Atherosclerosis and its consequence, cardiovascular disease were recognized in principle and documented at least 3000 years ago. The Ayurvedic medical treatises from as early as 1000 B.C. already referred to the detrimental outcome to overall health with unbalanced nutrition and a sedentary life style. These two factors were reported to contribute to 'coating and obstruction of channels', which translates to atheromatous changes in the blood vessels. To counteract this development, Ayurveda practitioners prescribed an amber-like resin, commonly known as gum guggul ¹, sapped from incisions made in the bark of the Commiphora mukul or Balsamodendron mukul (Hook.) and Commiphora wightii (Arpott) (N.O. Burseraceae) tree.

The pharmacology of gum guggul began to be studied in India in the 1960's, first at the Banaras Hindu University , Varanasi and later at the Central Drug Research Institute (CDRI), Lucknow , where the gum was evaluated for its potential in the treatment of elevated blood cholesterol. For these studies, a standardized gum guggul extract was prepared.

CLINICAL STUDIES

India Clinical studies

There are nine published human clinical trials performed in India evaluating the biological and hypolipidemic effects of gum guggul extracts:

•  Of these, five studies used GSE&Z standardized for daily delivery of approximately 75 mg of E- and Z-gugulsterones

•  two of these trials were randomized

•  one was placebo-controlled

In the two randomized studies, GSE&Z reduced, statistically significant, total cholesterol by 11%, low density lipoprotein cholesterol (LDL-C) by 12% and triglycerides (TG) by 15%. This effect was independent of age, sex or body weight, and the treatment was found especially useful in cases with total cholesterol levels of 220 mg/dl or higher and triglycerides of 170 mg/dl or higher. The other referenced clinical studies confirmed results reported in the two randomized studies.

The traditional experience of crude gum guggul described in Pharmacographia Indica, and some clinical trials done with standardized gum guggul extracts, reported transient side effects such as skin rashes, diarrhea and irregular menstruations.

Based on pre-clinical and clinical studies conducted mostly by the CDRI, the GSE&Z standardized preparation was approved by India 's Drug Regulatory Agency in the late 1980's for inclusion in the Indian Pharmacopoeia for the treatment of dislipidemia type IIb and IV.

US Clinical studies: IND (Investigational New Drug Application) study

In January 2000, the Sabinsa Corporation in cooperation with the Department of Medicine and Center for Clinical Epidemiology & Biostatistics, University of Pennsylvania , Philadelphia , PA , USA submitted documentation to the US FDA for an IND clinical study of GSE&Z. This was a pioneering effort, since until then there was no safety or efficacy data on gum guggul preparations in Western populations. To the best of the authors' knowledge this was the first IND (No. 59, 712 ) approved study on a botanical ingredient for its potential in the management of dislipidemias.

The results of the short-term (8 weeks) safety and efficacy study, consisting of two doses, standard-dose 75 mg gugguslterones per day and high-dose 150 mg guggulsterones per day, of a standardized guggul extract in healthy North American adults with hyperlipidemia eating a typical Western diet, showed the complex nature of treatment with GSE&Z. Compared with participants randomized to the placebo both standard-dose guggulsterones (SDG) and high-dose guggulsterones (HDG) patients reported raised levels of LDL-C by 4% and 5% respectively, at 8 weeks. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides (TG), or VLDL-C in response to treatment in the SDG and HDG groups in the intention-to-treat analysis. However, secondary analyses did find modest and statistically significant reductions in fasting TG in patients with elevated baseline LDL-C.

The results of this study showed, that besides the investigated clinical effects on dyslipidemia, Gugulipid have other potentially important systemic effects. The HDG reduced fasting glucose by 6 mg/dl and insulin by 1.9 mIU/ml. HDG increased quantitative insulin sensitivity check index (QUICKI) by 4.2%. HDG reduced median high-sensitivity C-reactive protein (hs-CRP) by 31%. Gugulipid reduced oxidized cholesterol oxLDL by 12%. In conclusion, Gugulipid at high doses modestly improves insulin sensitivity in non-diabetic adults, while lowering a validated serum marker of inflammation. Guggulipid also has some antioxidant properties in vivo, and may reduce serum uric acid, a recently recognized risk factor in cardiovascular disease.

While Gugulipid was generally well tolerated, 10% treated participants developed a hypersensitivity rash compared with none in the placebo group. In all 6 subjects the rash occurred within 48 hours of starting the study protocol and all symptoms resolved within 1 week of discontinuation of therapy. Five out of 6 patients were from the group receiving the higher dose of guggulsterones, i.e. 150 mg/day.

