma is uncertain due to its deacetylation to KBA in vivo [222]. ...
Natural compounds, in recent years, have attracted significant attention for their use in the prevention and treatment of diverse chronic diseases as they are devoid of major toxicities. Boswellic acid (BA), a series of pentacyclic triterpene molecules, is isolated from the gum resin of Boswellia serrata and Boswellia carteri. It proved to be one such agent that has exhibited efficacy against various chronic diseases like arthritis, diabetes, asthma, cancer, inflammatory bowel disease, Parkinson’s disease, Alzheimer’s, etc. The molecular targets attributed to its wide range of biological activities include transcription factors, kinases, enzymes, receptors, growth factors, etc. The present review is an attempt to demonstrate the diverse pharmacological uses of BA, along with its underlying molecular mechanism of action against different ailments. Further, this review also discusses the roadblocks associated with the pharmacokinetics and bioavailability of this promising compound and strategies to overcome those limitations for developing it as an effective drug for the clinical management of chronic diseases.
... This fact was confirmed through pharmacokinetic studies. [40] In this context, the beneficial effects of a fatty meal on the bioavailability of BAs combined with the improvement of absorption lately reported for a novel lecithin formulation of curcumin, Meriva [49] , have encouraged researchers to compare the bioavailability of BAs in a soy lecithin formulation of the extract of B. serrata with the unformulated extract. Husch et al. reported a novel data on the tissue distribution of BAs were provided through measurement of the concentration of the six major BAs in plasma as well as in different organs (brain, muscle, eye, liver, and kidney). ...
... This fact was confirmed through pharmacokinetic studies. [40] In this context, the beneficial effects of a fatty meal on the bioavailability of BAs combined with the improvement of absorption lately reported for a novel lecithin formulation of curcumin, Meriva [49] , have encouraged researchers to compare the bioavailability of BAs in a soy lecithin formulation of the extract of B. serrata with the unformulated extract. Husch et al. reported a novel data on the tissue distribution of BAs were provided through measurement of the concentration of the six major BAs in plasma as well as in different organs (brain, muscle, eye, liver, and kidney). ...
... However, a series of pharmacokinetic studies conducted in humans and in animal models indicate that after oral administration of Boswellia products, sufficient systemic concentration of AKBA is required for its anti-inflammatory activities. [50][51][52][53][54] Poor absorption through intestine and/ or extensive metabolism is the crucial factor affecting the systemic availability of AKBA and thus limiting the anti-inflammatory efficacy of Boswellia products. [54] Therefore, attempts were made to achieve an increased systemic availability of AKBA to improve further the anti-inflammatory potential of B. serrata extracts. ...
Osteoarthritis (OA) is the most common form of arthritis characterized by progressive destruction of joint cartilage tissue, pain and inflammation, stiffness, and impaired physical activity. It is the most prevalent and leading cause of pain and disability across the globe. During the pain and inflammatory process, 5-lipoxygenase (5-LOX) pathway is also involved, which generates leukotrienes (LTs), namely LTB4 and cysteinyl LTs. Osteoblasts also synthesize LTs, which stimulate and enhance the production of interleukin 1, tumor necrosis factor α, and various other cytokines that are potent inflammatory mediators. LT formation leads to cartilage degradation and compensates chondrocyte-mediated cartilage repair mechanism. Current therapies include nonsteroidal anti-inflammatory drugs, analgesics, and disease-modifying agents, but do not affect 5-LOX pathway. Boswellia serrata extract–derived boswellic acids are specific, non-redox inhibitors of 5-LOX, and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) possesses the most potent 5-LOX inhibitory activity. B. serrata extracts have shown significant efficacy and safety in the treatment of various inflammatory disorders such as OA, rheumatoid arthritis, asthma, and inflammatory bowel diseases. Aflapin® is a novel synergistic composition containing B. serrata extract selectively enriched with 20% AKBA and B. serrata nonvolatile oil. Aflapin® is a patented, selective, and most potent 5-LOX inhibitor, which significantly reduces joint pain, inflammation, stiffness, and improves physical function compared to placebo and other B. serrata extract. Aflapin® also significantly reduces matrix metalloproteinase levels, enhances chondrocytes proliferation, and increases glycosaminoglycans levels, thereby providing cartilage protection in arthritis. Numerous in vitro studies, preclinical studies, and clinical studies suggest the potential of Aflapin® as a useful therapeutic intervention for the management of arthritis.
... However, a series of pharmacokinetic studies conducted in humans and in animal models indicate that after oral administration of Boswellia products, sufficient systemic concentration of AKBA is required for its anti-inflammatory activities. [50][51][52][53][54] Poor absorption through intestine and/ or extensive metabolism is the crucial factor affecting the systemic availability of AKBA and thus limiting the anti-inflammatory efficacy of Boswellia products. [54] Therefore, attempts were made to achieve an increased systemic availability of AKBA to improve further the anti-inflammatory potential of B. serrata extracts. ...
