Alternative Medicine detail - MICROMEDEX®

7/25/2019 Alternative Medicine detail - MICROMEDEX

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SAW PALMETTOEvaluaciones de AltMedDex

DOSING INFORMATION

DOSAGE FORMS

A) MEDICINAL COMPONENTS:

1) BERRIES

a) The dried berries contain about 1.5% of a fruity-smelling oil containing saturated andunsaturated fatty acids and sterols. About 63% of this oil is composed of free fatty acidsincluding capric, caprylic, caproic, lauric, palmitic, and oleic acids. The remaining portion iscomposed of ethyl esters of these fatty acids and sterols, including beta-sitosterol and itsglucoside. Other components of the dried berries include carotenes, lipase, tannins, andsugars (Bombardelli & Morrazzoni, 1997).b) The lipid-soluble compounds may be the major pharmacological components. Theliposterolic extract used medicinally contains between 85% and 95% fatty acids and sterols.It consists of a complex mixture of saturated and unsaturated free fatty acids, their methyl-and ethyl-esters (approximately 7%), long chain alcohols in free and esterified form, andvarious free and esterified sterol derivatives. The free fatty acids in this extract are identifiedby gas chromatography and mass spectrometry as: caproic acid (C6), capric acid (C8),caprylic acid (C10), lauric acid (C12), myristic acid (C14), isomyristic acid (C14), palmitic acid(C16), oleic acid (C18:1), and stearic acid (C18). Lauric and myristic acid are the major fattyacids, accounting for approximately 30% of the fatty acid content. The identified alcoholsinclude those with n-C22, n-C23, n-C24, n-C26, n-C28, and n-C30 chains, phytol, farnesol,and geranylgeraniol, in addition to high molecular weight unsaturated polyphenols. Thesterolic fraction is composed of beta-sitosterol, stigmasterol, cycloartenol, lupeol, lupenone,and 24-methylcycloartenol. Many of these sterols are esterified with the fatty acids of theextract (Bombardelli & Morrazzoni, 1997).

B) SYNONYMS1) SERENOA REPENS

American dwarf palm tree

Cabbage palm

Dwarf palm tree

Dwarf palmetto

Fan palm

Fructus serenoae

Palma enana americana

Palmetto

Sabal

Sabal fructus

Sabal serrulatumSaegepalmen

Saegepalmenfruechte

Sal palmetto berries

Saw palmetto

Scrub palm

Serenoa

Serenoa serrulata

Serenoapalmu


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STORAGE AND STABILITY

A) CAPSULES, TABLETS, FRUITS

1) Store at room temperature, away from heat, moisture, and direct light.

ADULT DOSAGE

NORMAL DOSE

IMPORTANT NOTE

1) Dosing of herbal preparations is highly dependent on a variety of factors, suchas growing and harvesting conditions, plant parts and extraction methods used,and the dosage form chosen by the manufacturer. Standardization to singleconstituent markers has proven unreliable. Since no official standards have beenestablished to date to regulate the production of herbal medicines in the UnitedStates, dosage ranges must be employed as guidelines.

See Drug Consult reference:" HERBAL SUPPLEMENTS - DOSING"See Drug Consult reference:" HERBAL SUPPLEMENTS - SAFETY"

ORAL1) BENIGN PROSTATIC HYPERTROPHY, tablet/capsule: 1 to 2 g/day saw palmettoberry or 320 mg/day of the lipophilic extract either extracted with lipophilic solvents(90% v/v) or super-critical fluid extraction with carbon dioxide (Blumenthal et al,1998; Bach & Ebeling, 1996).

PEDIATRIC DOSAGE

A) Pediatric dosing not available.

PHARMACOKINETICS

ADME

DISTRIBUTION

DISTRIBUTION SITES

A) PROSTATE

1) Prostatic tissue uptake was greater than any other tissue, such as liver, seminalvesicles, and genital organs in a study done with rats given the n-hexane lipid-sterolic extract orally, supplemented with radiolabeled oleic, lauric, or beta-sitosterol. The most effective lipid agent in promoting absorption was oleic acid

(Chevalier et al, 1997).

EXCRETION

BREAST MILK

A) BREASTFEEDING: Unknown

1) Scientific evidence for the safe use of saw palmetto during lactation is notavailable.

HALF LIFE

PARENT COMPOUND


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A) ELIMINATION HALF-LIFE: 1.9 hours (De Bernardi et al, 1994).

1) Elimination half-life following a single 320 milligram dose in volunteers was 1.9hours (De Bernardi et al, 1994).

CAUTIONS

CONTRAINDICATIONS

A) Hypersensitivity to saw palmetto or any of its components

PRECAUTIONS

A) Hormone-dependent cancer: No information is available about the action of this herb in

patients with hormonal diseases, such as breast cancer or prostate cancer. The herb hasdemonstrated antiandrogenic (Dreikorn & Schonhofer, 1995), antiestrogenic (DiSilverio et al,1992), and estrogenic actions in animals (Elghamry & Haensel, 1969).

ADVERSE REACTIONS

BLOOD

HEMORRHAGE

1) Intraoperative hemorrhage, including a blood loss of about 2000 cm(3), wasreported in a 53-year-old male who was taking saw palmetto. The prolongedbleeding time normalized over 5 days after discontinuing saw palmetto.Preoperative and postoperative prothrombin time and partial thromboplastin timewere normal. No other predisposing factors for hemorrhage were reported. Theprolonged bleeding time was most likely due to platelet dysfunction resulting from

inhibition of cyclooxygenase by saw palmetto (Cheema et al, 2001).

