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Kava (Kava Kava)❧ Botany

" Piper methysticum

❧History" long used in the S. Pacific as a relaxant/recreational

drug

❧ Chemistry" contains lactone/pyrones that have CNS activity e.g.

methysticin

Kava (Kava Kava)" Pharmacology

• CNS activity resulting in mild tranquilizer-like activity (decreased anxiety, increasedeuphoria)

• local anesthetic

• mild muscle relaxant

• weak effects on GABA receptors ( but notbenzodiazepine)

• Additive interaction with alprazolam (Xanax)

• not inhibited by naloxone

" Evidence• 7 controlled, double blind studies done with a 70%

kavapyrone extract in patients. All showedimprovement in anxiety relative to placebo

• results not different than oxazepam and bromazepam(Woelk et al, Z. Allgemeinmed 69:271-277,1993)

• meta-analysis Pittler and Ernst, J ClinPsychopharmacol 20:84-89,2000

• example: study by Volz and Kieser,Pharmacopsychiatry 30:1-5,1997.

– N=101– 25 week– multicenter, randomized, placebo-controlled,

double blind trial

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Kava Kava Extract WS 1490 vs. PlaceboMain Efficacy R esults

(from Volz and Kieser, Pharmacopsychiat 30:1-5,1997)

0

5

10

15

20

25

30

35

0 4 8 12 16 20 24

Weektwo-sided U-test

HA

MA

-to

tal

sc

ore

WS 1490

Placebo

p<0.001p<0.001p<0.001p=0.002p=0.02p=0.24p=0.98

From Pittler and Ernst, J Clin Psychopharmacol 20:84-89,2000

Kava (Kava Kava)" Uses

• mild tranquilizer

" Precautions• additive effect with alcohol

• don’t drive etc

• don’t take with other CNS depressants (documentedproblem when combined with alprazolam, Zoloft)

• long use may result in rash and discolored skin orallergy

• not for use in pregnancy or depression• is a local anesthetic• Several case reports of liver toxicity including liver

failure

Kava (Kava Kava)" Products

• capsules of ground rhizome

• capsules of dried extract

• tinctures

• most extracts state standardization to 30-80% kavalactones

• 200mg TID for extracts

• want about 70mg kavalactones per dose

• avoid over 300mg/d kavalactones

• one good study used 210mg/d

Kava-Summary❧Summary

" Efficacy: long historical use; reasonableevidence for efficacy for mild to moderateanxiety.

" Safety: good but be careful as with anysedative/tranquilizer; rash with long use,rare hepatotoxicity (avoid long use)

" Drug interactions: none noted so far" Product selection: no advice" Dose: about 500mg of a root extract at HS" Questions remaining include

• How effective is this for occasional use?• How prevalent is hepatotoxicity?

Evening Primrose Oil

Botany

Oenothera sp., a wildflower/weed on the East USA coast

The seed is pressed to yield an oil

History

Many native American uses for the plant

Recent years have focused on the uses of the seed oil

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Chemistry

•Seed contains about 14% oil of which half isgamma linoleic acid (GLA); this is a omega –6essential fatty acid;

•note: omega –3 fatty acids are present in fishoils and flaxseed oils and have different uses(e.g. lower cholesterol and risk of cancer

•GLA is a precursor to prostaglandin E1whichmodulates inflammation

•Other rich sources of GLA are borage seed oil(20%GLA) and black current oil (15% GLA)

Pharmacology of GLA

•GLA is precursor to several prostaglandins and leukotrienes thatinfluence pain and inflammation

•The idea is to “flood the system” with precursor to enhancesynthesis.

•Linoleic acid is an essential amino acid widespread in our diet

•GLA is formed from linoleic acid and is not found in common foods

Uses of GLA and Evening Primrose Oil

• Cyclic mastalgia

•PMS

•Diabetic neuropathy

•Eczema

•Arthritis and many other uses

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Evidence

•The evidence is surprisingly weak for most uses

•Several placebo controlled trials in the 1980s showing improvementin breast pain associated with menses.

•No strong evidence to show improvement of other symptoms ofPMS or post menopausal symptoms

•Eczema use has been not effective in recent studies

•Use in diabetic neuropathy and rheumatoid arthritis looks promisingbased on a small number of controlled studies

•More evidence is needed to support use of EPO in Raynaudssyndrome, ADD, osteoporosis and obesity , hyperlipidemias

Safety

No special concerns at present

Dose: 2-6g of EPO/d or even higher

Evening Primrose Oil❧Summary

" Efficacy: uneven evidence for most uses; bestfor diabetic neuropathy, cyclic breast pain,and possibly rheumatoid arthritis

" Safety: good

" Drug interactions: none noted so far

" Product selection: Efamol is the best studied;has 1g/capsule

" Dose: 2-6g/d

" Questions remaining include• Does EPO really work for its many suggested

uses?

