Saw Palmetto - Healthcare Professionals

Herbal Potpourri 2006Barry A. Browne, PharmDDrug Information ServiceDepartment of PharmacyScott & White HospitalAssociate ProfessorDepartment of MedicineCollege of MedicineTexas A&M University Health Science Center

Introduction• Federal “Dietary Supplement Health andEducation Act” (DSHEA)• Passed by Congress in 1994: allows productsmarketed as “dietary supplements” to beexempted, in general, from Food and DrugAdministration (FDA) regulation

Introduction• If label does not contain specific claims ofeffectiveness in treating or preventing disease,the act provides:• production, distribution, advertisement, saleof “dietary supplements” is legal andunregulated by FDA• Products included as “dietary supplements”• “all-natural” sleep aids, weight-loss products,laxatives, “anti-aging” aging” products, “energy-boosters”

Introduction• No specific requirements for proof of efficacyor safety• Manufacturers not required to provideevidence of purity or to demonstrate thatlabeled ingredients are contained in theproduct• The result: availability of heavily promotedproducts----many of them clearly potentpharmacologic agents----unregulated in today’smarketplace

Glucosamine, Chondroitin• Glucosamine sulfate (GS) is an amino sugar utilized inbiosynthesis of glycoaminoglycans (GAGs)• GAG side chains: integral cartilage structural components• Chondroitin sulfate moities compose the major repeatingGAG side chain structures• OA characterized by predominance of degradation comparedto repair of cartilage proteoglycans• Hypothesis: glucosamine considered as “rate-limiting”molecular entity for GAG/cartilage synthesis

Glucosamine, Chondroitin• Glucosamine (MW 179 daltons) ) readily passesthrough biologic membranes• When taken orally, as is the case with most aminosugars, a substantial portion is metabolized to water,carbon dioxide and urea• Despite relatively poor oral bioavailability,glucosamine absorption is considered by someresearchers to be sufficient to increase GAGproduction of cartilage by chondrocytes• Poorly controlled, early clinical trials indicated benefitof glucosamine and chondroitin in OA patients

Glucosamine, Chondroitin• GS source is chitin extracted from crab shells• Product is relatively inexpensive (price for 60-90 capsules,tablets of 300-750mgglucosamine ranges from $20-$45)$45)• Usual GS dose: 500mg TID• GS often combined with chondroitin (obtained from bovinetrachea)• Chondroitin, , with larger MW (50-300x greater thanglucosamine), has poor oral bioavailability

Glucosamine, Chondroitin• Joint space narrowing data (Reginster(JY, Deroisy R,Rovati LC et at. Long-term effects of glucosaminesulphate on osteoarthritis progression: a randomized,placebo-controlled controlled clinical trial. Lancet 2001;357:251-6)• Randomized, double-blind, blind, placebo-controlled controlled trial• 212 patients with osteoarthritis of the knee receivedeither 1500mg glucosamine or placebo once daily forthree years

Glucosamine, Chondroitin• Study endpoints• Western Ontario and McMaster UniversitiesOsteoarthritis Index (WOMAC) scores• mean, minimum joint-space width (tibio(tibio-femoral joint medial compartment) evaluatedby weight bearing, antero-posterior radiographsof each knee• full extension radiographs taken atenrollment, at one year, and at trialcompletion (three years)

Glucosamine, Chondroitin• Results:• Authors reported placebo recipients had progressivejoint-space narrowing compared to GS-treatedpatients for three-year trial completers (GS 71/106patients, placebo 68/106)• mean narrowing: 0.31mm loss for placebo, 0.7mm gain for GS-treated patients, difference of0.38 mm (p=0.038) after three years• minimum (narrowest point measurement): 0.4mmloss for placebo, 0.11mm gain for GS-treatedpatients (p=0.002) after three years

Glucosamine, Chondroitin• Results• WOMAC percent score change (baseline,three-year completer results)• placebo: 9.8% mean WOMAC scoreincrease (71/106 patients)• GS: 24.3% mean WOMAC scoredecrease (68/106 patients)