Osteoarthritis (OA) is the most common form of arthritis characterized by progressive destruction of joint cartilage tissue, pain and inflammation, stiffness, and impaired physical activity. It is the most prevalent and leading cause of pain and disability across the globe. During the pain and inflammatory process, 5-lipoxygenase (5-LOX) pathway is also involved, which generates leukotrienes (LTs), namely LTB4 and cysteinyl LTs. Osteoblasts also synthesize LTs, which stimulate and enhance the production of interleukin 1, tumor necrosis factor α, and various other cytokines that are potent inflammatory mediators. LT formation leads to cartilage degradation and compensates chondrocyte-mediated cartilage repair mechanism. Current therapies include nonsteroidal anti-inflammatory drugs, analgesics, and disease-modifying agents, but do not affect 5-LOX pathway. Boswellia serrata extract–derived boswellic acids are specific, non-redox inhibitors of 5-LOX, and 3-O-acetyl-11-keto-β-boswellic acid (AKBA) possesses the most potent 5-LOX inhibitory activity. B. serrata extracts have shown significant efficacy and safety in the treatment of various inflammatory disorders such as OA, rheumatoid arthritis, asthma, and inflammatory bowel diseases. Aflapin® is a novel synergistic composition containing B. serrata extract selectively enriched with 20% AKBA and B. serrata nonvolatile oil. Aflapin® is a patented, selective, and most potent 5-LOX inhibitor, which significantly reduces joint pain, inflammation, stiffness, and improves physical function compared to placebo and other B. serrata extract. Aflapin® also significantly reduces matrix metalloproteinase levels, enhances chondrocytes proliferation, and increases glycosaminoglycans levels, thereby providing cartilage protection in arthritis. Numerous in vitro studies, preclinical studies, and clinical studies suggest the potential of Aflapin® as a useful therapeutic intervention for the management of arthritis.
... Syrovets et al. (2005b) studied the role of ABAs on activity of IKK and observed that ABAs promoted apoptosis in an androgen-independent PC-3 prostate cancer cell by inhibiting IKK in both in vitro and in vivo condition. On the basis of their findings, they concluded that AKβBA and associated molecules acting on IKK might offer a novel method for the treatment of chemoresistant human tumors such as androgen-independent human prostate cancers[42,43].Berthold et al. (2006) observed that extract of B. sacra inhibited the growth of prostate cancer cells of chemotherapy-resistant human PC-3 in vitro and provoked apoptosis as shown by activation of caspase 3 and the induction of DNA fragmentation[45,132]. ...
The Dhofar region of Oman is extremely opulent in plant biodiversity in comparison to other parts of the country. Most of the cultivated, medicinal and wild plants of the region are available in the mountainous side and hilly areas of Dhofar. The plants produce products from primary metabolism and others from secondary metabolism. On the basis of active constituents plants can be categorized into two groups:1. Medicinal plants and2. Aromatic plants.Over 250 complex chemicals have been recognized and extracted from herbal sources. In this review article, we discuss a selection of medicinal plants of the Dhofar region of Oman which are rich in active constituents and through recent reports discuss the application of the most active constituents. Among the medicinal plants of the Dhofar region, frankincense is also a well-known indicator of the region and has a unique position through its medicinal properties of its oil and gum resin.
... They are known to possess several pharmacological activities like anti-inflammatory, anti-arthritic, immunomodulatory, hypolipidemic, anti-tumor etc. [1][2][3]The major boswellic acids are β-boswellic acid (βBA), α-boswellic acid (αBA), Keto-βboswellic acid (KBA), Acetyl-Keto-β-boswellic acid (AKBA), Acetyl-αboswellic acid (AαBA) and Acetyl-β-boswellic acid (AβBA); out of these KBA and AKBA are therapeutically most active BAs [4,5]. Despite the fact that BAs are medicinal compounds their activity gets restricted due to low aqueous solubility owing to its lipophilic nature resulting in poor bioavailability [6][7][8][9]. Several reports were available on solubility enhancement of BAs such as hydrotropic solubilization [10] whereas, most others were based on phospholipid complexation used for absorption enhancement of BAs [11,12]. ...