Based on the above data the FDA has agreed to extend the IND approval for a follow-up clinical study. This study has been aimed to address potential short-comings of the original trial, e.g. increase length of treatment from 8 weeks to 12 weeks with a double-blind cross-over protocol, and to further explore potential hypolipidemic and systemic effects of GSE&Z in healthy North American adults with hyperlipidemia.

The follow-up was performed at Our Lady of Mercy Hospital ( New York , NY ) in form of a randomized, placebo-controlled, crossover design in which 30 volunteers were treated with GSE&Z (75mg/day) and placebo, during separate 12-week treatment periods, in three equally divided doses along with their daily meals. This study completed in September 2004, again did not support the hypothesis that 75 mg/day of plant-derived guggulsterones, in the form of Gugulipid, improves the serum lipid status of Northern American adults with hyperlipidemia. However, the significant reduction of markers of inflammation and oxidative stress, MDA by 40% and hs-CRP by 25%, following 12 weeks of daily Gugulipid treatment suggest a potential role for Gugulipid in addressing major risk factors for cardiovascular disease recently recognized and reported in literature and in clinical practice. None of the 30 volunteers in this study reported side effects, especially hypersensitivity or skin rash.

Findings from this second clinical trial under IND 59, 712 conform with the findings from the first Gugulipid study performed in Pennsylvania University, and published in JAMA (JAMA. 2003 Aug 13;290(6):765-72); the metabolic effects of Gugulipid are in the process of of being published in a peer review journal.

MECHANISM OF ACTION

In addition to previously discussed mechanisms of Gugulipid, the recently explored in vitro hypolipidemic mechanism of GSE&Z relates to the regulation of cholesterol conversion into bile acids in the liver.

Based on systematic study of gum guggul, it has been found that the ethyl acetate fraction of gum guggul shows significant anti-inflammatory and antioxidant effects in vitro (Phytochemistry. 2001 Apr;56(7):723-7). These biological properties have been attributed to a novel ferulate compound derived from gum guggul. Results of the in vitro study indicate that the ferulate compound may play an important role in the hypolipidemic and metabolic effects of a GSE&Z standardized gum guggul preparation ( Phytochemistry. 2001 Apr;56(7):723-7. United States Patent 6,436,991 granted August 20, 2002).

In summary, the cumulative data from in vitro, pre-clinical and clinical studies indicates that GSE&Z gum guggul preparations may exert cardiovascular effects by inhibiting cholesterol biosynthesis, modifying cholesterol metabolism, inhibiting platelet aggregation, normalizing fibrinolytic activity, anti-inflammatory and antioxidant properties and by lowering serum markers of inflammation. Furthermore, identification and characterization of the ferulate compound indicates that guggulsterones may not be the only active components of gum guggul responsible for its cardiovascular properties.

STANDARDIZATION AS CONDITION OF SAFETY AND EFFICACY OF GUGULIPID

Standardization of gum guggul extract is key to the safety and efficacy of the preparation. The analysis of standardization of gum guggul extracts include ultraviolet (UV) spectrophotometry and high pressure liquid chromatography (HPLC) which, respectively, yield the total amount of sterone, sterol and steroidal components present in the gum guggul extract and a more accurate analysis of the guggulsterones E and Z content, with each component quantified separately, giving accurate total guggulsterones readings.\

Further steps are being undertaken to improve the quality of gum guggul extract by removing substances responsible for allergic reactions experienced by some subjects. A newly developed extraction procedure now results in a 100% solvent free end product standardized for guggulsterones involving supercritical carbon dioxide solvent-free extraction (SCFE) of the ethyl acetate portion of gum guggul. Since most of the laboratory and clinical studies were done using the ethyl acetate portion of a Commiphora mukul extract, this is used as the starting material for the SCFE process. This process is repeated twice so that the material in the second extraction is solvent free. T he SCFE extract is standardized for 2.5 to 7.5% of guggulsterones E and Z and the HPLC analysis of the extract is practically identical to the solvent obtained extract.

In conclusion, because of its well documented long and safe human use, Gugulipid can be used responsibly to support health of the cardiovascular system in conjunction with dietary intervention and behavioral modification. The emerging clinical data indicate that Gugulipid can be particularly useful in addressing the inflammatory nature of cardiovascular disease, a newly recognized paradigm of cardiovascular disease.