Glucosamine, Chondroitin• Results (cont’d)• Completers mean change difference (p=0.016),ITT analysis (p=0.20)• Safety: authors reported “no substantialdifferences” in ADRs between the two groups• abdominal pain (17% placebo, 12% GS),blood pressure increases (14% in bothgroups) reported most commonly

Glucosamine, Chondroitin• Accompanying editorial (McAlindon(T. Glucosaminefor osteoarthritis: dawn of a new era? Lancet2001;357:247-8) ) suggests that administration of GSmay retard OA progression, as evidenced by thejoint-space narrowing data• Issues/Considerations• Difficulty in standardization of radiographicimaging of the tibio-femoral joint space• Pain impairment of ability to fully extend joint

Glucosamine, Chondroitin• Issues/Considerations (cont’d)• Relatively small change in joint spacenarrowing (mean 0.38 mm difference)…clinical significance?• Poor correlation between symptoms andstructure change scores• Use of radiographic imaging as a markerfor possible disease modification

Glucosamine, Chondroitin• Recent GAIT study (Clegg DO, Reda DJ, Harris CL etal. Glucosamine, chondroitin sulfate and the two incombination for painful knee osteoarthritis. N Engl JMed 2006;354:795-808)provides further insight• Glucosamine/chondroitinchondroitin ArthritisInterventionTrialmethods• NIH-sponsored, 24-week, R, DB, PC, MC trial(celecoxib 200mg daily active comparator)• Subjects: 40 years of age or older, knee OA diagnosis(WOMAC pain score/radiologicradiologic evidence)

Glucosamine, Chondroitin• Methods (cont’d)• Interventions• 500mg glucosamine (G) three times daily• 400mg chondroitin (C) three times daily• Combination 500mg glucosamine/400mgchondroitin (G/C) three times daily• 200mg celecoxib once daily• Placebo• Acetaminophen (up to 4000mg daily) only rescuepain medication

Glucosamine, Chondroitin• Methods (cont’d)• Outcome measures• Primary• Percentage of subjects with a 20% decrease inWOMAC pain score, baseline-week 24, for eachgroup• Secondary• WOMAC subscale scores for joint stiffness, function• Patient global response assessment (100mmVAS)• Investigator global assessment (100mm VAS)• Soft-tissue tissue swelling/effusion• Quality of life/physical function questionnaires• Acetaminophen use

Glucosamine, Chondroitin• Results• 1583 subjects enrolled, 1258 (79%) completed study• Mean age: 58 (64% female)• Primary outcome measure (percentage of patients with a 20% decrease inWOMAC pain score at 24 weeks)• C, G, G/C: no statistically significant difference in percentage ofpatients responding versus placebo• G: 3.9% response rate difference (64% vs. 60.1%, p=0.17, NSS)• C: 5.3% response rate difference (65.4% vs. 60.1%, p=0.3, NSS)• G/C: 6.5% response rate difference (66.6% vs. 60.1%, p=0.09, NSS)• Celebrex® response rate compared to placebo: 70.1% vs. 60.1%, p=0.008,SS)

Glucosamine, Chondroitin• Results (cont’d)• Only statistically significant difference in secondaryoutcome measures (all randomized subjects)• Percentage incidence of joint swelling/effusionwith chondroitin compared to placebo at 24 weeks• C: 7.5% incidence difference (12.4% vs. 19.9%,p=0.01, SS)• Severity stratification subanalysis (WOMAC)• Subjects stratified as “mild” (78%) “moderate-toto-severe” (22%)

Glucosamine, Chondroitin• Results (cont’d)• Stratification outcomes• Several outcome measures indicated statisticallysignificant differences for G/C subjects compared toplacebo at 24 weeks in “moderate-toto-severe” group• Primary endpoint (percentage of subjects with a20% decrease in WOMAC pain subscale at 24 weekscompared to placebo)• G/C: 79.2% responders vs. 54.3% placebo(p=0.002) SS• Celebrex®: 69.4% responders vs. 54.3% placebo(p=0.06) NSS