Boswellic acids (BAs) a group of pentacyclic triterpenes have therapeutic activities. However, their lipophilic nature limits their aqueous solubility and thus bioavailability. Hence, present study aims to enhance solubility and dissolution of BA by solid dispersion (SD) technique using poloxamer (PXM) 188 and 407 as hydrophilic polymeric carriers. Effect of increasing concentration of PXMs on solubility of BAs was examined using phase solubility studies. The stability constants were 1667.5 M⁻¹ (BA: PXM 188) and 3707.4 M⁻¹ (BA: PXM 407) with an AL type curve. Negative Gibbs free energy (ΔGtr°) values indicated spontaneous nature of BA solubilization which decreased with increasing concentration of carrier demonstrating favorability of reaction. 1:1 and 1:2 SDs synthesized using kneading (KN) and solvent evaporation (SE) method were subjected to physicochemical characterization by FTIR and DSC to assess solid state interactions between BAs and PXMs that suggested interaction between carrier and BAs. Efficiency of PXMs was evaluated using saturated solubility and in vitro drug release studies. SDs of PXM 188 (1:2) and PXM 407(1:1) by KN showed highest solubility and drug release profile indicating ability of PXMs as solubility enhancers of BAs. Thus, SD technique helps improve the solubility and dissolution rate of poorly soluble BAs.
BACKGROUND
Adverse radiation effects (AREs) can occur after stereotactic radiosurgery (SRS), and symptomatic cases are often treated with corticosteroids, pentoxifylline, and vitamin E. The supplement 5-Loxin (Boswellia serrata) is an extract of Indian frankincense that inhibits vascular endothelial growth factor expression and has been shown to reduce perilesional edema in brain tumor patients undergoing fractionated radiation.
OBSERVATIONS
Three patients underwent SRS for meningioma or metastasis and developed symptomatic AREs at 4 to 8 months. They were initially treated with corticosteroids, pentoxifylline, and vitamin E with transient improvement followed by recurrent neurological symptoms and imaging findings as steroids were tapered off. All patients were rescued by the administration of 5-Loxin with resolution of neurological symptoms and imaging changes, discontinuation of steroids, and no medication side effects.
LESSONS
The author’s early experience with 5-Loxin has been encouraging, and this supplement has become the author’s first-line treatment for acute radiation effects after SRS. The author reserves bevacizumab for significant mass effect or failure of oral therapy. 5-Loxin has many advantages including low cost, ease of use, and patient tolerability. More experience is needed to confirm the role of 5-Loxin in the upfront treatment of AREs.
Boswellic acids are series of pentacyclic triterpenes, derived from the gum resin of Boswellia Genus, mostly from Boswellia serrata Roxb. (Burseraceae) tree commonly known as Indian Frankincense or salai guggul and traditionally used as an anti-inflammatory agent. It acts by inhibiting 5-Lipoxygenase, C3-convertase, cyclooxygenase preferably COX-1, Human Leukocyte Elastase, NF-κB expression, Topoisomerase I and II and microsomal Prostaglandin E2 synthase-1. Boswellia species are reported to have various pharmacological potentials like anti-inflammatory, anti-cancer, anti-microbial, anti-arthritic, immunomodulatory activity, neuroprotective activity, and are also proved to be effective against ileitis, ulcerative colitis, hypolipidemic, hypertension and hepatotoxicity. Regardless of their multiple uses, pharmacokinetic studies of Boswellic acids revealed their poor oral bioavailability, high lipophilicity, and their degradation by hepatic Phase I mechanism. With low solubility and poor bioavailability, different approaches have been applied to improve the poor pharmacokinetic profile of Boswellic acids. Designing and developing novel delivery systems for its enhanced permeability, improved bioavailability with better efficacy has been of great interest.
The link between diabetes and cognitive dysfunction has been reported in many recent articles. There is currently no disease-modifying treatment available for cognitive impairment. Boswellia serrata (B. serrata) is used traditionally to treat chronic inflammatory diseases such as type 2 diabetes (T2D), insulin resistance (IR), and Alzheimer’s disease (AD). This review aims to highlight current research on the potential use of boswellic acids (BAs)/B. serrata extract in T2D and AD. We reviewed the published information through June 2021. Studies have been collected through a search on online electronic databases (Academic libraries as PubMed, Scopus, Web of Science, and Egyptian Knowledge Bank). Accumulating evidence in preclinical and small human clinical studies has indicated that BAs/B. serrata extract has potential therapeutic effect in T2D and AD. According to most of the authors, the potential therapeutic effects of BAs/B. serrata extract in T2D and AD can be attributed to immunomodulatory, anti-inflammatory, antioxidant activity, and elimination of the senescent cells. BAs/B. serrata extract may act by inhibiting the IκB kinase/nuclear transcription factor-κB (IKK/NF-κB) signaling pathway and increasing the formation of selective anti-inflammatory LOX-isoform modulators. In conclusion, BAs/B. serrata extract may have positive therapeutic effects in prevention and therapy of T2D and AD. However, more randomized controlled trials with effective, large populations are needed to show a definitive conclusion about therapeutic efficacy of BAs/B. serrata extract in T2D and AD.
Objectives
The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3- O -acetyl-11-keto- beta -boswellic acid (AKBA) and 11- keto -boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs.
Methods
The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software.
Results
Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration ( C max ) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life ( t 1/2 ) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively.
Conclusions
The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.
