PHAR 423: Botanical and other Nutraceutical Agents

Dr. Thomas AbrahamSpring 2004

Overview

Pharmacological Agents historically derived from plant sources

Drug Plant Source

d-tubocurarine Strychnos toxifera (poison arrow plant)reserpine Rauwolfia

atropine, scopolamine Atropa belladonnaMorphine, codeine Papaver somniferum (Opium poppy)Cocaine Coca plantDigitalis glycosides Foxglove; strophanthusQuinine, quinidine Cinchona treeVincristine, vinblastine Vinca plantPaclitaxel Pacific Yew treeTopotecan, irinotecan Camptotheca plantBishydroxycoumarin Sweet cloverVitamins various plant sources

Overview

Issues Important to Use of Botanical Preparations:

1. Identification of active ingredients.The majority of botanical products have unknown or unidentified “active” ingredients.

2. Standardization of various commercial preparations.

Most preparations are not standardized to any particular component due to lack of knowledge of active ingredient(s).A fingerprint of various chemical constituents may be more reliable than standardization of one component.

Issues Important to Use of Botanical Preparations:3. Efficacy.

Little or no research on shelf life or stability of the product conducted – expiration date may be meaningless.

4. Toxicity“Natural” SAFELittle or no toxicological testing has been conducted – manufacturers depend on anecdotal evidence of safety.

5. Regulatory control of Botanical products.Products are governed by Dietary Supplement and Health Education Act (1994) – no prescription required to use products and FDA evaluation of safety and efficacy are not required.

Overview

Echinacea

Potential active ingredients• Alkylamides, echinacosides and flavanoids

Pharmacodynamic Studies• increased phagocytic activity of human granulocytes in vitro.

• in vitro antiviral activity by “interferon-like” effect

• Prepared from E. augustifolia, E. purpurea and E. pallidapreparations usually contain extract of roots, rhizomes, leaf and flowers.

• First used by native americans to treat snakebites and septic wounds.

• Therapeutic claims include ability to be immunomodulator, anesthetic and anti-inflammatory agent.

O

O

OR

OH

RO

OH

Flavanoid

Echinacea

Clinical Studies

• A modest decrease in duration of symptoms for upper respiratory infections.

• Few dose finding studies have been conducted on Echinacea preparations.

Toxicity/Safety

• Mostly allergic reactions but more rarely hepatitis, asthma, rash, nausea, dizziness with swollen tongue and anaphylaxis have been reported.

Fever few

• Obtained from the Chrysanthemum plant Tanacetum parthenium.

• Traditionally warm infusions were used to purge cholera, fever, colds, cleanse kidneys, and expel worms.

• More recent use of feverfew for headaches and to aid digestion.

• These plants contain sesquiterpene lactones such as parthenolide which may beone of the active ingredients.

CH2

O

O

OCH

CHO O

Parthenolide

Fever few

Pharmacodynamics

• Lactones decrease release of serotonin from platelets and PMNsGood correlation between parthenolide content and antiplatelet activity

• Highly reactive -methylenebutyrolactones may covalently bind to thiol groups on cell proteins.

• Ability of feverfew extracts to inhibit phagocytosis by leukocytes may be useful as antiinflammatory agent.

Pharmacokinetics

• Much of the orally ingested parthenolides are probably inactivated by glutathione in the liver thus may not be relevant therapeutically.

Clinical Studies

• Small clinical trials suggested some benefit of 2-3 leaves in decreasing frequency or severity of migraine attacks.

• Benefits of feverfew in arthritis has not been demonstrated.

Fever few

Toxicology/Safety

• Adverse effects include mouth ulceration, contact dermatitis, GI disturbance, headache, tingling sensation. Rapid withdrawal from feverfew use has resulted in headaches, insomnia, joint stiffness and nervousness.

• No toxicity seen in rodents fed high doses of feverfew; non-mutagenic by microbial mutagenicity assay.

Ginkgo

• Prepared from the leaves of the Ginkgo biloba tree

• Traditionally used in Chinese medicine to treat asthma.

• Leaf extracts contain multiple components that may be active: flavone glycosides (quercetin); ginkgolides (A, B, C, J); bilobalides.

OO

O

O

OH

C (C H3 ) 3R 1

R 2

CO

O

OH

H

H3 C

O

H

Ginkgolides

Pharmacodynamic Effects• Ginkgolides are antagonists of PAF and decrease platelet aggregation and mast cell degranulation.

• Increased cerebral blood flow in experimental animals.

• Flavanoids may have antioxidant activity in CNS and LDL oxidation

Ginkgo (contd)

Pharmacokinetics

• Ginkgolides and bilobalides have relatively high bioavailability after oral ingestion and eliminated mostly unchanged in urine.

Clinical Studies

• Ginkgo found more effective than placebo in improving cognitive function in pts. with cerebral insufficiency.

• Evidence that ginkgo is more effective than placebo in delaying cognitive deterioration due to dementia or Alzheimer's.

• Ginkgo is about as effective as pentoxifylline in treating pts. with intermittent claudication.