Glucosamine, Chondroitin• Results (cont’d)• Secondary endpoints• 50% decrease in WOMAC pain score: 52.8%(G/C) vs. 32.9% placebo (p=0.02)• Other statistically significant differences comparedto placebo• WOMAC function score (p=0.008)• HAQ pain score (p=0.03)

Glucosamine, Chondroitin• Results (cont’d)• Three serious ADEs (judged by investigators as“related” to study treatment)• Combined G/C treatment arm: CHF• Celecoxib treatment arm: stroke• G treatment arm: chest pain• Number of subjects withdrawing from study due toADEs described as “similar” in all groups• 7 (Celebrex® group), 20 (C group)

Saw Palmetto• Extract of the dried ripe fruit of the American dwarf sawpalmetto (Serenoa(repens) ) first utilized by nativeAmericans in Florida in the early 1700s• testicular atrophy• erectile dysfunction• prostate gland inflammation/swelling• Medical literature reports since 1800s indicate utilizationof saw palmetto in treatment of benign prostatichyperplasia (BPH)• Currently utilized by more than 2 million men in the USfor BPH therapy

Saw Palmetto• Mechanism of action in BPH/LUTS (lower urinarytract symptoms) unknown• Alteration of cholesterol metabolism• Antiestrogenic, antiandrogenic, antiinflammatoryeffects• Possible decrease in sex hormone-binding globulin• Prostaselect, Prostagalen, Prostavigol, Talso, Curbicin,Serendar, Permixon, , PA109

Saw Palmetto• Clinical evaluation of saw palmetto (Gerber GS,Kuznetsov D, Johnson BC, Burstein JD.Randomized, double-blind, blind, placebo-controlled controlled trialof saw palmetto in men with lower urinary tractsymptoms. Urology 2001;58:960-5)5) provides data onsaw palmetto efficacy in BPH/LUTS• Study assessed urinary symptoms, sexual function,urinary flow rate

Saw Palmetto• Design: P, R, DB, PC, singe-site, site, six-month trialevaluating commercially available saw palmettopreparation (160mg BID, Nutraceutical, , Inc.,Ogden, UT) and placebo in 85 men with LUTS• One-month placebo run-in excluded placeboresponders (eight previously randomizedindividuals)

Saw Palmetto• Six-month results….• International Prostate Symptom Score (IPSS)• saw palmetto -4.4• placebo• Quality-ofof-Life Score• saw palmetto -0.7• placebo-2.2 (p=0.038)-0.3 (p=0.20)

Saw Palmetto• Six-month results…• Sexual Function Questionnaire• saw palmetto -0.1• placebo• Peak flow rate (mL(mL/s)-0.1 (NS)• saw palmetto +1.0• placebo+1.4 (p=0.73)

Saw Palmetto• Study limitations (author comments)• Results indicated no appreciable improvement inmean urinary flow rate overall, but showedimprovement in IPSS• Patients with normal urinary flow rates (greaterthan 15mL/s) but with other symptoms includedand likely affected flow rate results• Lack of difference also potentially due to lack ofstandardization of agent

Saw Palmetto• Recently published saw palmetto evaluation (Bent S, Kane C,Shinohara K et. al. Saw palmetto for benign prostatichyperplasia. N Engl J Med 2006;354:557-66)66) providesadditional data, more-rigorous rigorous study design• Larger subject population• 225 subjects vs. 85 (Urology(trial)• Agent standardization• Multi-center study design• Study length• 14-month duration vs. six months (Urology(trial)• NIH funding

Saw Palmetto• Methods• R, PC, DB, MC comparison of saw palmetto extract(160 mg twice daily) and matching placebo in malesubjects older than 49 years of age with moderate-toto-severe BPH• Patients receiving 5-alpha 5reductase inhibitors, alpha-adrenergic agents excluded• Primary outcome measures• American Urological Association Symptom Index(AUASI) score changes from baseline (score rangefrom 0-35) 0• Maximal urinary flow rate