Objectives
The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3- O -acetyl-11-keto- beta -boswellic acid (AKBA) and 11- keto -boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs.
Methods
The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software.
Results
Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration ( C max ) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life ( t 1/2 ) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively.
Conclusions
The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.
Inflammation and Natural Products brings together research in the area of the natural products and their anti-inflammatory action in medical, nutraceutical and food products, addressing specific chronic inflammatory diseases like cancer and the mechanistic aspects of the mode of action of some key natural products. Inflammation is a complicated process, driven by infection or injury or genetic changes, which results in triggering signalling cascades, activation of transcription factors, gene expression, increased levels of inflammatory enzymes, and release of various oxidants and pro-inflammatory molecules in inflammatory cells. Excessive oxidants and inflammatory mediators have a harmful effect on normal tissue, including toxicity, loss of barrier function, abnormal cell proliferation, inhibiting normal function of tissues and organs and finally leading to systemic disorders. The emerging development of natural product formulations utilizing the unique anti-inflammatory compounds such as polyphenols, polysaccharides, terpenes, fatty acids, proteins and several other bioactive components has shown notable successes. Inflammation and Natural Products: Recent Development and Current Status provides a comprehensive resource, ranging from detailed explanation on inflammation to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity. It is useful for graduate students, academic and professionals in the fields of pharmaceutical and medical sciences and specialists from natural product-related industries.
From ancient days onward, Boswellia and derived extracts had been used in many traditional systems of medicine. Traditional ayurvedic practices have referred the use of Boswellia referred as shallaki in different antiinflammatory disorders. The bioactive constituents responsible for the attributed pharmacological activities include the so-called boswellic acids. The antiinflammatory, analgesic, and antiarthritic activities of different boswellic acids mainly contribute to the benefitted pharmacological activities. Several preclinical and clinical studies report the availability of boswellic acids in the human brain and blood. Some of the studies have reported about related toxicities also. The chapter aims to present an overview on the phytochemical profiling, pharmacological activities, preclinical and clinical study overviews, bioavailability, etc.
This review is not intended to describe the triterpenes isolated from the Boswellia genus, since this information has been covered elsewhere. Instead, the aim is to provide insights into the biosynthesis of triterpenes in Boswellia. This genus, which has 24 species, displays fascinating structural diversity and produces a number of medicinally important triterpenes, particularly boswellic acids. Over 300 volatile components have been reported in the essential oil of Boswellia, and more than 100 diterpenes and triterpenes have been isolated from this genus. Given that no triterpene biosynthetic enzymes have yet been isolated from any members of the Boswellia genus, this review will cover the likely biosynthetic pathways as inferred from structures in nature and the probable types of biosynthetic enzymes based on knowledge of triterpene biosynthesis in other plant species. It highlights the importance of frankincense and the factors and threats affecting its production. It covers triterpene biosynthesis in the genus Boswellia, including dammaranes, tirucallic acids, lupanes, oleananes, ursanes and boswellic acids. Strategies for elucidating triterpene biosynthetic pathways in Boswellia are considered. Furthermore, the possible mechanisms behind wound-induced resin synthesis by the tree and related gene expression profiling are covered. In addition, the influence of the environment and the genotype on the biosynthesis of resin and on variations in the compositions and types of resins will also be reviewed.
Brain metastases are the most common intracranial neoplasms and are associated with an array of clinical problems that require complex medical management. These include focal neurologic deficits, seizures, cognitive impairment, and headache. We will review the data regarding the management of these problems. Iatrogenic sequelae and radiotherapy-related complications such as radiation necrosis will also be specifically addressed.
In India, traditional herbal medicines have been an essential part of therapy for the last centuries. However, a large portion of the general populace is using these therapies in combination with allopathy lacking a proper understanding of possible interactions (synergistic or antagonistic) between the herbal product and the allopathic drug. This is based on the assumption that herbal drugs are relatively safe, i.e. without side effects. We have established a comprehensive understanding of the possible herb-drug interactions and identified interaction patterns between the most common herbs and drugs currently in use in the Indian market. For this purpose, we listed common interactors (herbs and allopathic drugs) using available scientific literature. Drugs were then categorized into therapeutic classes and aligned to produce a recognizable pattern present only if interactions were observed between a drug class and herb in the scientific literature. Interestingly, the top three categories (with highest interactors), antibiotics, oral hypoglycemics, and anticonvulsants, displayed synergistic interactions only. Another major interactor category was CYP450 enzymes, a natural component of our metabolism. Both activation and inhibition of CYP450 enzymes were observed. As many allopathic drugs are known CYP substrates, inhibitors or inducers, ingestion of an interacting herb could result in interaction with the co-administered drug. This information is largely unavailable for the Indian population and should be studied in greater detail to avoid such interactions. Although this information is not absolute, the systematic literature review proves the existence of herb-drug interactions in the literature and studies where no interaction was detected are equally important.