CARDIOVASCULAR

CARDIOVASCULAR EFFECTS

1) In a saw palmetto clinical trial for the treatment of benign prostatic hypertrophy,305 patients completed the trial. Adverse effects were reported in 5% of patientsand included TACHYCARDIA, ANGINA PECTORIS, EXTRASYSTOLES, and

ANGIOPATHY (Braeckman, 1994). Mild HYPERTENSION was also reported as anadverse effect (Plosker & Brogden, 1996). None of these reactions were serious.2) POSTURAL HYPOTENSION (1.1%) was observed in subjects treated with oralSerenoa repens 320 mg daily in a 12-month, randomized, double-blind,comparative trial of a lipido-sterolic extract (Permixon(R)) and tamsulosin in thetreatment of benign prostatic hypertrophy (Debruyne et al, 2002).

CENTRAL NERVOUS SYSTEM

CENTRAL NERVOUS SYSTEM EFFECTS

1) HEADACHE (8%), DIZZINESS (2.9%), FATIGUE (1.7%), and ASTHENIA (1.1%)were observed in subjects treated orally with 320 milligrams Serenoa repens dailyin a 12-month randomized, double-blind, comparative trial of a lipido-sterolicextract of Serenoa repens (Permixon(R)) and tamsulosin in the treatment of benignprostatic hypertrophy (BPH) (Debruyne et al, 2002).

ENDOCRINE/METABOLIC

ENDOCRINE EFFECTS


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1) Saw palmetto berries contain 18.9 milligrams/100 milliliters (mg/mL) beta-sitosterol and 0.022 mg/mL beta-sitosterol-D-glucoside (Schoepflin et al, 1966;Haensel et al, 1964). Subcutaneously injected into immature female mice, beta-sitosterol is estrogenic. Pure beta-sitosterol is less than 1/10th as potent asestradiol and the saw palmetto extract is about 1/10,000th as potent (Duke, 1985;Elghamry & Haensel, 1969).2) Permixon(R), a commercial product from France, was without estrogenic orantiestrogenic effects in clinical trials (Stenger et al, 1982).3)A combination product that contains saw palmetto (PC-SPES) is reported tohave estrogenic effects.

See Drug Consult reference:" PC-SPES: TREATMENT FOR PROSTATE CANCER"

GASTROINTESTINAL

GASTROINTESTINAL EFFECTS

1) DRY MOUTH (0.9%) was observed in subjects treated orally with 320 milligrams(mg) Serenoa repens daily in a 12-month randomized, double-blind, comparativetrial of a lipido-sterolic extract of Serenoa repens (Permixon(R)) and tamsulosin inthe treatment of benign prostatic hypertrophy (Debruyne et al, 2002).2) Mild gastrointestinal discomfort was reported in 2% of the subjects treated with320 milligrams (mg) Serenoa repens daily compared to 6% in subjects treated with

480 mg Serenoa repens daily for 6 months in an open-label study of subjects withmarked prostatic obstruction and lower urinary tract symptoms (n=100). None ofthe subjects withdrew from the study due to adverse events (Giannakopoulos et al,2002).3) DIARRHEA and MILD GASTRIC DISTRESS were reported by 2 of 41 patientstaking saw palmetto in a double-blind, randomized, placebo-controlled study. Thediarrhea caused the patients to withdraw from the study (Gerber et al, 2001).4) Minor NAUSEA was reported in some large studies (Plosker & Brogden, 1996).In one study, 3 of 72 patients reported nausea and VOMITING serious enough todiscontinue taking the drug (Reece-Smith et al, 1986).5) Minor ABDOMINAL PAIN was occasionally reported in some large studies(Plosker & Brogden, 1996). Abdominal distress was the cause for leaving one study(Tasca, 1985).

KIDNEY/GENITOURINARYGENITOURINARY EFFECTS

1) Ejaculation disorders (0.6%) and reduced libido (0.3%) were observed insubjects treated orally with 320 milligrams (mg) Serenoa repens (Permixon(R))compared with 4.2% and 1.1%, respectively, for tamsulosin for the treatment ofbenign prostatic hypertrophy in a 12-month randomized, double-blind, comparativetrial. Six subjects in each treatment group developed acute URINARY RETENTIONwith 7 subjects requiring hospitalization (Debruyne et al, 2002).2) Reduced libido was reported in two of 100 subjects treated with Serenoa repens(320 mg and 480 mg daily) in a 6-month open-label study of subjects with markedprostatic obstruction and lower urinary tract symptoms. None of the subjectswithdrew from the study due to adverse events (Giannakopoulos et al, 2002).

3) Erectile dysfunction was reported in 1.1% of subjects treated with saw palmettodaily compared with 4.9% (p less than 0.001) of subjects treated with finasteride ina systematic review of randomized trials (Wilt et al, 2000).4) Saw palmetto extract has not been associated with erectile dysfunction,ejaculatory disturbance, or altered libido (Marks & Tyler, 1999).5) Incubation of hamster oocytes in saw palmetto for one hour did not affectsperm penetration or sperm motility (Ondrizek et al, 1999).

LIVER

HEPATIC EFFECTS


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1)After using saw palmetto for 2 weeks for nocturia and urinary hesitancy, a 65-year-old male developed CHOLESTATIC HEPATITIS. He discontinued the herbalmedication after the onset of JAUNDICE and severe pruritus. Serum laboratoryvalues on admission were: bilirubin 8.2 mg/dL, AST 1238 international units/L, ALT1364 international units/L, and alkaline phosphatase 179 international units/L. Aliver biopsy performed 2 months later showed a parenchymal infiltrate ofneutrophils and lymphocytes involving the portal tracts, early bridging, and mildperiportal fibrosis. Liver function returned to normal 3 months after discontinuingsaw palmetto. Cholestasis may be hormonally-related due to the mechanism ofaction of saw palmetto (Hamid et al, 1997).2) Severe CHOLECYSTITIS was reported in a patient receiving saw palmetto.However, a relationship between the herbal medication and cholecystitis could notbe causally established (Plosker & Brogden, 1996).