Saw Palmetto• Methods (cont’d)• Secondary outcome measures• Prostate volume change• Residual urinary volume after voiding• QOL measurements (validated instruments)• Laboratory markers• Reported ADE rates• Sexual function

Saw Palmetto• Methods (cont’d)• Single-source, single-lot lot saw palmetto extractutilized (Idena(USA)• GC samples consistent throughout lot provided bymanufacturer• Placebo capsule: similar appearance, taste• Subject recruitment• San Francisco VA Medical Center• Kaiser Permanente Northern California

Saw Palmetto• Results• 112 subjects received saw palmetto, 113 placebo recipients(ITT analysis)• Similar number of subjects lost to follow-up in each group(9 for placebo, 10 for SP)• Primary outcome measures:• Reduction in mean AUASI score (from baseline): NSS• Saw palmetto: 0.68• Placebo: 0.72• Increase in maximal urinary flow rate (from baseline):NSS• Saw palmetto: +0.42mls/sec• Placebo: -0.01mls/sec

Saw Palmetto• Results (cont’d)• No statistically significant differences in secondaryoutcome measures• Prostate volume• SP: 3.76mls P: 4.98mls (NSS)• Residual volume after voiding• SP: 14.10mls P: 18.62 mls (NSS)• Serum testosterone• SP: -16.82ng/dl P: -1.42ng/dl (NSS)• Quality of life, serum PSA, serum creatinine, , sexualfunction (NSS)• No statistically significant differences in ADEs

Saw Palmetto• Authors’ comment:• “No statistically or clinically significant differences” inoutcomes for subjects receiving saw palmetto or placebo• 3-point AUASI reduction required for “meaningfulclinical BPH improvement”• 0.68 observed for saw palmetto, 0.72 for placebo• Saw palmetto extract utilized “comparable to other SPproducts available in the US”• Positive outcomes in some previous trials may have beendue to inadequate blinding, study design flaws

Weight Loss Herbals• Variety of other herbals/dietary supplements advertised,utilized for weight loss• Hydroxycut®,Cortislim®,Puranol®• Product formulation• Vitamins, minerals• Vitamin C, calcium, chromiumpolynicotinate/picolinatepicolinate, , thiamin, riboflavin,magnesium• “Proprietary” weight loss compounds• Guarana, , green tea leaf extract, white willow bark,bitter orange peel extract, magnolia bark extract,ginseng, gingko biloba

Weight Loss Herbals• Hydroxycut®• Calcium, potassium, chromium polynicotinate,• Garcinia cambogia (tropical fruit)—hydroxycitricacid (HCA) source• MOA: purported to decrease fatty acid synthesis(RCT evidence contradictory)• Glucomannan—soluble fiber (guar gum, psyllium)• MOA: increase water absorption in gut, increasesatiety, decrease caloric absorption (RCTs(poorlydesigned, may provide limited weight loss)

Weight Loss Herbals• Hydroxycut® ® (cont’d)• Conjugated linoleic acid: trans-fatty acids• MOA: increased fat oxidation, decreasedtriglyceride adipose tissue uptake (RCT evidence:no BMI change in humans)• Willow bark extract: salicylate----antipyretic, anti-inflammatory, analgesic (Rev. Edmund Stone, 1760)• MOA: unclear, purported to increase utilizationof fatty acids

Weight Loss Herbals• Hydroxycut® ® (cont’d)• “HydroxyTea”—green tea extract, caffeine,guarana• MOA: green tea extract purported to increasefat oxidation (RCT not designed to detect weightloss)• Guarana----6% caffeine content (1-2% in coffee)• MOA: well-documentedmethylxanthine CNSstimulation• Hydroxycut Caffeine-Free®: 200mg green teaextract, no caffeine source