Ginkgo (contd)

Clinical trials

• Therapeutic value of ginkgo in treating tinnitis is uncertain but may be promising.

Toxicology/Safety

• Adverse effects are generally mild including headache, diarrhea, nausea, insomnia.

• Increased incidence of bleeding reported in pts. taking ginkgo extract and aspirin.

Ginseng

• From the Panax ginseng plants of American, Russian and Asian varieties.

• Chinese herbalists use ginseng for palpitations, insomnia, restlessness, laboured breathing, chest/abdominal distention.

• Western herbalists use ginseng as general health tonic, stimulant for anorexia, digestive disorders, neuralgia, depression, asthma, convulsions and paralysis.

• The roots of the plant contain saponins called ginsenosides; polysaccharides, oils and polyacetylenes.

OHglucose-D--O

O--D-glucose

Ginsenoside

Ginseng

Pharmacodynamics

• Ginseng extracts have hypothalamic effects to decrease ACTH release (short-term) and decrease glucocorticoid release in prolonged stress.

• Animal studies suggest effects of ginseng extract on adrenal glands and immune cells.

• Animal studies also support anticancer activity of ginseng.

Pharmacokinetics

• Ginsenosides may decompose in GI (bacterial flora) and release the prosapogenins which have appreciable oral bioavailability.

Ginseng

Clinical Trials• Majority of studies are not well designed however some evidence exists for improved exercise tolerance, maximal oxygen uptake, decreased heart rate and decreased lactic acid production in athletes.

• May improve general well-being and quality of life in chronic consumers. Also evidence of lowered cancer risk in chronic consumers and improved immune system.

Toxicology/Safety• Greater than 1g/day may result in hypertension, nervousness, euphoria, insomnia, skin eruptions, diarrhea. Mastalgia, vaginal bleeding, severe headache and Stevens-Johnson syndrome also reported.

Ginseng

Drug Interactions• Reduced warfarin efficacy when ginseng was added to a controlled pt.

• Potential interaction with phenelzine and other MAOIs.

St. John’s Wort

• Also known as hypericum (Hypericum perforatum) is a common weed in many parts of Europe and North America.

• Traditionally used for nervous conditions (excitability, menopausal neurosis, hysteria) and disorders of the spine (neuralgia, sciatica, spinal injuries).

.

• Preparations are made from leaves and flowers of the flowering plant and used dried or fresh to produce infusions, extracts and tablets.

• Key constituents in extracts: hypericin, psuedohypericin hyperforin and other flavanoids. Preparations generally standardized to 0.3% hypericin.

OHO OH

HO OHO

CH3

CH3

HO

HO

Hypericin

St. John’s Wort

Pharmacodynamics• Animal studies document antidepressant effects and leads to adaptive changes in - and 5HT receptors in CNS with chronic treatment.

Hypericum extract has antiviral and antibacterial activity in vitro.

• Photoactivated hypericin has activity against basal and squamous cell carcinomas.

Pharmacokinetics• Hypericin and pseudohypericin have oral bioavailability of 15-30%; the bioavailability of other constituents is less well known.

O

O O

OH

Hyperforin

St. John’s Wort

Clinical trials• Multiple studies have demonstrated efficacy of hypericum extract in treating symptoms of mild to moderate depression.

• The ability of hypericum extract to treat viral infections (HIV), cancer and menopausal symptoms are less well characterized or underway.

Toxicology/Safety• Generally considered to have better safety profile than conventional antidepressants; photosensitivity, GI disturbance, dizziness, fatigue, dry mouth and vertigo are most often seen.

• Hypericum extract does not appear to have carcinogenic or teratogenic effects, however long-term data in humans is unavailable.

St. John’s Wort

Drug Interactions

• Ability of hypericum extracts to induce cytochrome P450 enzymes has been documented. Hyperforin appears to induce the levels of CYP3A4 in human liver cells. May also induce the expression of P-glycoprotein in GI and other cells.

• Additive serotonin syndrome in pts. coadministering hypericum extract and SSRIs e.g. paroxetine, sertraline.

Kava Kava

• Made from the roots of a pepper plant: piper methysticum. Used as a ceremonial drink by inhabitants of Polynesian islands.

• The dried root may be administered as a tablet, liquid extracts or decoction.

• Traditionally kava extract used to treat kidney/bladder troubles, coughs, colds, sore throat and as diuretic. Also used as contraceptive and for gonorrhea.

• Root extracts contain kava lactones such as kavain, dihydrokavain and methysticin as well as various flavanoids.

O

OCH3

O

Kavain

Kava Kava

Pharmacodynamics• Animal studies indicate kava extract produces sedation and analgesia.

• May antagonize dopamine receptors in the CNS.

Pharmacokinetics• GI absorbance of kava lactones appears to be greater in the total extract than when administered individually.

• In mice pharmacologically relevant levels of lactones are found in the brain after intraperitoneal administration.

Kava Kava

Clinical Trials• Various clinical studies indicate kava extract to be as effective as benzodiazepines in the treatment of chronic anxiety. Onset of effect was observed in as little as 1 week and maintained for up to 6 months.

