Tuesday, July 12, 2011

ALN-PCS: Hypercholesterolemia

ALN-PCS: Hypercholesterolemia

Alnylam is developing ALN-PCS, an RNAi therapeutic, to treat hypercholesterolemia, or high levels of cholesterol in the blood, that contributes to many diseases, most notably cardiovascular disease — the leading cause of death in the U.S.
ALN-PCS works by silencing the gene proprotein convertase subtilisn/kexin type 9, or PCSK9, which human genetics studies indicate to be an ideal target to treat hypercholesterolemia. Individuals with a genetically increased PCSK9 activity were found to have increased levels of LDL cholesterol, or bad cholesterol, together with an increased risk of cardiac disease. In contrast, individuals with genetically less PCSK9 activity were found to have significantly lower levels of LDL cholesterol and a significantly reduced risk of cardiac disease. Because of its novel mechanism of action, we believe that ALN-PCS has the opportunity to treat hypercholesterolemia in a way that is un-addressable by current therapies, such statin drugs.
In 2007, we advanced ALN-PCS in pre-clinical studies and we have seen very promising results, including a greater than 50% reduction in levels of LDL cholesterol in non-human primates. As we advance this program towards a Phase I study in humans, we look forward to demonstrating safety and tolerability in healthy volunteers. In this same early clinical study, we may also have the opportunity to evaluate the efficacy of ALN-PCS in reducing LDL cholesterol levels.

ALN-PCS Clinical Timeline

Hypercholesterolemia is a condition characterized by very high levels of cholesterol in the blood. The body needs cholesterol to build cell membranes, make certain hormones, and produce compounds that aid in fat digestion. Too much cholesterol, however, increases a person's risk of developing a form of heart disease called coronary artery disease. This condition occurs when excess cholesterol in the bloodstream is deposited in the walls of blood vessels. The abnormal buildup of cholesterol forms clumps (plaque) that narrow and harden artery walls. As the clumps grow, they can clog the arteries and restrict the flow of blood to the heart. The buildup of plaque in coronary arteries causes a form of chest pain called angina and greatly increases a person's risk of having a heart attack.

Wednesday, December 22, 2010

Banefits of Guggal for lowering LDL VLDL Tryglisride

Benefits of Guggul:


High cholesterol: Studies show that a 14-27% of LDL cholesterol and 22-30% of triglycerides levels were reduced when guggul was given to men and women with high cholesterol for 12 weeks with no change in diet or exercise. Several clinical studies were published in the Indian Journal of Medicine (volume 84) in 1986, Indian Pharmacoepia and in the Journal of the Association of Physicians in India (vol. 34 & 37) all stating the efficacy of guggul in lowering LDL cholesterol and triglycerides. Dr. David Moore and his team at the Baylor College of Medicine in Houston found that the guggulsterone, the active ingredient in the Guggul extract, blocks the activity of a receptor in the liver's cells called Farnesoid X Receptor (FXR). Later, Dr. David Mangelsdorf at University of Texas Southwestern Medical Center in Dallas confirmed that the guggul blocked the receptor and affected how cholesterol is metabolized.

Weight Loss: Research with laboratory animals suggests guggul may help enhance thyroid function. Since the thyroid gland produces hormones that are needed to regulate metabolism, it can help in weight loss. Studies show guggul may change thyroid hormone metabolism, increase levels of circulating T3, or triiodothyroxine, a thyroxine metabolite known to raise overall metabolism, which in turn increases fat burning.

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Guggul Clinical Studies:

Cholesterol - Baylor College of Medicine in Houston found that the guggulsterone, the active ingredient in the Guggul extract, blocks the activity of a receptor in the liver's cells called Farnesoid X Receptor (FXR). Later, Dr. David Mangelsdorf at University of Texas Southwestern Medical Center in Dallas confirmed that the guggul blocked the receptor and affected how cholesterol is metabolized.

Cholesterol - Another study conducted at Kerala University in India established that "guggul given to laboratory animals reduced their blood lipid levels quickly and effectively without side effects". They found that improved liver enzyme activity was one of the ways Guggul reduced the blood cholesterol. Kerala Univ., Indian J. Exp. Biol. 33, 1995

Obesity - In one double-blind study - a combination of guggul, phosphate salts, hydroxycitrate, and tyrosine (along with healthy exercise) improved the mood of overweight patients with a slight tendency to improve weight loss. However, there appeared to be no effect on thyroid gland function in the people studied.