RESPIRATORY

RHINITIS

1) Rhinitis was observed in 8.6% of patients who received oral Serenoa repens 320mg daily compared with 12% of patients who received tamsulosin in a 12-month,randomized, double-blind trial (p=0.14) (Debruyne et al, 2002).

SKIN

PRURITUS1) Pruritus, which resolved spontaneously, was cited in a case report of a patientusing saw palmetto for benign prostatic hyperplasia (Grasso et al, 1995).

MUSCULOSKELETAL

MUSCLE PAIN

1) Muscle pain has been reported as a minor adverse effect in a small percentageof patients in clinical trials (Plosker & Brogden, 1996; Braeckman, 1994).

TERATOGENICITY/EFFECTS IN PREGNANCY

TERATOGENICITY1) Studies have demonstrated that liposterolic extract had no teratogenic effects whengiven at dosages up to 600 milligrams/kilogram in rats and rabbits (Bombardelli &Morrazzoni, 1997).

EFFECTS IN PREGNANCY

1) Scientific evidence for the safe use of saw palmetto during pregnancy is not available.2) Pregnant rats given saw palmetto fruits as 50% of their diets had suckling rats withdepressed growth, but the dams did not seem to be affected (Feurt & Fox, 1954).

DRUG INTERACTIONS

DRUG-DRUG COMBINATIONS

WARFARIN

1) Summary: Intraoperative bleeding was reported in a patient taking sawpalmetto (Cheema et al, 2001). Two cases of increased international normalizedratio (INR) have been reported in patients taking a combination of saw palmetto,pumpkin seed, and vitamin E (Curbicin(R)). One of the patients had been stableusing warfarin prior to starting Curbicin(R). The other patient was not taking anyconcomitant anticoagulant therapy (Yue & Jansson, 2001). Caution is advised.2)Adverse Effect: increased risk of bleeding3) Clinical Management: Caution is advised if saw palmetto is taken with warfarin.


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Monitor the INR and signs and symptoms of excessive bleeding.4) Severity: moderate5) Onset: delayed6) Documentation: fair7) Probable Mechanism: cyclooxygenase inhibition by saw palmetto8) Literature Report:

a) Two cases of elevated international normalized ratio (INR) have been reportedassociated with taking pumpkin seed (cucurbita), saw palmetto, and vitamin E. A61-year-old male taking warfarin with stable INR (about 2.4) experienced anincreased INR of 3.4 after six days of taking five tablets of Curbicin(R) daily, anherbal combination with pumpkin seed, saw palmetto, and vitamin E (10milligrams/tablet). His INR returned to the therapeutic range within one week ofstopping Curbicin(R). A 73-year-old male not on anticoagulant therapy experiencedan INR of 2.1 during hospitalization for deterioration secondary to a common cold.He had been taking Curbicin(R) three tablets daily for over one year. His INRimproved (1.3 to 1.4) with vitamin K treatment, then normalized to 1 afterstopping Curbicin(R) for one week (Yue & Jannson, 2001).b)A 53-year-old male taking saw palmetto developed brisk bleeding during asurgical procedure for resection of a brain tumor. In an attempt to control thebleeding, the patient received four liters of crystalloid fluids, four units of packedred blood cells, three units of pooled platelets, and three units of fresh frozen

plasma. The procedure was prematurely terminated and estimated blood loss wastwo liters. Preoperative measures of prothrombin time (PT), activated partialthromboplastin time (aPTT), complete blood count, and blood chemistry werenormal. No thromboprophylaxis was used prior to surgery. Postoperative PT andaPTT were normal; however, bleeding time was prolonged to 21 minutes (normal2 to 10 minutes). Two days after surgery, bleeding time remained prolonged at 14minutes, which normalized over five days. Workup for bleeding disorders wasnegative. The patient then disclosed his use of saw palmetto (Cheema et al,2001).

CLINICAL APPLICATIONS

PLACE IN THERAPY

A) SUMMARY OF SCIENTIFIC EVIDENCE: Numerous controlled clinical trials have documented

the effectiveness of saw palmetto in the treatment of benign prostatic hypertrophy (BPH)symptoms such as urine flow, dysuria, nocturia, residual urine, urgency, prostate volume, and

subjective complaints. However, conflicting data indicate saw palmetto fruit extract was nomore effective than placebo in reducing lower urinary tract symptoms in BPH in a double-blind,

multicenter, randomized trial. In comparison studies, saw palmetto and alfuzosin were equallyefficacious and a combination of saw palmetto and cyproterone produced a significantdecrease in prostate volume. Results were inconclusive when comparing finasteride and saw

palmetto, whereas prazosin was slightly more efficacious than saw palmetto.B) COMMON USES IN COMPLEMENTARY AND ALTERNATIVE MEDICINE: The main clinical use

of saw palmetto is for a variety of urinary tract conditions in men including benign prostatichyperplasia and urinary tract infection. Topical saw palmetto ointment has been used for

androgen-induced acne.C) HISTORICAL USES: Saw palmetto has been historically used as a treatment for prostate

enlargement and chronic cystitis as well as a mild diuretic.D) TOUTED USES: Saw palmetto has been touted as an aphrodisiac, to increase spermproduction, and to produce breast enlargement; however, no clinical evidence has been


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presented.E) REGULATORY/SAFETY INFORMATION: Saw palmetto is approved by the German

Commission E for the treatment of urinary problems of benign prostatic hyperplasia stage I(abnormal frequent urination, nocturia, delayed onset of urination, and weak urinary stream

and stage II (urge to urinate and residual urine) (Blumenthal et al, 1998). The American HerbalProducts Association rated saw palmetto as class I (can be safely consumed if usedappropriately) (McGuffin et al, 1997). Saw palmetto is available as a dietary supplement in the

United States under the Dietary Supplement Health and Education Act of 1994 (DSHEA).