Weight Loss Herbals• Cortislim®• Vitamin C, calcium, chromium• “Cortiplex”: magnolia bark extract, l-theaninel• Magnolia bark extract----CNS stimulant(cholinergic agonist, anti-inflammatory/antiinflammatory/anti-platelet activity)• l-theanine--major amino acid found in green tea

Weight Loss Herbals• Cortislim®• “Leptiplex”: green tea leaf extract, bitter orangepeel extract• Bitter orange peel extract: ephedra alkaloid• “Insutol”: vanadium (5mcg)• MOA: trace mineral, augmentation of insulineffect and increase cellular glucose uptake

Weight Loss Herbals• Puranol®• “Feeling tired? Sluggish? Bloated?• ….chances are your body is toxic!”• “5-day detoxifying cleanser”• “…the average person has somewhere between5 and 10 pounds of compacted waste and toxicpoisons built up in their body!”

Weight Loss Herbals• Puranol® ® (cont’d)• Cleansing Herbal Blend• Senna (stimulant laxative)• St. John’s bread (lipase, protease, amylase inhibitor)• Cassia (potentiation(of insulin action)• Only limited data on possible effectiveness forcassia, SJ bread• Fluid Balance Blend• Cranberry juice or “condensed tannins” (mayinterfere with E. coli adherence to urinary tractepithelial cells)

Weight Loss Herbals• Puranol® ® (cont’d)• Fiber Blend• Vegetable cellulose• Oat, soy fiber• Citrus, apple pectin• Digestive Enzyme Blend• Papain, , amylase, protease, lipase, lactase

Weight Loss Herbals• Slimagain Plus®• Pyruvate, , fenugreek seeds (chitosan(chitosan)• Pyruvate: : three-carbon compound generated throughglycolysis• MOA: purported to increase fat oxidativemetabolism (RCT trial data: modest benefit)• Chitosan: : derived from either crustacean shell chitin orfrom fenugreek seeds (Middle East, India)• MOA: positively charged polymer, prevention of fatabsorption by binding negatively charged fatmolecules within the gut lumen (RCTs(RCTs: : no differencecompared to placebo)

Weight Loss Herbals• Pur-HoodiaPlus®• Hoodia gordonii• “Miracle cactus,” “South African cactus,” “P57,”“Kalahari cactus”• Utilized by natives in the Kalahari Desert of SouthAfrica as appetite suppressant• Phytopharm, , UK pharmaceutical company, completed“P57” clinical trial in conjunction with Pfizer in 2002• Pfizer discontinued development program in 2003(product supply concerns)

Weight Loss Herbals• Pur-HoodiaPlus® (cont’d)• Structure: steroidal glycoside (similar to molecular corestructure of digitalis glycoside)• Hypothesized MOA (Mclean DB. Brain Research2004;1020:1-11)11)• P57 increases ATP concentration in hypothalamicneurons• Metabolic/nutrient sensing role for hypothalamus?• “Triggering” of appetite-suppressantneural/endocrine responses

Weight Loss Herbals• Pur-HoodiaPlus® (cont’d)• Phytopharm study (unpublished, available on websitewww.purhoodiapluspurhoodiaplus.com)• DB, PC trial of overweight, other-wise healthy males• Results• “Large” doses of P57 extract produced“Statistically significant” reductions by study day15 in subjects receiving study agent compared toplacebo recipients• Average daily caloric intake (1000 kcal/day)• Body fat content• No other data currently available

Weight Loss Herbals• Pur-HoodiaPlus® (cont’d)• Other ingredients• Green tea leaf• Banana leaf• preliminary clinical data suggest thatcorosolic acid 1% extract may lower serumglucose concentrations• MOA: insulin receptor activation?