Objectives:
Dietary supplements are increasingly used by people with osteoarthritis. Boswellia serrata extract, curcumin, pine bark extract and methylsulfonylmethane have been identified as having the largest effects for symptomatic relief in a systematic review. It is important to understand whether any pharmacokinetic interactions are among the major constituents of these supplements so as to provide information when considering the combination use of these supplements. The aim of this study was to investigate the pharmacokinetics of the constituents alone and in combination.
Methods:
This study was a randomized, open-label, single-dose, four-treatment, four-period, crossover study with 1-week washout. The pharmacokinetics of the constituents of these supplements when dosed in combination with methylsulfonylmethane were compared to being administered alone. Plasma samples were obtained over 24 h from 16 healthy participants. Eight major constituents were analysed using a validated ultra-high-performance liquid chromatography-tandem mass spectrometry assay.
Key findings:
The pharmacokinetics of each constituent was characterized, and there were no significant differences in the pharmacokinetic profiles of the constituents when administered as a combination, relative to the constituents when administered alone (P > 0.05).
Conclusions:
These data suggest that interactions between the major constituents of this supplement combination are unlikely and therefore could be investigated to manage patients with osteoarthritis without significant concerns for possible pharmacokinetic interactions.
Acetyl- Keto-β-boswellic acid (AKBA) is a pentacyclic triterpenic acid found in gum resin of Boswellia serrata. Even though it is shown to have anti-inflammatory activity, its bioavailability gets limited due to its poor aqueous solubility and permeability. The present study, hence, deals in enhancement of the intestinal absorption of AKBA from total boswellic acid fraction (TA fraction) using cyclodextrin (CD) and poloxamer solid dispersion (PXM SDs) formulations. Absorption studies were performed using the everted gut sac model prepared from rat jejunum. The glucose uptake assay was performed to show viability of gut sac tissue. The apparent permeability (Papp) value of AKBA from TA fraction was 1.08 ± 0.17 × 10⁻⁶ which was found to be increased by 10–14 fold with CD complex and SD formulations. The intestinal absorption studies showed highest absorption of AKBA from HP-β-CD complex and PXM 407 SD as compared to that from TA fraction. From this study, it can be concluded that HP-β-CD and PXM 407 effectively enhanced intestinal absorption through improved solubility, highlighting their role as efficient drug delivery agents and bioavailability enhancers.
OA is a chronic and disabling joint disease with limited evidence-based pharmacological treatment options available that improve outcomes for patients safely. Faced with few effective pharmacological treatments , the use has grown of dietary supplements and complementary medicines for symptomatic relief among people living with OA. The aim of this review is to provide a summary of existing evidence and recommendations supporting the use of supplements for OA. Systematic reviews and randomized controlled trials investigating oral supplements for treating OA were identified. Limited research evidence supports recommendations for the oral use of Boswellia serrata extract and Pycnogenol, curcumin and methylsulfonylmethane in people with OA despite the poor quality of the available studies. Few studies adequately reported possible adverse effects related to supplementation, although the products were generally recognized as safe. Further high quality trials are needed to improve the strength of evidence to support this recommendation and better guide optimal treatment of people living with OA.
Scope:
To assess bioavailability of terpenes in human plasma and their effect on oxidative stress biomarkers.
Methods and results:
In this open-label and single arm postprandial trial, seventeen healthy male volunteers (20-40 years old) followed a low-phytochemical diet for 5 days. Next, after overnight fasting, volunteers consumed Mastiha powder (a natural resin rich in terpenes) dispersed in water. Blood samples were collected on time-points 0h (before ingestion) and 0.5h, 1h, 2h, 4h, 6h, 24h (post-ingestion). Ultra High Pressure Liquid Chromatography-High Resolution Mass Spectrometry (UHPLC-HRMS) was applied for high throughput analysis of plasma. Serum resistance to oxidation and oxidized LDL (oxLDL) levels were measured. UHPLC-HRMS/MS analysis showed that major terpenes are bioavailable since 0.5h after administration, reaching a peak between 2h and 4h. Serum resistance to oxidation, expressed as difference of tLAG (time point-0h), started to increase from 0.5h. This increase reached statistical significance at 4h (402.3 ± 65.0sec), peaked at 6h (524.6 ± 62.9sec) and remained statistically significant until 24h (424.2 ± 48.0sec). oxLDL levels, expressed as %change from 0h, were reduced significantly from time point-1h until time point-6h.
Conclusion:
Results demonstrate the terpene bioavailability pattern after oral administration of Mastiha. Terpenes are potential mediators of antioxidant defense in vivo. This article is protected by copyright. All rights reserved.
