Herbal SupplementsAn Overview of the Pharmacognosy,

Pharmacology, Clinical Therapeutics and Use of Selected Herbal ProductsScott F. Long, R.Ph., Ph.D.

Assistant Professor of Pharmacology & Toxicology

Endocrine System

Selected Herbs

Saw PalmettoBotany

• Source -- Serenoa repens Bartram. -- Native to the Southern Atlantic coast through the Gulf coast from South Carolina through Texas. The Palm achieves a height of 6-10 feet. Fruit are irregularly spherical to oblong, ranging in length from 1/2 to 1 inches and 1/2 inch diametre, are deep red-brown and wrinkled.

• Active Part – Berry

Saw PalmettoMiscellany

• Alternate Names– American Dwarf Palm, Cabbage Palm

• Trade Names– Permixon®, Propalmex ®, Strogen ®

• Dosage Forms– Tablets, Capsules, Tea, Berries, Liquid Extract

Saw PalmettoChemical Constituents

• n-Hexane liposterolic extract, containing– lauric acid and other fatty acids– phytosterols– polysaccharides– monoacylglycerides

Saw PalmettoProposed Uses

• Saw Palmetto is claimed to be effective in the treatment of genitourinary problems, including benign prostatic hypertrophy (BPH)

• Other purported uses– to increase sperm production– to increase breast size in women– to increase libido– mild diuresis

Saw PalmettoPharmacology

• Inhibition of 5-alpha reductase (in vitro)

• Antagonism of DHT at androgen receptors

• Some evidence exists for– Anti-inflammatory actions (MOA unknown)– Inhibition of prolactin (MOA unknown)– Inhibition of prostatic cell proliferation

Saw PalmettoClinical Trials

• Men, 60-70 years old

• Criteria

– Urinary frequency

– Urine flow rate

• Significant improvement relative to placebo

– Champault et al. 1984

• Similar in efficacy relative to finasteride

– Carraro et al. 1996

• Less (though not significantly) effective than alpha1 adrenergic blockade

Saw PalmettoDosing Recommendations

• Human clinical trials have used 320 mg p.o. in divided doses, twice daily

• Herbal Usage– 1 to 2 G fresh saw palmetto berries– 0.5 to 1 G dried berries– in a decoction or tea p.o. t.i.d.

Saw PalmettoAdverse Reactions

• Abdominal and back pain

• Constipation or diarrhœa

• Decreased libido or impotence

• Dysuria and urinary retention

• Headache

• Hypertension

• Nausea

Saw PalmettoContraindications

• Pregnancy

• Women of child-bearing age

• Due to actions potentially similar to those produced by finasteride

Saw PalmettoClinical Considerations

• Saw Palmetto does not apparently alter prostate size

• May produce a false-negative prostate-specific antigen (PSA) result -- baseline measurements should be made prior to initiation of therapy

• Take with meals to minimise GI side effects

Saw PalmettoSummary

• Some active constituent of saw palmetto does appear to have beneficial effects in the treatment of BPH, although the exact mechansim is unknown

• Use should be controlled and supervised by health care professionals to minimise potential risks and to judge efficacy of treatment

• Approved by the German Commission E for use in BPH-related urinary problems.

NettleBotany

• Source -- Urtica dioica L., a perennial of the nettle family (Urticaceæ), native world-wide. The plant grows 2-3 feet high with heart-shaped, serrated leaves. Plants are gender specific, with flowers in long,branched clusters appearing June-September. The plant is hirsute, with each hair serving as a small, hollow, needle-like form of protection.

• Active Parts -- Leaves, Stems, Roots

NettleMiscellany

• Alternate Names– Common nettle, Greater nettle, Stinging nettle

• Trade Names– Nettle Capsules, Nettle Liquid Extract

• Dosage Forms– Capsules, Dried Leaf and Root Extract,

Tincture

NettleChemical Constituents

• Stems (non-therapeutic) --– Histamine, serotonin, choline, formic acid

• Roots --

– Phenylpropanes and lignans

• Roots and Flowers --

– Scopoletin, steryl derivatives, lignan glycosides, flavonol glycosides

• Whole Plant --

– B, C, and K vitamins, sitosterol and other steroid related compounds

NettleProposed Uses

• Diuresis -- hypertension, heart failure, and urinary, bladder, and kidney dysfunction

• Benign Prostatic Hypertrophy

• Other Uses -- Rheumatoid arthritis, antispasmodic, expectorant, asthma, cough, tuberculosis, locally for alopecia, epistaxis, uterine bleeding, diabetes, gout, cancer, eczema, wound healing.