See Drug Consult reference:" HERBAL SUPPLEMENTS - SAFETY"See Drug Consult reference:" GERMAN COMMISSION E - APPROVED HERBS"See Drug Consult reference:" BOTANICAL SAFETY HANDBOOK TERMS - DEFINITIONS"See Drug Consult reference:" THE DIETARY SUPPLEMENT HEALTH AND EDUCATION ACT OF1994"

MECHANISM OF ACTION/PHARMACOLOGY

A) MECHANISM OF ACTION

1) SUMMARY: In human studies, saw palmetto's mechanism of action in the treatment ofbenign prostatic hyperplasia (BPH) may have multiple sites of action and involvesantiandrogenic, antiestrogenic, and estrogenic properties (Stenger et al, 1982; Elghamry &Haensel, 1969).

a)Although the primary action of saw palmetto for treatment of BPH is related to itstestosterone-altering effects, in animal and tissue studies anti-inflammatory, antineoplastic,cholesterol-blocking, enzyme inhibition, platelet inhibition, and protein synthesis inhibitionproperties have been observed (Stenger et al, 1982; Elghamry & Haensel, 1969).

2)ANTIANDROGENIC EFFECTS:

a) The effect of the liposterolic extract of serenoa on experimental prostate enlargement wasinvestigated in three groups of rats: shams treated with serenoa extract (sham rats),castrated animals treated with estradiol and testosterone (castrated rats), and castratedanimals treated with estradiol/testosterone and treated with serenoa extract (castrated and

treated rats). Following three months of continuous hormonal treatment, the weight ofprostates in estradiol/testosterone-treated castrated rats was significantly increased incomparison with sham-operated rats. Such an increase started rapidly, reached a maximumby 30 days and remained at a plateau or slightly declined thereafter. The increase of prostatetotal weight induced by the hormone treatment was inhibited by administration of serenoaextract. The weight was significantly lower at day 60 and day 90 for the dorsal and lateralregions of the prostate. The weight of the ventral region of the prostate was significantlylower after 30 and 60 days treatment with LSESR. These results demonstrated thatadministering serenoa extract to hormone-treated castrated rats inhibited the increase inprostate wet weight (Paubert-Braquet et al, 1996).b) The lipophilic-sterol extract inhibited the formation of testosterone metabolites in a studydone on cultures of epithelial cells and fibroblasts from benign prostatic hyperplasia andprostatic cancer tissues (Newall et al, 1996).

c) Saw palmetto lipophilic extract significantly reduced the amount of radioactivedihydrotestosterone and radioactive testosterone uptake by cytol receptors of 11 humantissues (el-Sheikh et al, 1988).d) In animal and tissue studies, a hexane extract of the berries appeared to haveantiandrogenic properties by inhibiting the enzyme testosterone-5-alpha-reductase whichconverted testosterone to dihydrotestosterone. It also inhibited 3-ketosteroid reductase fromconverting dihydrotestosterone to an androgen compound and has a direct action on theestrogen receptors (Champault et al, 1984; Sultan et al, 1984).

1) In a double-blind study of 35 men with benign prostatic hyperplasia, 18 were given sawpalmetto extract 160 milligrams twice daily and 17 were given placebo. At the end of the 90day study, both androgen, estrogen, and progesterone receptors from prostate tissue


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samples were evaluated by two different techniques. The results from the androgen receptoranalysis demonstrated there was no change in the number of cytosol androgen receptors,but the number of nuclear androgen receptors was significantly lower in the saw palmettogroup (60% of the placebo group were positive for the nuclear receptor compared to 10% inthe saw palmetto group). These results indicated that the saw palmetto extract probablycompetitively blocks the translocation of the cytosol androgen receptor to the nucleus(DiSilverio et al, 1992). Saw palmetto acts directly at the level of the androgen receptor(Carilla et al, 1984).

e) In vitro studies demonstrated that lipophilic extract competitively inhibiteddihydrotestosterone from binding to cellular sites and nuclear androgen receptor sites,causing increased metabolism and excretion of dihydrotestosterone (Sultan et al, 1984).

3)ANTIESTROGENIC EFFECTS:

a) In a double-blind study of 35 men with benign prostatic hyperplasia (BPH), 18 receivedsaw palmetto extract 160 milligrams twice daily and 17 received placebo. At the end of the 90day study, both androgen, estrogen, and progesterone receptors from prostate tissuesamples were evaluated by two different techniques. Men receiving the saw palmetto extracthad significantly lower cytosol and nuclear receptor values for estrogen and progesteronecompared to the placebo group. Since the progesterone receptor content is linked toestrogenic activity, the results of the evaluation implied that the saw palmetto extract exertedsignificant antiestrogenic effect. Antiestrogenic agents inhibited stromal prostatic mass growth

in BPH patients (DiSilverio et al, 1992).4)ANTI-INFLAMMATORY EFFECTS:

a)Antiedemic effects have been noted in rat, mice, and guinea pigs. Hexane extracts havedemonstrated anti-inflammatory activity (Breu et al, 1992; Champault et al, 1984; Tarayre etal, 1983; Wagner et al, 1981). A possible mechanism is inhibition of histamine-inducedpathways, increasing the capillary permeability (Stenger et al, 1982).