Adverse effects• Lethargy, disorientation, shortness of breath, liver toxicity, dry skin, hair loss, decreased appetite and dyskinesias have been reported.

Drug Interactions• May have additive sedative effects with alcohol, benzodiazepines or other CNS depressants.

• May antagonize the effects of levodopa in Parkinson’s therapy

Chondroitan and Glucosamine

Chondroitan• A biological polymer that is a flexible connecting matrix between protein filaments in cartilage.

• Oral administration results in 5-13% bioavailability with renal route of elimination.

• Predominant use of chondroitan in treating pain and inflammation due to osteoarthritis.

• Clinical studies on efficacy of chondroitan for hip, knee and finger joint disease has been equivocal.

Chondroitan and Glucosamine

Chondroitan• Has heparin-like thrombolytic action which may result in interaction with other anticoagulants.

• It has been used to decrease pain and inflammation resulting from extravasation of antineoplastic drugs such as ifosfamide, vincritine, doxorubicin.

• Generally chondroitan is considered to have little or no adverse effects and is better tolerated than NSAIDS.

Glucosamine• Found in the mucopolysaccharides of catilage and chitin (insect and marine animal exoskeleton)

• Commercially prepared from chitin or by organic synthesis and glucosamine sulfate is the preferred form.

Chondroitan and Glucosamine

• Glucosamine is almost completely absorbed after oral ingestion.

• Clinical studies indicate significant improvement in osteoarthritis symptoms with 1.5 g glucosamine daily over placebo and better pain management and joint function than obtained with NSAIDS.

• Generally glucosamine is better tolerated than NSAIDS with few adverse effects.

• Due to the requirement of both chondroitan and glucosamine for cartilage synthesis these two components are often supplied together in one formulation.

Saw Palmetto

• The ripe berry of the American dwarf palm is used as the principle medicinal component.

• Traditionally extracts of the berry used to treat respiratory complaints, irritation of the genito-urinary tract and prostatic hypertrophy.

• Typically liposterolic extracts and pressed oils of saw palmetto are sold commercially, however alcoholic extracts, tinctures and tablets are also found.

Pharmacodynamics• In vitro liposterolic extracts inhibit type 2 5-reductase activity to prevent conversion of testosterone to 5-dihydroxytestosterone (DHT).

Saw Palmetto

Pharmacodynamics• LESP has actions to inhibit contractility of smooth muscles of the genito-urinary tract.

• LESP can inhibit cyclooxygenase and 5-lipoxygenase activity in in vitro experiments.

Pharmacokinetics• Fatty acid components of liposterolic extracts are absorbed into the blood after oral delivery and parenterally administered LESP appears to partition to prostatic tissues.

Saw Palmetto

Clinical Studies• On average most studies indicate LESP is effective in improving peak urine flow and decreasing nocturia in BPH patients.

• Appears to be effective in treating mild to moderate BPH.

Toxicology/Safety• No adverse effect in hematological, histological and biochemical parameters observed in rats fed 360 times the usual human dose for up to 6 weeks.

• No influence on fertility reported in rats fed 80 times the human dose over 6 month period.

Adverse effects• Most often cited effects of saw palmetto: GI disturbance, nausea, fatigue and depression.

• No interaction with other drugs have been reported.

Milk Thistle

O

O

OHO

OH O

CH2OH

OCH3

OHOH

Silybin

• Also known as St. Mary’s Thistle and found endogenously in the Mediterranean region but grown world-wide.

• Generally the seeds from the fruit are used medicinally but the leaf and roots hava also been used.

• Medicinal preparations are decoctions, liquid extracts or tablets of the dried seed and usually taken internally.

• Traditionally used to treat jaundice, hepatitis, hepatic and biliary disorders, hemorrhoids and pleurisy. External application of Milk Thistle decoction for tumors and infusions of roots and seeds used to breaking gallstones and treat dropsy.

• Extracts contain flavanolignans such as silybin, silychristin (collectively called silymarin), oils, flavanoids and sterols.

Milk Thistle

Pharmacodynamics• Silybin has free radicle scavenging and antioxidant activities in in vitro cultured cells.

• Oral administration of extracts in rats resulted in increased hepatic cytochrome P450 enzyme activity.

• Flavanolignans appear to protect against liver toxicity by agents such as carbon tetrachloride, galactosamine, acetaminophen and ethanol.

• In vitro and animal experiements indicate silymarin has antitumor and antiinflammatory effects.

Pharmacokinetics• Oral bioavailability of silymarin is 20-50% of the ingested dose with about 80% elimination in the bile.

• Flavanolignans appear to accumulate in the liver and biliary system.

Milk Thistle

Clinical Trials• Some evidence of protective effect of silymarin in pts. with hepatitis, liver

toxicity and alcohol-induced cirrhosis.

• Reduction in mortality after silybin and penicillin for the treatment of amanita mushroom poisoning.

Toxicology/Safety• No acute toxicity of silymarin observed in mice, dogs or humans; longer-term

studies also indicate no carcinogenic or teratogenic potential.

Adverse Effects• Rarely seen but may include GI disturbance, laxative effect and allergic

reactions.