Milk Thistle

❧ Botany" Silybum marianum

" Asteraceae family (daisy, thistles, artichoke)

❧History" long used to treat “liver problems

❧ Chemistry" fruits/seeds contain flavonolignans

" silymarin=crude mixture of flavonolignans; actually ismixture of several e.g. silybin

Milk Thistle❧ Pharmacology

" silymarin has strong antioxidant properties

" has ability to block toxin entry through membranes

" stimulates liver regeneration

" increases GSH

" stimulates ribosomal RNA polymerase

" has anti-carcinogenic activities in vitro and in animals

❧Uses" liver cirrhosis

" hepatitis A,B,C

" liver toxin poisoning (e.g. amanita mushroom)

Evidence (review:Pepping; Am J Health-Syst Pharm 56:1195-1197,1999

Viral Hepatitis (A or B)

in several studies patients “normalized” hepatic function tests fasterin the milk thistle group compared to placebo; shorter hospital stay

Toxin and Drug Inducted Hepatitis

both animal and some small patient studies show protective effect ofmilk thistle or silymarin

Alcohol Related Liver Disease

some improvement in liver function tests compared to placebo inlimited studies

cirrhosis: Pares et al. J. Hepatol 28:615-621, 1998; no effect onsurvival or clinical course of alcoholics; n=200; 2yr study

cirrhosis: (Ferenci et al. J. Hepatol 9:105-113, 1989 showed 58% 4yrsurvival in treated vs 39% placebo (p=0.036); 4 yr study

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Milk Thistle

❧Cautions" Nothing special

❧ Interactions" None of significance reported as yet although it

may be a P450 3A4 inhibitor

❧Products" flavonolignans are not water soluble" extract used" extracts containing at least 70% silymarin are

best

Milk Thistle" dose: 200mg TID of a product with 80% silymarin

❧ Summary" Efficacy: helpful for liver injury due to hepatitis and

drugs and possible alcohol. May not work for severalcoholic cirrhosis

" Safety: good

" Drug interactions: none noted so far

" Product selection: extract containing 80% silymarinis best

" Dose: 200mg TID

" Questions remaining include• Does milk thistle really work for its hepatitis C and for

alcoholic liver disease?

Grape Seed Extract❧ Botany

" Seeds from Vitis vinifera

❧History" Relatively recent use as an antioxidant

❧ Chemistry" seeds contain proanthocyanidins (OPC)

" OPC s are oligomeric or polymeric flavonoid likepolyphenolic compounds

" OPC s have strong antioxidant and free radicalscavanging activities

" OPC s are also high in pine bark (see pycnogenol)

Pharmacology

•In vitro will prevent destruction of elastin, collagenand hyaluronic acid

•In animal models will reduce capillarypermeability and decrease swelling andinflammation

•Action due to the ability of OPC s to block freeradical damage and otherwise protect againstoxidative damage

Uses

•Treatment of varicose veins

•Reduce swelling due to surgery or injury

•Treat and prevent macular degeneration

•To reduce the risk for cancer and heart disease

•Treat diabetic retinopathy and neuropathy

•other

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Evidence

•Varicose veins

•Reasonable evidence based on placebocontrolled trials. Trials published in French andItalian thus not readily evaluated by all

•Reduce pain and swelling due to injury/surgery

•Three controlled studies (in French)

•Vision - one study

•Other – limited evidence from animal or in vitrostudies

Safety

Considered nontoxic

Interactions

OPCs have antiplatelet adhesion properties so thatan anticoagulant effect could be noted at higherdoses; avoid concurrent use with warfarin and otheranticoagulants

Products

Grape seed extract products contain 100mg ofextract per capsule. Dose: 100mg TID

Grape Seed Extract❧ Summary

" Efficacy: probably effective for peripheral venousinsufficiency. May help vision and maculardegeneration. Other uses need more work.

" Safety: good

" Drug interactions: careful with anticoagulants

" Product selection: ? Most are not standardized toOPCs

" Dose: 100mg TID

" Questions remaining include• Will grape seed extract help in vascular diseases other than

varicose veins? What about coronary disease?