1)An in vitro study using human polymorphonuclear neutrophils (PMN) demonstrated thatthe anti-inflammatory effects may be due to inhibition of 5-lipoxygenase metabolites and theproduction of PMN cells (Paubert-Braquet et al, 1997).2) There is an inhibitory influence on the biosynthesis of the inflammatory arachidonic acidmetabolites. In vitro tests done with fruit extracts demonstrated inhibition of cyclooxygenaseand 5-lipoxygenase pathways (Breu et al, 1992).3) The anti-inflammatory effect may be due to a polysaccharide with a molecular weight

over 100,000 (Wagner & Flachsbarth, 1981; Wagner et al, 1981).

5)ANTINEOPLASTIC EFFECTS:

a) Two acylglycerides (l-monolaurin and l-monomyristen) were isolated from a 95% ethanolextract of the powdered fruits. These two substances demonstrated some activity in a brineshrimp lethality test against renal (A-498 cells) and pancreatic (PACA-2) human tumor cells. Aborderline cytotoxicity was demonstrated against human prostatic (PC-3) cells (Shimada et al,1997).

1) There was weak cytotoxic activity and some cell proliferation inhibition in CA-PC3 cellcultures using 50 micrograms/milliliter (mcg/mL) of a sterol extract. When 10 mcg/mL wasused, there was some cell proliferation stimulation. At a concentration of 400 mcg/mL, aweak cytotoxic activity was reported. Levels were measured using tritium-labeled thymidineuptake (Ravenna et al, 1996).

6)ANTIHYPERLIPIDEMIC EFFECTS:

a) Phytosterols have improved benign prostatic hyperplasia (BPH). A double-blind studyconsisted of 200 men receiving beta-sitosterol (20 milligrams) or placebo three times daily.The beta-sitosterol produced an increase in maximum urine flow rate from a baseline of 9.9milliliters/second (mL/s) to 15.2 mL/s and a decrease in mean residual urinary volume of 30.4mL from 65.8 mL (Berges, 1995).b) Sitosterols have been given orally as a treatment for atherosclerosis. There are sitosterolsin saw palmetto which compete with cholesterol for absorption sites in the gastrointestinaltract (Tyler et al, 1981).

7) ENZYME INHIBITION EFFECTS:


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a)Acetylcholine

1) Lipidic (0.3 to 1 milligram/milliliter) and saponifiable extracts of saw palmetto antagonizedthe contracting effect of acetylcholine (0.1 to 100 micromoles) on rat urinary bladders. Theresults were concentration dependent (Gutierrez et al, 1996).

b) Lipoxygenase

1)A study done in cell cultures at a concentration of 18 micrograms/milliliter inhibitedlipoxygenase (Breu et al, 1992).

c) Hydroxysteroid (3-alpha) dehydrogenase1) The sterol extract, in doses of 5.7 units/milliliter of saw palmetto, demonstrated inhibitoryeffects on hydroxysteroid (3-alpha) dehydrogenase (androgen metabolism) in humans(Sultan et al, 1984).

d) 5-alpha-reductase (5aR)

1) There are two isoforms of 5-alpha-reductase (5a-R). The lipido-sterol extract of sawpalmetto (LSESr) inhibited both in insect cell cultures. LSESr illustrated non-competitiveisozyme type 1 and uncompetitive inhibition for isozyme 2. The inhibition may be due tomodulating the membrane environment of 5-alpha-reductase (Iehle et al, 1995).2)An in vitro examination of the structural necessities of free fatty acids in saw palmettowhich caused 5-alpha-reductase (5a-R) inhibition demonstrated a strongly polar end-groupand a molecular skeleton allowing non-polar interactions with 5a-R were necessary

(Niederprum et al, 1994).3) 5a-R was inhibited by saw palmetto lipid extract at a concentration (IC50) of 0.025milligram/milliliter. The test was done in vitro on human foreskin fibroblast (Hagenlocker etal, 1993).4) In a study of 20 men with benign prostatic hyperplasia who had testosterone, folliclestimulating hormone, and luteinizing hormone measured before and after 30 days oftreatment, no differences in hormone levels were demonstrated. The 20 men were given 160milligrams of a lipophilic extract of Serenoa repens twice daily. The mechanism of actiondoes not involve serum hormone level reductions (Casarosa et al, 1988).

8) ESTROGENIC EFFECTS:

a) In a 3-month, double-blind, controlled study of men with benign prostatic hyperplasia(BPH), saw palmetto demonstrated estrogenic and antiprogesterone activity demonstrated byestrogen and progesterone receptor action (DiSilverio et al, 1992).b) Saw palmetto berries contain 18.9 milligrams/100 milliliters (mg/mL) beta-sitosterol and0.022 mg/mL beta-sitosterol-D-glucoside (Schoepflin et al, 1966; Haensel et al, 1964).Subcutaneously injected into immature female mice, beta-sitosterol is estrogenic. Pure beta-sitosterol is less than 1/10th as potent as estradiol and the saw palmetto extract is about1/10,000th as potent (Duke, 1985; Elghamry & Haensel, 1969).c) Permixon(R), a commercial product from France, was without estrogenic or antiestrogeniceffects in clinical trials (Stenger et al, 1982).

9) PLATELET INHIBITION EFFECTS:

a) Saw palmetto is not used to inhibit platelet function. Rat studies using a concentration of700 micrograms/milliliter did not have an effect on arachidonic acid transformations (Tarayreet al, 1983).

10) PROLACTIN INHIBITION EFFECTS:

a)A study done on Chinese hamster ovary cells determined that saw palmetto extract mayinhibit prolactin-induced prostate growth by inhibiting several steps of prolactin receptorsignal transduction (Vacher et al, 1995).