Boswellic acids (BAs) are a group of pentacyclic triterpenes present in gum-resin of Boswellia serrata. They are well known for their anti-inflammatory, hypolipidemic, immunomodulatory and anti-tumor activity, but they have poor aqueous solubility and limited bioavailability. In order to enhance their aqueous solubility, inclusion complexes of BAs with β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were synthesized and their drug release profiles were studied. Molecular associations of β-CD and HP-β-CD with BAs were investigated by phase solubility studies. The stability constants were found to be 380.2 and 145.9 M⁻¹ for BA: β-CD and BA: HP-β-CD inclusion complexes, respectively with AN- type curve. BA: β-CD and BA: HP-β-CD inclusion complexes were synthesized using kneading (KN), co-precipitation (CP) and solvent evaporation (SE) methods in 1:1 as well as 1:2 ratios. Further these were characterized by Fourier transform infrared (FTIR) spectrophotometry, Powder X-ray Diffraction (P-XRD) and Differential scanning calorimetric (DSC) analysis. FTIR analysis showed shifting of frequencies in complexes as compared to CDs and BAs. P-XRD data obtained for BA: β-CD complexes synthesized by CP and SE methods showed amorphous pattern. Also, DSC analysis showed a change in thermal behaviour for synthesized complexes. In vitro drug release studies of BA: β-CD complexes showed enhanced release with 1:2 complexes than 1:1 complexes at pH 1.2 and pH 6.8. Similarly, drug release enhancement was observed more with BA: HP-β-CD complexes in 1:2 ratio than 1:1. To understand the interaction of BAs with CD cavity molecular modelling studies were performed which favored 1:2 complex formation over 1:1 complexes. The study thus highlights that CDs can be used for solubility and dissolution enhancement of BAs.
Pentacyclic triterpenes from the 11-keto-boswellic acid series were identified as the active principal ingredients of Boswellia resin, inhibiting the key enzyme of leukotriene biosynthesis, 5-lipoxygenase (5-LO). Of the genuine boswellic acids hitherto characterized, 3-O-acetyl-11-keto-beta-boswellic acid, AKBA (1), proved to be the most potent inhibitor of 5-LO. In the course of purification of further boswellic acid derivatives from Boswellia resin, we observed the degradation of the natural compound 3-O-acetyl-11-hydroxy-beta-boswellic acid (2) to the thermodynamically more stable product 3-O-acetyl-9,11-dehydro-beta-boswellic acid (4). The metastable intermediate of this conversion, under moderate conditions of workup in methanolic solutions, was identified as 3-O-acetyl-11-methoxy-beta-boswellic acid (3). The novel artifactual boswellic acid derivatives inhibited 5-LO product formation in intact cells with different characteristics: 4 almost totally abolished 5-LO activity, with an IC50 of 0.75 mu M, whereas 3 and 9,11-dehydro-beta-boswellic acid (5), the deacetylated analogue of 4, were incomplete inhibitors. The data suggest that the conditions chosen for the workup of Boswellia extracts could significantly influence the potency of their biological actions and their potential therapeutic effectiveness.
3α-Acetyl-β-boswellic acid (1), 3α-acetyl-α-boswellic acid (2), 3α-acetyl-9,11-dehydro-β-boswellic acid (3), 3α-acetyl-9,11-dehydro-α-boswellic acid (4) and 3α-acetyl-11-keto-β-boswellic acid (5) were isolated from the gum resin of Boswellia serrata. 1D and 2D NMR (COSY45, HMQC, HMBC, ROESY) spectra at 500 MHz were used for shift assignments and structure verification. All boswellic acids investigated share the cis conformation at ring D/E and the 3α orientation of the acetyl ester group. Owing to high-order spectra, NMR could not determine the exact conformation of H-20/H-30 of the β-boswellic acids. 3α-Acetyl-β-boswellic acid methyl ester (1′) was synthesized for experiments with a shift reagent, Eu(fod)3, that enhanced the resolution considerably. The oxygen atoms of the 3α-acetyl group form the apparent complex binding site for the shift reagent. Copyright © 2003 John Wiley & Sons, Ltd.
Background: Leukotrienes and prostaglandines are important mediators of inflammation. While prostaglandine synthesis can be influenced by NSAIDs therapeutical approaches to the 5-lipoxygenase pathway are rare. Resinous extracts of Boswellia serrata (H15, indish incense), known from traditional ayurvedic medicine, decrease leukotriene synthesis in vitro. Case reports suggest a clinical role for that drug. Methods: Outpatients with active RA have been enrolled into a multicenter controlled trial. Patients received 9 tablets of active drug (3600 mg) or placebo daily in addition to their previous therapy. Doses of NSAIDs could be adjusted on demand. Efficacy parameters, Ritchies Index for swelling and pain, ESR, CRP, pain on VAS and NSAID dose were documented at baseline and 6 and 12 weeks after initiation. Mean values and medians were calculated to compare the groups for significant or clinically relevant change from baseline or difference between both groups at any time point of observation. Results: A total of 78 patients were recruited in 4 centers, the data have been published in abstractform. Only 37 patients (verum 18, placebo 19), enrolled in Ratingen were available for detailled efficacy and safety analysis. All evaluations in these patients were performed by one investigator (G.H.). There was no subjective, clinical or laboratory parameter showing a significant or clinically relevant change from baseline or difference between both groups at any time point of observation. The mean NSAID dose reduction reached levels of 5.8% (H15) and 3.1% (placebo). One patient in each group showed a good response in all parameters but 4 patients in each group worsened. The others showed no alteration of their disease. Conclusion: Treatment with H15 showed no measurable efficacy. Controlled studies including a greater patient population are necessary to confirm or reject our results.