Bilberry

•Botany- extract of the fruit of the “European Blueberry” which has awhite inside

•History-used by English pilots in WWII to improve night vision

•Chemistry-contains anthocyanosides (glycosides of anthocyanodins);these like OPCs (see grape seed extract) are powerful antioxidants

•Pharmacology- antioxidant and free radical scavanging activities withmaybe special action in the eye

•Use-poor night vision, cataracts,macular degeneration,diabeticretinopathy

•Evidence-conflicting small studies. More work needs to be done

•Safety-OK Interactions-none

•Products-look for extracts standardized to 25% anthocyanosides; 100mgqd or BID

Black Cohosh❧ Botany

" Cimicifuga racemosa. A tall perennial shrub in NE USA; roots andrhizomes used

❧ History" Used by Native Americans for women’s health problems and a

variety of other uses; A component of Lydia Pinkham’s elixir, aformally very popular remedy for dysmenorrhea and menopausalsymptoms

" In Europe a special black cohosh extract has been used since the1950s for symptoms of menopause and PMS

❧ Chemistry" Contains phytosterin, salicylic acid, tannins, and triterpine

glycosides that may be important for activity" The triterpine glycosides include acetin, 27-deoxyacetin, and

cimicifugoside

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Black Cohosh

Pharmacology

•There is disagreement whether compounds in theextract of back cohosh bind to estrogen receptors,i.e., black cohosh may not have phytoestrogenactivity

•In vitro and animal work show estrogen bindingactivities but a human study indicated no estrogenicchanges

Uses

•reduce symptoms associated with menopause

•PMS

•dysmenorrhea

•hasten childbirthing

•Evidence

•early studies with Remifemin show support for reducinghot flashes, etc in menopause; benefit seen only afterseveral weeks

•a recent study showed no effect in reducing hot flashesassociated with breast cancer treatment

•PMS-not much

Safety

•GI upset, headache, dizziness possible

•due to possible estrogenic effects, use with cautionpregnancy

•in vitro does not stimulate breast cancer cells but in vivothe risk is uncertain.

•Products

•Remifemin (SK Beecham) is a good product that has beenused successfully in controlled trials; it is standardized tocontain 1mg of 27-deoxyacetin per 20mg tablet.

•1 BID

Black Cohosh❧Summary

" Efficacy: reasonable evidence for benefit formenopausal symptoms

" Safety: good

" Drug interactions: none noted so far

" Product selection: extract of roots andrhizomes. Remifemin is the best studiedproduct

" Dose: 20mg BID

" Questions remaining include• Does black cohost help in PMS?

• What, if any, is the risk of use in breast cancer?

• Does it have estrogenic activities in vivo?

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Pychnogenol

•Botany- extract of the bark of the “French maritime pine”, Pinuspinaster also known as Pinus maritima

•History-pychnogenol is patented by Horphag Research Ltd; 60-65%OPCs per 50mg tablet The name is a registered trademark.

•Chemistry-contains OPCs (see grape seed extract)

•Pharmacology- antioxidant and free radical scavenging activities

•Use-venous insufficiency, prevent and improve heart disease etc (seegrape seed extract)

•Evidence-some evidence of a variety of benefits in improving capillaryfunction

Pychnogenol•Safety-OK Interactions-none except possibly to be used with cautionwith immunosuppresive drugs

•Products-?

•Summary-safe but unproven product for vision problems

•Questions remaining- is this more expensive product better and moreversatile therapeutically than grape seed extract which also is rich inOPCs

•Summary-safe and interesting product with ability to improve capillaryfunction with prolonged use. $

Green Tea

Botany-Camillia sinensis leaves

Chemistry-the hot water extract of the leaves containsOPCs and other antioxidant/free radical scavengingcompounds (see grape seed extract)

Pharmacology-protective activity against experimentalcancers in animals and some epidemiological evidencefor protective effects for stomach, colon, pancreaticcancers

Uses-probably need multiple cups/d; tablets of thedried extract are commercially available but do theyhave the same effect?

Green Tea

Evidence-increased consumption correlates todecreased risk of cancer and possible heart disease instudies on Japanese

Cautions-caffeine! Although the amount is less than ina cup of coffee; contains vitamin K so be careful withwarfarin

Products-as I am preparing this slide I am enjoying acup of Salada green tea made with a “tea bag”; GNCand others make a dried extract in capsule form

Questions-how much? Does black tea have the sameeffect? How much benefit?