11) PROTEIN SYNTHESIS STIMULATION EFFECTS:

a) One study demonstrated a weak ability to stimulate protein synthesis when using 25 to 50micrograms/milliliter of the sterol extract in cell cultures (Sultan et al, 1984).

12) SPASMOLYTIC EFFECTS:

a) The spasmolytic effect of the lipidic fraction of saw palmetto is at least partially due tosodium/calcium exchanger activation and interference with intracellular calcium mobilization.Protein synthesis is also involved (Gutierrez et al, 1996a).


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1) Total lipidic and saponifiable extracts of saw palmetto produced a dose dependentrelaxation on rat aorta tonic contractions produced by noradrenaline and on toniccontractions of rat uterus induced by potassium chloride. The effect is related to theinhibition of calcium ions inward flow, acting at the plasma membrane level (Gutierrez et al,1996).2) Calcium is not required to obtain the relaxation. Calcium ion flux inhibition is not the mainmechanism of action. Maximal relaxation was greater than 90% in both cases. The effectiveconcentration where there was 50% relaxation (EC50) was significantly lower with the lipidicfraction in the uterine study, but there was no difference in the aorta study (Gutierrez et al,1996).3) dL propranolol (1 micromole) potentiated the effects of the extracts; cycloheximide (10micrograms/milliliter) antagonized the effect of the lipidic but not the saponifiable extract.Haloperidol (1 micromole) did not inhibit the spasmolytic effect. Neither genistein (a tyrosinekinase inhibitor) (10 micromoles) nor alpha difluoromethyl-ornithine (an ornithinedecarboxylase inhibitor) (10 millimoles) had any effect on the relaxation response. Theseeffects are not produced by receptor activation because the beta-blocker propranolol and thedopamine receptor antagonist haloperidol did not inhibit the effect (Gutierrez et al, 1996).

b) Spasmolytic activity was tested in guinea pigs using an extract produced by a 95%ethanolic extract in a concentration of 0.15 milligram/milliliter. The dose had somespasmolytic activity in the bladder, ileum, and vas deferens against potassium chloride ornorepinephrine-induced contractions (Odenthal, 1996).

B) REVIEW ARTICLES

1) ENGLISH

a)A review on the mechanism of action and clinical studies pertaining to saw palmettoconcluded that saw palmetto may have a significant effect on urinary flow rates and symptomscores (Gerber, 2000).b) Controlled trials involving phytotherapeutic agents for the treatment of benign prostatichypertrophy are critiqued (Lowe et al, 1998) and a meta-analysis of 18 recent trials involvingsaw palmetto is available (Wilt et al, 1998).c) The causes and methods of treatment of benign prostatic hypertrophy are discussed andcomparisons made between synthetic agents and phytopharmaceuticals used in treatment(Bach et al, 1997).d) The pharmacology and therapeutic effects of saw palmetto in the treatment of benignprostatic hyperplasia are reviewed (Plosker & Brogden, 1996).

THERAPEUTIC USES

BENIGN PROSTATIC HYPERTROPHY

1) OVERVIEW:

EFFICACY: Adult, possibly effective

DOCUMENTATION: Adult, excellent

2) SUMMARY:

- Increasing doses of saw palmetto fruit extract

were no more effective than placebo in reducing

lower urinary tract symptoms in benign prostatic

hyperplasia (BPH) in a double-blind,

multicenter, placebo-controlled, randomized

trial (n=369) (Barry et al, 2011); however, a

systematic review of 18 randomized clinical

trials (n=3000) conducted between 1983 and 1997

concluded that saw palmetto or saw palmetto


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herbal combination products provided some

benefit in controlling lower urinary tract

symptoms and flow measures (Wilt et al, 2000).

- A lipido-sterolic extract of Serenoa repens

exhibited similar efficacy to tamsulosin in

the treatment of benign prostatic hypertrophy

in a 12-month, randomized, double-blind,

multicenter, international trial (n=704)(Debruyne et al, 2002).

- Saw palmetto extract had no effect on levels

of testosterone, dihydrotestosterone, follicle-

stimulating hormone, luteinizing hormone

(Strauch et al, 1994; Casarosa et al, 1988;

Reece-Smith et al, 1986), or PSA (Braeckman,

1994).

3)ADULT:

a) In a double-blind, multicenter, placebo-controlled, randomized trial (n=369),increasing doses of saw palmetto fruit extract were no more effective than placebo inreducing lower urinary tract symptoms (LUTS) in male patients with benign prostatichyperplasia (BPH). Patients were randomized to receive saw palmetto extract 320mg/day, with dose escalations to 640 mg/day at week 24 and 960 mg/day at week 48,or placebo. The patients had a mean age of 61 years, were 80% white, and had a mean

American Urological Association Symptom Index (AUASI) score of 14.6 (SD, 4.5). For theprimary outcome of a change in AUASI score from baseline to 72 weeks, there was nodifference in the saw palmetto group at any dose level (mean score decrease, -2.2points) and the placebo group (mean score decrease, -2.99 points) (1-sided p=0.91).There was also no difference between the groups in the secondary outcomes of qualityof life (International Prostate Symptom Score), nocturia (AUASI), peak flow rate, post-void residual volume, and PSA level, or in the scores for several indices (BPH Impact