Osteoarthritis - The Southern California University of Health Sciences (SCUHS) in Whittier, Calif., USA, started a study on the Usefulness of guggul (Commiphora mukul) for osteoarthritis of the knee in March of 2001.

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Guggul Scientific Research

Guggul (Commiphora mukul) potentially ameliorates hypothyroidism in female mice.

Phytother Res. 2005 Jan;19(1):78-80.

The efficacy of guggul, the gum resin of Commiphora mukul in regulating hypothyroidism was evaluated in female mice. In addition to estimating serum levels of thyroxine and triiodothyronine, hepatic 5' monodeiodinase, hepatic glucose-6-phospatase and lipid-peroxidation (LPO), the activities of the anti-oxidative enzymes, superoxide dismutase (SOD) and catalase (CAT), were investigated. While 6-n-propyl-2-thiouracil (PTU, 10.00 mg/kg/d for 30 days) induced hypothyroidism in mice, as evidenced by a decrease in thyroid hormone concentration and in hepatic 5'D-I activity, simultaneous administration of guggul (200 mg/kg/d for 30 days) reversed this effect, indicating its potential to stimulate thyroid function. Although in PTU treated animals a marginal increase in hepatic LPO was observed, when simultaneously treated with guggul, it was decreased. A parallel increase in the activity of endogenous antioxidants, SOD and CAT, in the latter group indicated the safe and antiperoxidative nature of guggul. These findings suggest the possible use of guggul in the amelioration of hypothyroidism.

Guggul and Prescription Drugs

The Journal of Pharmacology and Experimental Therapeutics, August 2004.

Guggul may interfere with many prescription drugs, including the popular anti-cholesterol drugs called statins. In a preliminary study, guggulsterone, the active ingredient in the herbal remedy guggul, causes changes in human and rodent cells that induce the body to break down many drugs, including cancer drugs and AIDS medications. Resin from the guggul tree has been used for more than 3,000 years in India to treat a range of disorders. Previous research showed that guggul lowers cholesterol by blocking a substance that keeps the body from getting rid of cholesterol. Guggulsterone likely affects other drugs because it binds to a protein known as pregnane X receptor (PXR). This, in turn, induces the body to "turn on" a gene that encodes another protein that breaks down many different types of drugs, thereby reducing their levels in the body. Some anticancer drugs, such as cyclophosphamide, need to be broken down by PXR to become active. Guggulsterone may interfere by augmenting that process, thereby raising levels of the drugs in the body. Moreover, guggulsterone appears to also turn some other drugs, such as acetaminophen, into toxic compounds. St. John's wort, also activates PXR, and can therefore interfere with other drugs. Guggulsterone has been used for years, and is likely safe if people are not taking any prescription medications. However, guggulsterone should be used cautiously by people who take prescription drugs.

Guggulipid for the treatment of hypercholesterolemia: a randomized controlled trial.

JAMA. 2003 Aug 13;290(6):765-72.

Herbal extracts from Commiphora mukul (guggul) have been widely used in Asia as cholesterol-lowering agents, and their popularity is increasing in the United States. Recently, guggulsterones, the purported bioactive compounds of guggul, have been shown to be potent antagonists of 2 nuclear hormone receptors involved in cholesterol metabolism, establishing a plausible mechanism of action for the hypolipidemic effects of these extracts. However, there are currently no published safety or efficacy data on the use of guggul extracts in Western populations.

OBJECTIVE: To study the short-term safety and efficacy of 2 doses of a standardized guggul extract (guggulipid, containing 2.5% guggulsterones) in healthy adults with hyperlipidemia eating a typical Western diet.

DESIGN: Double-blind, randomized, placebo-controlled trial using a parallel design, conducted March 2000-August 2001.

PARTICIPANTS AND SETTING: A total of 103 ambulatory, community-dwelling, healthy adults with hypercholesterolemia in the Philadelphia, Pa, metropolitan area.

INTERVENTION: Oral, 3 times daily doses of standard-dose guggul (1000 mg), high-dose guggul (2000 mg), or matching placebo.

MAIN OUTCOME MEASURES: Percentage change in levels of directly measured low-density lipoprotein cholesterol (LDL-C) after 8 weeks of therapy. Secondary outcome measures included levels of total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and directly measured very low-density lipoprotein cholesterol (VLDL-C), as well as adverse events reports and laboratory safety measures including electrolyte levels and hepatic and renal function.

