PHYTOTHERAPY FOR LIPID DISORDERSOktavia Rahayu A, S.Farm., M.Biomed

Department of Pharmacy, Faculy of Medicine, Universitas Brawijaya 2018

Learning Outcome

• Mahasiswa mampu memahami pengaruh gangguan lipid pada sistem kardiovaskuler

• Mahasiswa mampu memahami jenis dan mekanisme kerja OT yang digunakan untuk gangguan lipid

• Mahasiswa mampu memahami ESO yang potensial terjadi pada penggunaan OT untuk gangguan lipid

• Mahasiswa mampu mengaplikasikan fitoterapi pada penyakit gangguan lipid

How do statins work?

C5

C10

C15

C30

BIOSYNTHESIS OF CHOLESTEROL

Isoprene unit

steroid

Lipoproteins of the blood

Composition of lipoprotein complexes

Potentially proinflammatory

TG

Apo

Cho

LIPID METABOLISM

lipoprotein lipase remove fatty acid

Major lipid trials:The relation between LDL-c levels and rate of coronary events

Development of Atherosclerosis

suatu responsinflamasi kronikterhadap deposisilipoprotein padadinding arteri

Development of Atherosclerosis

Initial Development of Fatty Streak

OxLDL-LOX-1 Signaling Pathway

Chronic Heart Disease/Coronary Artery Disease

Carotic Artery Disease

Lipid lowering drugs

Selected herbal therapiesHerbs Lipid Disorders Grades

Alfafa Atherosclerosis, hyperlipidemia C

Ashwagandha Hypercholesterolemia C

Astragalus Coronary heart disease C

Avocado Hypercholesterolemia B

Barley Hyperlipidemia B

Beet Hyperlipidemia C

Beta-glucan Hyperlipidemia A

Beta-sitosterol, Sitosterol Hypercholesterolemia A

Borage Hyperlipidemia C

Carob Hypercholesterolemia B

Chia CVD prevention/ atheroclerosis B

Cordyceps Hyperlipidemia B

Selected herbal therapiesHerbs Lipid Disorders Grades

Elder Hypercholesterolemia C

Fenugreek Hyperlipidemia C

Flax Atheroclerosis/ CAD, hyperlipidemia C

GarlicHyperlipidemia B

Familial hyperlipidemia, atherosclerosis C

Ginseng CAD, Hyperlipidemia C

Globe artichoke Hyperlipidemia B

Goldenseal Hypercholesterolemia C

Grapefruit Heart disease C

Grape seed Hypercholesterolemia C

Guggul Hyperlipidemia C

Gymnema Hyperlipidemia C

Selected herbal therapiesHerbs Lipid Disorders Grades

Lemongrass Atheroclerosis/ hyperlipidemia C

Milk thistle Hyperlipidemia C

Nopal Hyperlipidemia C

Omega-3 fatty acid, ALAHyperlipidemia C

Hypercholesterolemia D

Policosanol Hypercholesterolemia A

Psyllium Hypercholesterolemia A

Pycnogenus Hypercholesterolemia C

Red clover Hypercholesterolemia C

Red yeast riceHypercholesterolemia A

CHD C

Reishi mushroom CHD C

Selected herbal therapies

Herbs Lipid Disorders Grades

Rhubarb Hypercholesterolemia C

Safflower Familial hyperlipidemia,hypercholesterolemia, atherosclerosis

C

Soy Hypercholesterolemia, CVD A

Spirulina Hypercholesterolemia C

Sweet almond Hypercholesterolemia B

Tea Hypercholesterolemia, hypertriglyceridemia C

Turmeric Hypercholesterolemia C

White horehound Hypercholesterolemia C

Wild yam Hypercholesterolemia C

Yucca Hypercholesterolemia C

SUMMARY

Grade A

• Beta-glucan

• Beta-sitosterol, Sitosterol

• Policosanol

• Psyllium

• Red yeast rice

• Soy

Grade B

• Avocado

• Barley

• Carob

• Chia

• Cordyceps

• Garlic

• Globe artichoke

• Sweet almond

Grade C

• Fenugreek

• Flax

• Goldenseal

• Grapefruit

• Grape seed

• Gymnema

• Red yeast rice

• Reishi mushroom

• Safflower

• etc.