Index, International Index of Erectile Function scale, Male Sexual Health Questionnaire-Ejaculatory Dysfunction scale, International Continence Society male incontinence scale,Jenkins Sleep Dysfunction scale, and the National Institutes of Health Chronic ProstatitisSymptom Index) (Barry et al, 2011).b)A systematic review of 18 randomized clinical trials comprising approximately 3000subjects conducted between 1983 and 1997 concluded that saw palmetto or sawpalmetto herbal combination products provided some benefit in controlling lower urinarytract symptoms and flow measures in men with benign prostatic hypertrophy (BPH). Themajority of trials evaluated the effectiveness of oral doses of 320 mg saw palmetto dailyfor a mean duration of 9 weeks, although doses tested ranged from 100 mg to 640 mgdaily and trial duration ranged from 4 to 48 weeks. Saw palmetto improved urinarysymptoms (measured using a variety of scales), nocturia, peak urine flow, mean urineflow, and residual urine volume by 28%, 25%, 24%, 28%, and 43%, respectively,

compared with placebo. Similar adverse events were reported in treatment and placebosubjects; all were considered mild. Efficacy of saw palmetto was comparable tofinasteride in control of urinary symptoms, nocturia, and flow measures in subjects withBPH in the one comparative study included in this analysis. Significantly more subjectstreated with finasteride exhibited erectile dysfunction (4.9%) compared with subjectstreated with saw palmetto (1.1%) (p less than 0.001). Trials were included in thisanalysis only if the following criteria were met: subject inclusion criteria wassymptomatic BPH, the therapy evaluated was saw palmetto or saw palmetto herbalcombination products, placebo-control or other active-control, and treatment durationwas at least 4 weeks. Of the trials included in this analysis, 16 used double-blindmethodology, 14 included placebo controls, and 4 evaluated herbal combination


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products containing saw palmetto. Interpretation of the results of this analysis should beviewed with caution due to inherent flaws related to the data available for analysis.Problems identified included use of variable doses and preparations of saw palmetto,lack of consistency in outcome measures between studies, use of non-validated urologicsymptom scales in the majority of trials evaluated, and short duration of the study (Wiltet al, 2000; Wilt et al, 1998).c)A lipido-sterolic extract of Serenoa repens (Permixon(R)) exhibited similar efficacy tothe alpha-blocker tamsulosin in the treatment of benign prostatic hypertrophy (BPH) in a

12-month randomized, double-blind, multicenter international trial (n=704; mean age65.5 years). Following a 4-week placebo lead-in period, subjects were randomlyassigned to oral therapy with 320 mg Serenoa repens daily or 0.4 mg tamsulosin dailyfor 12 months. Reductions of 4.4 in the International Prostate Symptom Score (IPSS)compared to baseline (mean IPSS=15.3 at baseline) were observed after treatment forone year in both groups (differences between groups were not significant). Significantdifferences between groups were not observed in IPSS score for irritative or obstructivesymptoms. Peak urinary flow was increased by 1.79 mL/sec in subjects treated withSerenoa repens compared with 1.89 mL/sec in subjects treated with tamsulosin(difference was not significant). Prostate volume was reduced slightly (0.99 cubic mL) insubjects treated with Serenoa repens compared to a slight increase (0.22 cubic mL) insubjects treated with tamsulosin although this difference was not significant. Nosignificant changes were observed in serum prostate specific antigen (PSA) in either

group. Significant differences between groups were not observed in sexual function asevaluated using the male sexual function questionnaire (MSF-4). Six subjects in eachgroup developed acute urinary retention that resulted in hospitalization in 4 tamsulosinsubjects and 3 Serenoa repens subjects. Ejaculation disorders were present in 4.2% ofsubjects treated with tamsulosin compared to 0.6% of subjects treated with Serenoarepens (p=0.001). Other adverse events were similar between groups and includedrhinitis, headache, dizziness, fatigue, asthenia, postural hypotension, dry mouth, andreduced libido. Withdrawals were similar between groups, with 542 subjects completingthe study. Important inclusion criteria for this study included IPSS greater than or equalto 10, maximum urinary flow rate between 5 to 15 mL/sec, voided volume of at least150 mL, residual urine volume less than 150 mL, prostate volume of at least 25 mL, andPSA levels less than 4 nanograms/mL (Debruyne et al, 2002).d) In a 2-year open-label study, a lipido-sterolic extract of Serenoa repens (Permixon

(R)) was a safe and efficacious treatment for benign prostatic hypertrophy (BPH)(n=155; mean age 65.3 years). Subjects with symptomatic BPH for greater than 6months and an International Prostate Symptom Score (IPSS) of 6 or higher (mean 12.8)entered a one-month single-blind, placebo lead-in period followed by oral treatment with160 milligrams (mg) Serenoa repens twice daily for 2 years. Progressive improvementover the 2-year period was observed for the main efficacy outcome, IPSS. Reductions inIPSS total score compared to baseline of 31%, 38.6%, 40.6%, and 41.4%, respectively,were observed at 6, 12, 18, and 24 months (p=0.001). Quality of life measures werealso significantly improved compared to baseline beginning at 6 months and continuingthroughout the study (p less than 0.001). Significant increases in maximum urinary flowrate compared to baseline of 34.7%, 27.2%, 7.9%, and 9.5%, respectively, wereobserved at 6, 12, 18, and 24 months (p value not provided). Although maximumurinary flow rate was observed to gradually decrease at all time points after the 6

months treatment measurement, maximum urinary flow rate remained significantlyhigher than that observed at baseline at all measurement points. Significantimprovements in sex life as evaluated using the male sexual function questionnaire(MSF-4 score) compared to baseline were observed at 18 and 24 months (p less than0.001). At 6 months, a 14.6% reduction in prostate volume was noted. No furtherchanges in prostate volume were noted for the duration of the trial. No changes wereobserved in prostate specific antigen (PSA) levels, plasma hormone levels, hematologicand biochemical measurements, or vital signs. Three subjects withdrew from the studydue to lack of efficacy. Adverse events occurred in 5.8% of subjects but none wereattributed to Serenoa repens. Other inclusion criteria included maximum urinary flowrate between 5 to 15 milliliters/second (mL/s), voided volume between 150 to 400 mL,