Ginkgo Biloba• Dried extract from leaf of Ginkgo biloba,characterized as the world’s oldest tree species• Individual trees may live as long as 1000 years• Species almost eradicated worldwide during thelast Ice Age but survived in China• Brought to Europe in 1730...now a popularornamental tree in parks and gardens throughoutthe world

Ginkgo Biloba• Pharmacology: active constituents includeflavonoid glycosides and terpenes• Physiologic mechanisms poorly understood• Arterial, venous, capillary vasodilation• Inhibition of platelet aggregation• Free-radical radical “scavenging” (anti-oxidant) effect• Mild anti-inflammatory inflammatory effects

Ginkgo Biloba• Preparation: concentrated Ginkgo biloba extract(GBE)• Utilized in Europe for perceived benefits oncirculatory system• 1997: physicians in Germany wrote more than5 million prescriptions for GBE• Adverse effects: stomach or other GI upset(rarely), occasional headache

Ginkgo Biloba• LeBars and colleagues (LeBarsPL, Catz MM, BermanN et al. A placebo-controlled, controlled, double-blind, blind, randomizedtrial of an extract of Ginkgo biloba for dementia. JAMA1997;278:1327-1332)1332) evaluated GBE in 309 patientswith Alzheimer's disease and multi-infarct infarct dementia• First clinical trial utilizing GBE in the United States• Double-blind, blind, placebo-controlled, controlled, multi-center,Randomized, parallel-group design• Dosage of GBE 120mg/daily for 52 weeks in variablydemented patients

Ginkgo Biloba• Outcome measures included three different toolsdesigned to detect differences in cognitivebehaviors and daily living/social behavior• Less than half of patients completed study• Two of three outcome tools indicated “modest”stabilization/improvement for patients over a sixmonth-toto-one one year period

Ginkgo Biloba• Performance-based cognitive testing• Worsening of 1.5 mean score (1-70 scale) for placebo,No change for treatment group (p=0.006)• Caregivers rating scale• Reduction of .06 mean score (1-5 5 scale, with higherscore indicating poor performance) in treated patients,mean increase of .08 in placebo group (p=0.004)• Clinician rating scale• Worsening of 0.2 mean score (1-7 7 scale, with lowerscore indicating worsening psychopathology) for bothgroups

Ginkgo Biloba• Numerous ginkgo products also marketed for “memoryenhancement”• Labeling claims• “Enhanced mental focus”• “Improvement in memory and concentration”• “Benefits with…4 weeks of uninterrupted use”• “50 clinical trials demonstrate benefit”• Despite such marketing claims, only limited trial dataactually available

Ginkgo Biloba• Recent trial (Solomon PR, Adams F, Silver A etal. Ginkgo for memory enhancement. JAMA2002;288:835-40)evaluated the effects of ginkgobiloba and placebo on memory enhancement• Study sponsored by Institute on Aging, NationalInstitutes of Health

Ginkgo Biloba• Study design: P, R, DB, PC, single-site, site, six-week trial in203 healthy patients older than 60 years of age withnormal cognitive function• Drug regimen: ginkgo biloba (Ginkoba®,BoehringerIngelheim Pharmaceuticals) 40mg TID, matching placebo• Primary outcome measures: standardizedneuropsychological tests

Ginkgo Biloba• Fourteen standardized evaluations, measured at baselineand at six weeks• Verbal/nonverbal learning and memory (16-itemshopping list)• Attention/concentration (repetition of number strings)• Expressive language (naming pictures of specific objects)• Patient subjective self-report• Global evaluations by spouse, relative, friend, caregiver

Ginkgo Biloba• Results…• No statistically significant differences between meanscores for the ginkgo and placebo groups in objectiveneuropsychological evaluations• Attention/concentration• Verbal/nonverbal learning• Naming tests• Verbal fluency• No difference in baseline patient subjective self-reportsor spouse/relative/friend evaluation

Ginkgo Biloba• Study limitations (author comments)• Possible dose-response considerations (higher doses,longer treatment time may have provided benefit)• Product labeling suggested benefit at four weeks• Quality control of herbal product (manufacturerclaims of quality control for Ginkoba®• Age-related “ceiling” effect on memory (selected testsnormalized for the age group studied)