NettlePharmacology

• Nettle apparently does possess some diuretic activity, although the mechanism is not known.

• Shown to stimulate uterine contractions in rabbits.

• Possesses immunostimulant (lectin protein) and anti-inflammatory actions (scopoletin)

• Inhibits BPH in mice.

NettleClinical Trials

• Nettle extracts have been shown to reduce urine flow, nocturia, and residual urine in humans.

• Use as a bladder irrigant in humans resulted in reduces postoperative blood loss, bacteriuria, and inflammation.

• Use in humans has shown some efficacy in the treatment of allergic rhinitis.

NettleDosing Recommendations

• Allergic rhinitis– 150 or 300 mg capsules as needed

• Tea– 1-2 teaspoonfuls of dried herb in 1 cup of

boiling water, up to twice daily

• Tincture– 1/4 to 1 teaspoonful up to twice daily

NettleAdverse Reactions

• Contact dermatitis (especially fresh)

• Decreased urine volume, frequency

• Diarrhœa

• Œdema

• GI irritation

NettleContraindications

• Pregnancy

• Children under 2 years old

• Elderly patients

Drug Interactions• Diuretics

NettleClinical Considerations

• Contact dermatitis associated with cutaneous exposure may cause intense burning for 12 hours or longer. Following exposure, the individual should wash thoroughly with soap and water and medicate with antihistamines and steroid cream as needed.

• The FDA consideres nettle to be of undefined safety.• Approved by the German Commission E to treat

urinary inflammation and prevent urinary calculi.

NettleSummary

• There is both scientific and clinical evidence to support the use of nettle as a mild diuretic, urinary anti-inflammatory, and anti-allergic.

• Oral dosing rarely results in severe adverse reactions and the herb is generally considered safe.

• Further research is required to confidently recommend nettle as an alternative therapy.

• Approved by German Commission E for urinary inflammation and prevention of urinary gravel. Also externally for rheumatism.

PumpkinBotany

• Source -- Cucurbitaceæ family, Cucurbita pepo L., C. moschata., widely cultivated in North America and Australia.

• Active Parts -- Seeds

PumpkinMiscellany

• Alternate Names– Cucurbita, Pumpkinseed oil, Vegetable marrow

• Trade Names– Available in combination with palmetto as

Ultimate Oil®, Proleve 40® and others.

• Dosage Forms– seeds (whole or crushed), seed extract or oil,

tablets, tea

PumpkinChemical Constituents

• Cucurbitin ((-)-3-amino-3-carboxypyrrolidine) a water soluble amino acid.

• Pumpkin Seed Oil -- Unsaturated fatty acids (c. 25% oleic and 55% linoleic acids), phytosterols

PumpkinProposed Uses

• The current lay recommendations for the use of pumpkin is in the treatment of benign prostatic hypertrophy.

• Historically, pumpkin has been used to treat tape and other intestinal parasitic helminthic infections.

PumpkinPharmacology

• Cucurbitin exhibits anthelminthic activity against pinworms and tapeworms in mice. It has also been shown to inhibit the growth of immature Schistosoma.

• The beneficial effects in BPH are purported to be due to the fatty acids and phytosterols, however this claim has not been substantiated.

PumpkinClinical Trials

• Clinical trials of pumpkin as a single entity have not been performed. In combination with saw palmetto, patients have shown an improvement in urinary flow, micturition time and frequency, and reduced residual urine. No changes in prostate size have been noted.

PumpkinDosing Recommendations

• Anthelminthic -- Doses vary from 60 to 500 G of pumpkin seed in three divided doses daily, either as a tea or an emulsion of crushed seeds in powdered sugar and milk or water.

• Many cultures report the ingestion of a handful of seeds daily for the treatment of both helminthic infections and BPH.

PumpkinAdverse Effects

• Electrolyte Imbalance (from the mild diuretic actions)

Drug Interactions

• Diuretics (potentiation of fluid loss and electrolyte imbalance)

PumpkinContraindications

• Pumpkin should not be used in prostatic hypertrophy of unknown etiology. Neither should it be used in patients who are pregnancy or are breastfeeding.

PumpkinClinical Considerations

• Patients taking pumpkin should be monitored for electrolyte imbalances.

• If used as an anthelminthic, the patients should be monitored to ensure efficacy.