Grade A

Plantago ovata

Psyllium

Glycine max

Soy

Red yeast rice

Red Yeast RiceGrade A: Strong scientific evidence for hypercholesterolemiaGrade C: Unclear/conflicting scientific evidence for CHD

Mechanism of action

• Red yeast rice is a product of the yeast Monascus purpureus grown on rice contains monacolin K (lovastatin), substances known to inhibit cholesterol synthesis (inhibitor of HMG-CoA reductase) in 2007, FDA issued a warning to consumed RYR

• MoA: inhibitor of HMG-CoA reductase, inhibition of cholesterol absorption (sterol component), increase clearance of cholesterol, antioxidant effect

Scientific evidence

• Hypercholesterolemia ↓ TC, LDL-c, TG in pc mild-moderate hypercholesterolemia

• CHD ↑ blood flow through ↑ dilatation of blood vessels, ↓ levels of C-reactive protein (CRP)

Dose

• No well-known standardization

• 120 mg of concentrated red yeast powder capsules two times daily with food for 8 weeks

• Red yeast rice 1200-2400 mg daily for 2-6 weeks found to ↓ serum CRP and ↑ flow-mediated dilatation

Adverse effects

• Should avoid during pregnancy & lactation due its estrogenic activity fetal abnormalities

• Contain mycotoxin citricin teratogenic

Lovastatin Monacolin K

Psyllium (Plantago spp.)Grade A: Strong scientific evidence for hypercholesterolemia

Mechanism of action

• Proposed mechanism: “displacement” of dietary fat by soluble fiber ↓ cholesterol available for absorption

• ↑ Fecal excretion of bile acids & cholesterol, bind bile acids & cholesterol in intestines, allow less circulation for reabsorption & cause the liver to use more cholesterol to make bilde acid

• Fatty acids proprionate & acetate are produced from soluble fiber by bacteria in the colon indirecty inhibit cholesterol biosynthesis on the liver

Scientific evidence

• Meta analysis (8 studies) ↓ serum total cholesterol, LDL. Apo B:apo A-1 ratio; no effect on serum HDL

• Approved by FDA as dietary fiber that may reduce the risk of coronary heart disease not recommended to px with severe/moderate hypercholesterolemia (compared w/ lovastatin)

DIETARY FIBER MAY REDUCE RISK OF CHD

Psyllium (Plantago spp.)Grade A: Strong scientific evidence for hypercholesterolemia

Dose

• 3,4-45 g/day in 2-3 divided doses for 8-12 weeks

Adverse effect

• Chocking take psyllium w/ at least 8 ounces of water

Interaction

• Anticoagulants

• Antidepressant

• Oral agents

• Orlistat

• Vitamin B12 taken 1 h / 4 h after psyllium

DIETARY FIBER MAY REDUCE RISK OF CHD

β-sitosterol, SitosterolGrade A: Strong scientific evidence for hyperlipidemia

Mechanism of action

• Phytosterol β-sitosterol, campesterol, stigmasterol, stanol

•β-sitosterol noncholesterol sterol (the main plant sterol)

• β-sitosterol mechanism interfering the intestinal absorption of cholesterol & ↑ bile acid secretion; inhibition of sterol reductase

Scientific evidence

• Many animal & human studies have demonstrated that supplementation of β-sitosterol into the diet decreases total serum cholesterol & LDL-c (product: margarine enrinched w/ phytosterol esters)

Dose

• 1,5-6 g/day in divided doses administeted before meals

Interactions

• Acarbose acarbose decrease β-sitosterol concentration

• Activated charcoal decrease β-sitosterol

• Anticoagulationt/antiplatelets risk of increased bleeding

• Blood glucose hypoglychemic

β-glucanGrade A: Strong scientific evidence for hyperlipidemia

Mechanism of action

• β-glucan soluble fiber derived from the cell walls of algae, bacteria, fungi, yeast, plants (barley & oats)

• Soluble fibers may ↑ the viscosity of food mass in the small intestine & lead to the formation of a thick, watery layer adjacent to the intestinal mucosa this layer may act as a physical barrier to reduce the absorption of nutrients & bile acids and prevent cholesterol absorption