A validated HPLC method for the determination of 11-keto-β-boswellic acid (KBA) in human plasma was developed. The method involves the solid-phase extraction of KBA from plasma followed by a separation with reversed-phase HPLC. Calibration was based on external standardisation and ranged between 0.1 and 2.0 μg KBA per ml plasma. Linearity was established over the entire calibration range and in each case the coefficient of correlation (r2) was above 0.99. The recovery of KBA from plasma was 85.7%. It was further demonstrated that the method can be applied successfully to monitor the level of KBA in plasma.
Suspensions of rat peritoneal polymorphonuclear leukocytes (PMNL) elicited with glycogen were stimulated by calcium and ionophore to produce leukotrienes and 5-HETE from endogenous arachidonic acid (AA). We investigated the effect of ethanolic extracts of the gum resin exudate of Boswellia serrata. A concentration-dependent inhibition of LTB4 and 5-HETE production by different charges of exudate extracts were found. All products of the 5-lipoxygenase (5-LOx) from endogenous arachidonic acid (AA) in PMNL were reduced to the same extent by the extracts tested. The ethanolic extract of the gum resin also decreased 5-LOx mediated metabolisation of exogenously added AA to LTB4 and 5-HETE. Since steroidal-type anti-inflammatory drugs do not exert an immediate effect in the test system used, we conclude that the activity of the 5-LOx itself represents the side of inhibition by the gum resin extract. Therefore, an inhibition of 5-LOx catalysed mediator synthesis might be involved in the previously reported anti-inflammatory activity in vivo.
Pentacyclic triterpenes (PTs) as aglycones of saponins have a wide distribution in plants, and many of them have been used as anti-inflammatory remedies in folk medicine. This survey critically reviews the effects of PTs on proinflammatory mediator signalling pathways and data from experimental animal models and clinical trials. Because the knowledge of their actions is far from being satisfactory a critical summary of the partly promising but mostly scattered and preliminary data might promote productive research on chances and risks of PTs. Antiproliferative and anti-infectious actions and effects on intracellular cell signalling and hormone metabolism are beyond the scope of this short review, although such effects might also contribute to the understanding of the systemic anti-inflammatory actions of aglycones.
19 children and adolescents with intracranial tumors received a palliative therapy with H 15 at a maximum dose of 126 mg/kg BW/day. All patients had previously been treated with conventional therapy. No side effects were observed during a median 9 months application. The recently reported antiedematous effect of H 15 was documented by MRI in one patient with a peritumoral edema, thus sparing steroid therapy with its typical side effects. Five/19 children reported an improvement of their general health status; this might be a psychological effect of hope for tumor response during palliative care. Three/17 patients with malignant tumors showed a mainly transient improvement of neurological symptoms such as pareses and ataxia. Three further patients showed an increased muscular strength and one cachectic patient achieved a weight gain. These improvements might be attributed to the antiedematous effect of H 15. Because of the palliative situation of these patients, H 15 application was performed without prior rebiopsy for histological evaluation. Overlapping effects with a previous radiotherapy or chemotherapy may have occurred. An antiproliferative effect cannot be stated. To prevent an uncritical use of H 15, further studies with prospective central documentation have to be initiated to evaluate the clinical indications for H 15 in palliative therapy, optimal dosage and duration of application.
The purpose of this clinical trial was to compare efficacy and safety of the Boswellia serrata extract H15 with mesalazine for the treatment of active Crohn's disease.
Randomised, double-blind, verum-controlled, parallel group comparison for which 102 Patients were randomised. The per protocol population included 44 patients treated with H15 and 39 patients treated with mesalazine. As primary outcome measure the change of the Crohn Disease Activity Index (CDAI) between the status of enrolment and end of therapy was chosen. H 15 was tested on non-inferiority compared to standard treatment with mesalazine.
The CDAI between the status of enrolment and end of therapy after treatment with H15 was reduced by 90 and after therapy with mesalazine by 53 scores in the mean. In this non-inferiority-trial the test hypothesis was confirmed by the statistical analysis. The difference between both treatments could not be proven to be statistically significant in favor to H15 for the primary outcome measure. The secondary efficacy endpoints confirm the assessment of the comparison of H15 and mesalazine. The proven tolerability of H15 completes the results of the shown clinical efficacy.