• Caution should be taken to monitor urine output. As with any diuretic, forced diuresis with urinary obstruction may cause nephrotoxicity.

PumpkinSummary

• There is no evidence, either scientific or clinical, to support the use of pumpkin in the treatment of BPH. The potential benefit from the diuretic effects of the fatty acids is, at best, mild and minor. Better agents with known side effect and toxicity profiles provide better choices for the treatment of prostatic hypertrophy.

• Approved by German Commission E for urinary irritation and BPH related problems.

Black CohoshBotany

• Source -- Cimicifuga racemosa Nutt and other species native to Eastern North America, they are tall (1-3 feet), herbaceous plants that flower in June/July with feathery racemes of white blossoms.

• Active Part -- Roots and rhizomes

Black Cohosh Miscellany

• Alternate Names– Black snakeroot, Bugbane, Bugwort,

Rattleweed, Rattleroot, Squaw root

• Trade Names– Estroven®, Femtrol®, Remifemin®

• Dosage Forms– Caplets, Capsules

Black Cohosh Chemical Constituents

• Steroidal terpenes

• Acteina

• Cimigoside

• 27-Deoxyactein

• Others -- tannins, salicylic acid, and the isoflavone formononetine

Black Cohosh Proposed Uses

• Astringent

• Diuretic

• Anti-diarrhœal

• Anti-inflammatory

• Menopause

Black Cohosh Pharmacology

• Acteina is thought to produce vagal-mediated hypotension (animal studies)

• Black cohosh has been shown to occupy œstrogen receptors to decrease the release of leutinising hormone (LH) without altering follicle stimulating hormone (FSH) in mice

Black Cohosh Clinical Trials

• Clinical trials have shown similar effects on LH as those produced in the laboratory.

• Another clinical trial resulting in significant reductions in LH secretion and non-significant reductions in FSH.

• Changes were not significantly different than those produce by standard œstrogen therapy.

Black Cohosh Dosing Recommendations

• Doses vary and are not standardised.

• Clinical trials have utilised doses ranging from 8 mg to 2400 mg daily

Black Cohosh Adverse Effects

• Hypotension

• Nausea

• Vomiting

• Miscarriage at high doses

Black Cohosh Contraindications

• Pregnancy

• Patients with low blood pressure

• Patients with œstrogen-dependent cancers or who are at risk for developing such cancers.

Black Cohosh Drug Interactions

• Anti-hypertensive– Effects may be additive to cause a precipitous

drop in blood pressure.

Black Cohosh Clinical Considerations

• Blood pressure should be closely monitored in patients taking black cohosh.

Black Cohosh Summary

• Clinical evidence does exist that supports the use of black cohosh as an alternative therapy in the treatment of post-menopausal symptoms. However, many of these trials used low numbers of subjects. More extensive clinical trials are needed to better assess the safety and efficacy of cohosh.

• German Commission E has approve black cohosh for the treatment of premenstrual discomfort, dysmenorrhœa, and signs and symptoms of post-menopause.

Evening PrimroseBotany

• Source -- Œnethera biennis L., a biennial, flowering herb that grows in North America and Europe.– 3-4 feet high

– 3-5 inch leaves, 1 inch wide

– yellow flower (June) typically

opening around 6:00-7:00 P.M.

• Active Part -- Seeds

Evening Primrose Miscellany

• Alternate Names– King’s Cure All

• Trade Names– Efamol®, Epogram®

• Dosage Forms– Capsules, Gelcaps

Evening Primrose Chemical Constituents

• Primarily Essential Fatty Acids– Linoleic acid– gamma-Linoleic acid– Oleic acid– Palmitic acid– Stearic acid

Evening Primrose Proposed Uses

• Historically, evening primrose has been used to treat asthmatic cough, GI disturbances, whooping cough, eczema, breast pain, premenstrual syndrome, psoriasis, multiple sclerosis, rheumatoid arthritis, hypercholesterolæmia, asthma, Raynaud’s syndrome, Sjögren’s syndrome, diabetic nephropathy, and as a sedative, astringent, analgesic, and vulnerary.

Evening Primrose Pharmacology

• No specific mechanism of action has been shown for evening primrose.

• Supporters of its use claim that the beneficial effects are derived from the linoleic and gamma-linoleic acid constituents. These are essential fatty acids that must be obtained from the diet, since they cannot be synthesised de novo.

• Animal studies have supported its use for diabetic neuropathy.

• Additional animal studies have shown that high levels of linoleic and gamma linoleic acid will decrease mammary tumours.