Scientific evidence

• TC & LDL-c reduced by 5-9% in a group of px who received oat β-glucan (0,75 L daily for 5 weeks)

Dose

• 3-16 g daily (FGA approved & recommends that 3 g of β-glucan daily is needed to reduce cholesterol levels)

Interactions

• Blood glucose reduce BG

• Cytochrome P450 substrates lentiman suppresses hepatic CYP450-1A

• Oral agents reducing GT transit time

Soy (Glycine max)Grade A: Strong scientific evidence for hypercholesterolemia, CVD

Mechanism of action

• Contains phytoestrogens (isoflavon genisterin & dadzein)

Scientific evidence

• Hypercholesterolemia ↓ 10% TC & LDL-c, ↓ TG

• CVD dietary sor may ↓ cardiovascular risk . FDA recommends at least 25 g/day to ↓ risk of CAD

Dose

• To lower cholesterol FDA recommend at least 6,35 g of soy/serving (total 25 g daily)

Adverse effects

• Allergic rx

• Stomatch & intestinal difficulties (blotting, nausea, constipation)

Interaction

• Blood glucose, blood pressure, estrogenic agent, gingseng, iron

Grade B

Persea americana

Avocado

Hordeum vulgare

Barley

Avocado (Persea americana)Grade B: Good scientific evidence for hypercholesterolemia

Mechanism of action

• Cholesterol-lowering effects may result from monounsaturated fatty acid content (oleic acid)

• Avocado is rich source of β-sitosterol

Scientific evidence

• All the studies substituted some of initial fat in the diet w/ fat from avocado ↓ TC, LDL-c, TG and apoB, ↑ HDL

Dose

• 0,5-1,5 avocado daily for 2-4 weeks

Avocado-enriched diets (75% fat from avocado) have been used for 2-4 weeks for hypercholesterolemia

Interactions

• Anticoagulant/antiplatelet, MAO inhibitor

Barley (Hordeum vulgare)Grade B: Good scientific evidence for hyperlipidemia

DIETARY FIBER MAY REDUCE RISK OF CHD

Mechanism of action

•Barley is rich source of β-glucan low gastric emptying time, prolong the feeling the fullness, & stabilized blood glucose levels

•d-α-tocotrienol works in the liver to inhibit cholesterol production

Scientific evidence

•High-fiber barley, barley bran fluor & barley oil elicit small reduction in serum cholesterol levels by ↑ cholesterol excretion

•Strong evidence supports the use of barlet along w/ a cholesterol-lowering diet in px w/ mild hypercholesterolemia

•Barley consumption appears to ↓ TC & LDL-c, but doesn’t appear to affect TG or HDL

Dose

•Barley diet 6 weeks

•barley bran fluor 30 g for 30 days

•barley oil extract 3 g for 30 days

Adverse effects

•Abdominal fullness, should be avoided in px which allergy or hypersensitivity to grass / wheat

Interactions

•Cathecolaminergic agents, oral agents (reduce GI transtit time)

Barley (Hordeum vulgare)

Soy (Glycine max)

Grade C

Ganoderma lucidum

Reishi mushroom

Cathamus tinctorius

Safflower

Reishi mushroom (Ganoderma lucidum)Grade C: Unclear/conflicting scientific evidence for CHD

Mechanism of action

• Reishi regulates lipid metabolism, ↑ antioxidation and ↓ lipid peroxidation

• Oxigenated triterpenes, ganodermic acids (terpenes) and its derivates (sterol VI) are responsible for the inhibition of cholesterol absorption & synthesis (HMG CoA inhibitor)

• 26-oxysterol inhibit lanosterol 14α-demethylase, which converts 24,25 dihydrolanosterol to cholesterol

Scientific evidence

• Ganopoly, a G.lucidum polysaccharide extract, improved major symptom of CHD, including decreasing serum cholesterol levels

Dose

• 1,8 g 3 dd 1 has been used for CAD

Adverse effects

• Skin rash, dizziness, headache

Interactions

• Acyclovir synergic antiherpetic

• Anticoagulant/antiplatelet prolongation of PT bleeding

• Blood glucose reduce BS

• BP lower BP

• HMG-co A reductase inhibitor

Safflower (Cathamus tinctorius)Grade C: Unclear/conflicting scientific evidence for familial hyperlipidemia, hypercholesterolemia, atherosclerosis