The study confirms that therapy with H15 is not inferior to mesalazine. This can be interpreted as evidence for the efficacy of H15 according to the state of art in the treatment of active Crohn's disease with Boswellia serrata extract, since the efficacy of mesalazine for this indication has been approved by the health authorities. Considering both safety and efficacy of Boswellia serrata extract H15 it appears to be superior over mesalazine in terms of a benefit-risk-evaluation.
Acetyl-11-keto-beta-boswellic acid (AKBA) is a naturally occurring pentacyclic triterpene isolated from the gum resin exudate of the tree Boswellia serrata (frankincense). Because pentacyclic triterpenes have antiproliferative and cytotoxic effects against different tumor types, we investigated whether AKBA would act in a similar fashion on primary human meningioma cell cultures. Primary cell cultures were established from surgically removed meningioma specimens. The number of viable cells in the absence/presence of AKBA was determined by the non-radioactive cell proliferation assay. The activation status of the proliferative cell marker, extracellular signal-regulated kinase-1 and -2 (Erk-1 and Erk-2) was determined by immunoblotting with the antibody that recognizes the activated form of these proteins. Treatment of meningioma cells by AKBA revealed a potent cytotoxic activity with half-maximal inhibitory concentrations in the range of 2 - 8 microM. At low micromolar concentrations, AKBA rapidly and potently inhibited the phosphorylation of Erk-1/2 and impaired the motility of meningioma cells stimulated with platelet-derived growth factor BB. The cytotoxic action of AKBA on meningioma cells may be mediated, at least in part, by the inhibition of the Erk signal transduction pathway. Because of the central role the Erk pathway plays in signal transduction and tumorigenesis, further investigation into the potential clinical use for AKBA and related boswellic acids is warranted.
The aim of the study was to investigate the antitumor and/or preventive effect of BC-4, an isomeric compound isolated from the plant Boswellia carteri Birdw. containing alpha- and beta-boswellic acid acetate in 1:1, MW 498.3. We used the MTT (3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide) assay to study the growth inhibition activity of BC-4. Tumor cells migration within a three-dimensional collagen matrix was recorded by time-lapse videomicroscopy and computer-assisted cell tracking. Topoisomerase II was isolated from mouse melanoma B16F10 cells and its activity was determined by its ability to cut plasmid pBR322 DNA. The secretion and activity of matrix metalloproteinases (MMPs) from human fibrosarcoma HT-1080 cells were determined by gelatin zymography. BC-4 was a cytostatic compound and could induce the differentiation of B16F10 mouse melanoma cells, blocked the cell population in G1 phase and inhibited topoisomerase II activity. The G1 phase population of B16F10 cells was increased from 57.4 to 87.7%, while S phase population was reduced from 33.3 to 5.9% after treatment with BC-4 at 25 microM concentration for 48 h. BC-4 also inhibited the migration activity of B16F10. BC-4 could induce apoptosis of HT-1080 cells, as proved by acridine orange fluorescence staining, Wright-Giemsa staining, electromicroscopy, DNA fragmentation and flow cytometry. BC-4 inhibited the secretion of MMPs from HT-1080 cells, too. In conclusion, if it turns out that BC-4 is a well tolerated substance, exhibiting no significant toxicity or side effects, being evaluated currently in China, BC-4 is a good candidate for the prevention of primary tumor, invasion and metastasis.
For the determination of pentacyclic triterpenes of the boswellic acid family in human plasma a novel sensitive method was developed combining serial extraction on diatomaceous earth and graphitized carbon black followed by reversed phase high-performance liquid chromatography (HPLC) and photodiode array detection. The overall average extraction yield of 12 different pentacyclic triterpenic acids was approximately 66%. The calibration graphs were linear with coefficients of correlation for all compounds greater than 0.999. The overall within-day and between-day coefficients of variation (CV) for the 12 pentacyclic triterpenic acids were 5.6 and 6.8%, respectively. This HPLC procedure delivers the analytical sensitivity, precision and accuracy required for clinical pharmacokinetic and therapeutic studies.
An HPLC gradient method with photodiode array detection was developed for the simultaneous analysis of 12 different pentacyclic triterpenic acids in Indian and African frankincense gum resins as well as in related phytopharmaceuticals. The triterpenic acids were obtained by an exhaustive extraction procedure. Identification of the compounds was based on retention times, UV-spectra and add on technique with standards isolated from African frankincense. The method allows differentiation of frankincense of different origin and standardization of frankincense-based phytopharmaceuticals. Further, this is the first report identifying a novel pentacyclic triterpene, lupeolic acid, as a constituent of frankincense gum resins.