Evening Primrose Clinical Trials

• No benefit was seen in two large trials using evening primrose constituents to treat atopic dermatitis. Meta-analysis of nine other studies indicated improvement.

• Breast pain and tenderness associated with PMS and benign breast disease showed significant improvement with evening primrose.

• Use with fish oils indicated a reduced need for analgesics in arthritis, but no improvement in disease progression was seen.

• Gamma Linoleic acid has been shown to reduce serum cholesterol and blood pressure in both humans and animals.

• One clinical trial indicated beneficial effects in the treatment of attention deficit/ hyperactivity disorder.

Evening Primrose Dosing Recommendations

• Most doses are based upon evening primrose standardised to 8% gamma linoleic acid.

• Eczema -- 320 mg to 8 G daily for adults and 1/2 that dose for children

• Mastalgia -- 3 - 4 G daily

Evening Primrose Adverse Effects

• Headache• Inflammation (chronic)• Thrombosis (chronic)• Immunosuppression (chronic)• Nausea• Rash• Temporal lobe epilepsy, especially in schizophrenic

patients or those taking phenothiazines.

Evening Primrose Contraindications

• Pregnancy

• Patients with schizophrenia

• Patients taking any epileptogenic drug

Evening Primrose Drug Interactions

• Phenothiazine anti-psychotics or anti-emetics– the aforementioned convulsions

Evening Primrose Clinical Considerations

• Any patient with a history of seizure disorders should not use evening primrose.

• Despite the promise it has shown with ADHD, it should not be indiscriminantly used in children.

Evening Primrose Summary

• Underlying mechanisms of fatty acid metabolism may contribute to numerous disease states including ADHD, DM, CV disorders, hypercholestolæmia, cancer, and dermatologic conditions. Evening primrose could beneficial for these disorders. However the risk of seizures probably outweighs any potential benefit.

• Neither the FDA nor the German Commission E has approved the use of evening primrose for any disease state.

GinsengBotany

• Source -- American Ginseng, Panax quinquifolius, Asian or Chinese Ginseng, P. ginseng, and Siberian Ginseng, Eleutherococcus senticosus.

• Active Part -- Root

Ginseng Miscellany

• Alternate Names– Devil’s shrub (Siberian)

• Trade Names– Vigoran® (Siberian)

• Dosage Forms– Powders, Teas, Tinctures, Capsules, Tablets,

Oils

Ginseng Chemical Constituents

• Ginsenosides (panaxosides) -- American and Chinese

• Eleutherosides -- Siberian

• Vitamins (A, B, C, D) in varying concentrations

• Essential oils

• Resins

Ginseng Proposed Uses

• Although different uses exist for the various forms of Ginseng, the numerous uses for any may include diabetes mellitus and stress and for their adaptogenic, immuno-stimulant, anti-cancer, and cognitive (American and Chinese) actions.

Ginseng Pharmacology

• May act as agonists at mineralocorticoid, glucocorticoid, progestin, and œstrogen (Siberian) receptors.

• Decrease both fasting and post-prandial blood glucose levels

• Has been shown to increase T lymphocyte cell counts.

• American ginseng has been shown to have numerous opposing effects

Ginseng Clinical Trials

• Numerous large and small human trials have been performed to evaluate the numerous claims of ginseng.

• There are no consistent results that indicate definitive therapeutic benefits.

• Many studies contradict other studies.

Ginseng Dosing Recommendations

• Wide ranges of doses have been used for ginseng.

• Ranges from 200 mg to 2 G daily.

Ginseng (Siberian)Adverse Effects

• Diarrhœa• Difficulting in concentrating• Dizziness• Euphoria• Hypertension• Increased Agitation• Nervousness• Skin Eruptions• Vaginal bleeding and other œstrogenic effects

Ginseng Contraindications

• Pregnancy

• Children

• Known Hypersensitivity

Ginseng (Siberian)Drug Interactions

• Digoxin -- elevates digoxin levels

• Barbiturates -- inhibits barbiturate metabolism

• B and C Vitamins -- increases vitamin excretion

• Oral Hypoglycæmics -- synergistic actions, potential hypoglycæmia

Ginseng Clinical Considerations

• Most literature, including herbal literature, recommend use for no more than three (3) weeks

• Patients should be monitored for any changes in stress response for electrolyte abnormalities

Ginseng Summary

• Many of the purported claims for ginseng have not been supported with laboratory data.