RESULTS: Compared with participants randomized to placebo (n = 36), in whom levels of LDL-C decreased by 5%, both standard-dose guggul (n = 33) and high-dose guggul (n = 34) raised levels of LDL-C by 4% (P =.01 vs placebo) and 5% (P =.006 vs placebo), respectively, at 8 weeks, for a net positive change of 9% to 10%. There were no significant changes in levels of total cholesterol, HDL-C, triglycerides, or VLDL-C in response to treatment with guggul in the intention-to-treat analysis. While guggul was generally well tolerated, 6 participants treated with guggul developed a hypersensitivity rash compared with none in the placebo group.

CONCLUSIONS: Despite plausible mechanisms of action, guggul did not appear to improve levels of serum cholesterol over the short term in this population of adults with hypercholesterolemia, and might in fact raise levels of LDL-C. Guggulipid also appeared to cause a dermatologic hypersensitivity reaction in some patients.

The effectiveness of Commiphora mukul (guggul) for osteoarthritis of the knee: an outcomes study.

Singh BB,. Southern California University of Health Sciences, USA.

Altern Ther Health Med. 2003 May-Jun;9(3):74-9.

CONTEXT: Ayurveda, the traditional system of healthcare in India, has many remedies for Osteoarthritis (OA). One of the ingredients most commonly found in Ayurvedic arthritis formulas is guggul, an oleoresin of the herb Commiphora mukul. The authors have conducted both preclinical and clinical investigations of guggul for reduction of pain, stiffness, and improved function, and to determine tolerability in older patients with a diagnosis of OA of the knee.

CONCLUSIONS: Overall data indicate significant improvement with guggul for participants during the trial in both scales and objective measures used for assessment purposes. There were no side effects reported during the trial. Guggul appears to be a relatively safe and effective supplement to reduce symptoms of OA.

Guggul Laboratory Studies The hypolipidemic natural product Commiphora mukul and its component guggulsterone inhibit oxidative modification of LDL.

Atherosclerosis. 2004 Feb;172(2):239-46.

There is accumulating evidence that LDL oxidation is essential for atherogenesis, and that antioxidants that prevent this oxidation may either slow down or prevent atherogenesis. In the present study, we found that Commiphora mukul (guggul) and its cholesterol-lowering component, guggulsterone, effectively inhibited LDL oxidation. This inhibition by guggul was assessed by the decrease in the following parameters describing LDL oxidation: conjugated dienes, relative electrophoretic mobility (REM), thiobarbituric acid reactive substances, lipid hydroperoxides, oxidation-specific immune epitopes as detected with a monoclonal antibody against oxidized LDL, and the accumulation of LDL derived cholesterol esters in mouse peritoneal macrophages. We concluded that guggul and its lipid-lowering component, guggulsterone, significantly inhibit LDL oxidation. The combination of antioxidant and lipid-lowering properties of guggul and guggulsterone makes them especially beneficial against atherogenesis.

Monday, March 15, 2010

Hope for Inherited, Dangerously High Cholesterol -homozygous familial hypercholesterolemia

SUNDAY, March 14 (HealthDay News) -- A new drug called mipomersen reduced low-density lipoprotein (LDL) "bad" cholesterol by nearly 25 percent when added to current therapy in people with a rare genetic condition that causes extremely high cholesterol, a new study finds.

Mipomersen is designed to decrease the formation of apolipoprotein B (the main structural protein in LDL cholesterol) and its release from the liver or intestine. This reduces circulating LDL cholesterol concentrations.

Inherited high cholesterol (homozygous familial hypercholesterolemia) affects one in every one million people. Patients with the disorder have severely elevated LDL cholesterol and a high risk of early cardiovascular disease. If untreated, these patients rarely live past the age of 30.



This phase 3 clinical trial included 51 patients with homozygous FH who were already taking lipid-lowering drugs, including high-dose statins. The patients were randomly selected to receive either 200 milligrams of mipomersen or placebo per week for 26 weeks.



At the end of the treatment period, LDL cholesterol levels had decreased 24.7 percent in the mipomersen group, compared with 3.3 percent in the placebo group.



"Mipomersen could be a valuable addition to the drugs used in the management of homozygous FH and should prove useful in the management of other forms of severe refractory hypercholesterolemia," wrote an international team of researchers led by Frederick Raal of the University of Witwatersrand, Johannesburg, South Africa.



The study was published online March 13 in advance of print publication this week in The Lancet, and was slated to be presented Saturday at the annual meeting of the American College of Cardiology in Atlanta.