Mechanism of action

• Safflower oil is a good source of linoleic acid, an essential unsaturated fatty acid

• High-oleic acid safflower oil (MUFA) and safflower oil (PUFA) increase hepatic uptake of cholesterol

Scientific evidence

• Familial hyperlipidemia SO significantly reduced TC, LDL, TG and total apoB levels in px receiving a safflower (omega-6 fatty acid)-enriched diet

• Hypercholesterolemia SO also decrease malondialdehyde-LDL (MDA-LDL)

• Atheroclerosis increase oxidation of LDL and lower thiobarbaturic acid (TBARS) compared w/ fish oil

Dose

• 14 fgdaily of linoleic acid for 6 weeks shown to decrease LDL

• 97 g of safflower oil daily for 14 days shown to decrease cholesterol

• 15 g of safflower oil daily has been used for atherosclerosis in postmenopause woman

Adverse effects

• Allergic to daisies / daisy family (Asteraceae/Compositae) such as ragweed, chrysanthemums, marigold

Interactions

• Anticoagulant/antiplatelet

• Blood glucose increase insulin resistance

• blood pressure decrease BP

• WBC count alter parameters of cellular imunity

ADJUNCT THERAPIES

1

• The main goal is to reduce the risk of developing heart disease or having a heart attack

• Two main ways to lower cholesterol therapeutic life changes (TLC) & drug therapy

• TLC TLC diet, physical activity, weight management

2

• TLC diet is a low-saturated fat, low-cholesterol eating plan

• If LDL is not decreased enough px can increase consumption of dietary soluble fiber (psyllium, β-glucan)

• Certain food products that contain plant sterols can also be added to TLC diet (drinking green tea, chromium picolinate)

3• Regular psysical activity for at least 30 minutes, 3-4 times a week

4

• Qoenxyme Q10 (CoQ10) supplementation may also be benefical in px with lipid disorders reduce angina

INTEGRATIVE THERAPY PLANIndividuals age 20 and older should have their cholesterol levels measured at least once every 5 years

In general, prescription drugs should be taken 1 hour before or 2 hours after taking psyllium or barley. Doses of 3.4 to 45 g daily of psyllium, in two to three divided doses for 8 to 12 weeks, have been used in clinical trials

The FDA has approved a health claim stating that soy products (containing at least 6.25 g of soy protein for serving, one fourth the effective level of 25 g daily) may reduce the risk of coronary heart disease by lowering blood cholesterol levels. Caution is advised for women with hormone-sensitive conditions, because soy contains phytoestrogen and may have estrogenic effects.

Omega-3 fatty acids from fish or fish oil supplements significantly reduce blood TG levels. But, fish oil supplements increase LDL.

Beta-sitosterol is one of the most prevalent diaetary phytosterols (plant sterols) found in plants, as in fruits, vegetables, soybeans, breads, peanuts, and peanut product. Many human and animal studies have demonstrated that supplementation with beta-sitosterol decrease total and LDL cholesterol.

Review Questions

1. True or false: FDA has approved health claims that two dietary fibers (β-glucan & psyllium) may reduce the risk of CHD

2. Which substances in red yeast rice are known to inhibit cholesterol synthesis?

a. Phenolic diterpenes

b. Polyphenols

c. Hydroxybenzenes

d. Monacolins

3. True or false: FDA approved a health claim that soy products may reduce the risk of CHD by lowering blood cholesterol levels

Review Questions

4. Which of the following statements is true concerning the use of psyllium or its constituents?

a. Psyllium should not be taken within 1 hour of taking medications or other oral agents

b. Psyllium is systemically absorbed

c. Psyllium products are considered to be unsafe during all three trimesters of pregnancy

d. There is nor enough evidence to support the use if psyllium in reducing cholesterol levels

References

• Bone K, Mills S. 2013. Principles and Practice of Phytotherapy: Modern Herbal Medicine, 2nd Edition. New York: Churchill Livingstone.

• Ulbricht C, Seamon E. 2010. Natural Standard Herbal Pharmacotherapy: An Evidence-Based Approach. Canada: Mosby Inc.