• Endocrine effects, including ability to lower glucose and effects on steroid receptors, may represent pharmacologic effect, but the risk:benefit analysis precludes indiscriminat use.

• German Commission E has approved ginseng for use to increase vigour and fortitude.

DandelionBotany

• Source -- Taraxacum officinale and T. lævigatum, ubiquitous in the Northern Hemisphere

• Active Part -- Leaves and Roots

DandelionMiscellany

• Alternate Names– Lion’s tooth, Swine’s snout, Priest’s crown,

Wild endive

• Trade Names– Various, all incorporating “dandelion”

• Dosage Forms– Capsules, Extracts, Teas

Dandelion Chemical Constituents

• Acids -- Caffeic acid, Parahydroxyphenylacetic acid, Chlorgenic acid

• Essential Fatty Acids -- Linoleic, Linolinic, Oleic, and Palmitic acids

• Others -- Taraxasterol, Taraxacin, Taraxacum, Taraxerin, Taraxerol, Taraxanthin (a carotenoid)

• Trace elements, vitamins (A, B, C, D), resins, terpenes, and phytosterols.

Dandelion Proposed Uses

• Herbalists recommend dandelion for liver and gall bladder disorders, cholecystitis, digestive problems, constipation, and as a diuretic.

• Currently, it is recommended for diabetes mellitus and as a stomach aid.

• It is claimed to possess laxative, diuretic, bile-stimulant, and anti-rheumatic actions.

Dandelion Pharmacology

• Taraxacum has been shown to increase salivary, gastric, and biliary secretions and laxative actions.

• Dandelion has been shown to decrease blood glucose levels.• Both diuretic and anti-inflammatory actions have been

shown in rodents.• Dandelion extracts have been shown to inhibit tumour cell

growth.• Broad “beneficial” effects in jaundice, liver congestion,

gallstones, hepatitis, and cholecystitis have been claimed but not convincingly substantiated.

Dandelion Clinical Trials

• Very few clinical trials have been performed using dandelion.

• One study in a small group of patients indicated that dandelion could successfully treat abdominal pain, constipation, and diarrhœa associated with chronic, non-specific colitis.

Dandelion Dosing Recommendations

• Dried root -- 2-8 G by infusion or decoction thrice daily

• Dried leaf -- 4-10 G infusion thrice daily• Fluid extract (1:1 in 25% ethanol) -- 4-8 ml

thrice daily• Tincture of root (1:5 in 45% ethanol) -- 5-10

ml thrice daily• Juice of root -- 4-8 ml thrice daily

Dandelion Adverse Effects

• Hypoglycæmia

• Gastrointestinal obstruction

• Biliary obstruction

• Contact dermatitis

• Other allergic reactions

• Cholecystitis

• Cholelithiasis

Dandelion Contraindications

• Pregnancy

• Breast-feeding

• Known hypersensitivity

Dandelion Drug Interactions

• Anti-diabetic agents -- synergistic actions, resulting in hypoglycæmia

• Anti-hypertensives -- synergistic actions, resulting in hypotension

• Diuretics -- synergistic actions, contributing to drops in blood pressure and potentially dangerous electrolyte imbalances.

Dandelion Clinical Considerations

• Patients should be monitored for changes in blood glucose, blood pressure, and electrolyte imbalances.

• Dandelion, used as a food source, contains more vitamin A and carotenoids than carrots.

Dandelion Summary

• Dandelion has long been used and recently enjoyed a resurgence as a food product, especially in salads. Taken in these small amounts, dandelion appears relatively safe and free of adverse effects.

• Clinical evidence is lacking to support its use as a herbal medication. Dandelion should not be taken in quantities greater that those ingested as food.

• German Commission E has approved dandelion to stimulate appetite and to treat dyspepsia and flatulence.

Selected Bibliography

• Professional’s Handbook of Complementary and Alternative Medicines, C. W. Fetrow and J. R. Avila, Eds. Springhouse Corporation, Springhouse PA, 1999

• Medicinal Plants of the World, I. A. Ross, Humana Press, Totawa NJ, 1999

• The Complete German Commission E Monographs: Therapeutic Guide to Herbal Medicines, M. Blumenthal et al. Eds., American Botanical Council, Austin TX, 1998

• A Modern Herbal: The medicinal, culinary, cosmetic, and economic properties, cultivation, and folklore of herbs, grasses, fungi, shrubs, and trees with all their modern scientific uses. M. Grieve, Jonathan Cape, Ltd., Chatham Kent, 1931.