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residual urine volume less than 150 mL, prostate volume of at least 25 cubiccentimeters, and PSA levels of less than 4 nanograms/mL (Pytel et al, 2002). The validityof efficacy results of this study should be interpreted with caution due to methodologicalflaws, including open-label study design and lack of a placebo control group.e)A lipido-sterolic extract of Serenoa repens (Permixon(R)) was effective in improvingsubjective and objective parameters of benign prostatic hypertrophy (BPH) in subjectswith mild to moderate disease in an open-label study (n=75; 52 to 78 years). Subjectswith an International Prostate Symptom Score (IPSS) of less than 19 (mean 8.2)

received oral treatment with 160 milligrams (mg) Serenoa repens twice daily for 9 weeks(n=57) or no treatment (n=18; controls). IPSS total score and quality of life index pointreductions of 26.8% and 18.2%, respectively, were reported compared to baseline (pless than 0.001) in subjects treated with Serenoa repens while no changes wereobserved in the control group. Maximum urinary flow rate increased by 6% whileopening detrusor pressure and detrusor pressure at maximum flow decreased by 12.6%and 12.8%, respectively, compared to baseline in subjects treated with Serenoa repens(p less than 0.001). Subjects treated with Serenoa repens also exhibited a 12.6%reduction in residual urine volume compared to their baseline levels (p less than 0.05).Similar improvements were not observed for any of these measurements in controlsubjects. Mean prostate volume was reduced in subjects treated with Serenoa repenswhile it was increased in the control group (differences were not significant compared tobaseline in either group) (Al-Shukri et al, 2000). A similar open-label study reported

similar efficacy in improving subjective and objective parameters of benign prostatichypertrophy (BPH) for two dose levels of a lipido- sterolic extract of Serenoa repens(Libeprosta(R)) in subjects with marked obstruction and lower urinary tract symptoms(n=100; average age 63.67 years) (Giannakopoulos et al, 2002). The validity of theresults of these studies should be interpreted with caution due to methodological flaws,including open-label study design, non-randomization, and lack of a placebo controlgroup.f)A combination product containing saw palmetto, cernitin, B-sitosterol, and vitamin Eimproved subjective but not objective symptoms of benign prostatic hyperplasia (BPH)compared to placebo in a randomized clinical trial (n=144). Subjects were randomlyassigned to receive two tablets of a combination product containing 286 milligrams (mg)of saw palmetto/phytosterol (saw palmetto standardized to 40% to 50% free fatty acids/B-sitosterol standardized to 43%), 378 mg cernitin, and 100 international units of

vitamin E daily or placebo for three months. After treatment for three months, meantotal American Urological Association Symptom Index (AUA) score was reduced by 33%in subjects treated with the combination herbal product compared to a 18% reduction insubjects treated with placebo (p=0.014). Subjects treated with the herbal combinationproduct exhibited a 90% improvement in the total AUA score over three monthstreatment compared to placebo (p=0.009). Improvement of 242% in daytime urinaryfrequency and 258% in nocturia were also observed compared to placebo over thethree-month treatment period (p=0.031 and p less than 0.001, respectively). Nosignificant differences were observed between groups on measures of maximum andaverage urinary flow rates, residual urine volumes, or prostatic specific antigen (PSA)levels. Adverse events in the treatment group included flatulence (n=3), headache(n=1), urinary tract infection (n=1), herpes zoster (n=1), and right arm laceration(n=1). Important inclusion criteria included no evidence of cancer, maximum urinary

flow rate between 5 to 15 milliliters/second (mL/s), and voided volume greater than 100mL (Preuss et al, 2001). It is not known if this study incorporated any type of blinding.g)A saw palmetto herbal blend caused involution of the prostatic epithelium in menwith symptomatic and uncomplicated BPH. The study included ambulatory men (n=44),45 to 80 years, who participated in a six-month randomized, double-blind, placebo-controlled trial. Men were randomized to receive 106 milligrams (mg) saw palmettoherbal blend or placebo three times daily with meals. The herbal blend consisted of sawpalmetto (106 mg), nettle root extract (80 mg), pumpkin seed oil extract (160 mg),lemon bioflavonoid (33 mg), beta-carotene (190 international units), and other minoringredients. Prostate epithelial contraction was significant, especially in the transitionzone, and histological studies revealed an increase in the atrophy rate from 17.8% at


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baseline to 10.7% after six months of saw palmetto herbal blend (p less than 0.01). Theclinical effects, such as the International Prostate Symptom Score (IPSS), uroflowmetry,and post void residual urine volume had a slight advantage in the saw palmetto groupversus the placebo group. No significant change was noticed in prostate specific antigenor prostate volume. No serious adverse effects were demonstrated in the treatmentgroup. Results cannot be attributed to saw palmetto alone because a combination herbalblend was used (Marks et al, 2000).h)A fixed combination of extracts of saw palmetto fruit (Serenoa repens) and nettle

root (Urtica dioica) (PRO 160/120) produced the same effect as the 5-alpha-reductaseinhibitor finasteride in men with benign prostatic hyperplasia (BPH), regardless of thebaseline prostate volume. The study assessed a subgroup of men (n=431), 50 to 88years, who participated in a 48-week randomized, multicentre, double-blind clinical trial.The patients were randomized to receive either two capsules of PRO 160/120 and oneplacebo capsule or 5 milligrams (mg) finasteride capsule and two placebo capsules(double-dummy method). Prostate volumes at baseline were similar in the two groupsand the clinical exam was done at six-week intervals during the double-blind period andat the end of the 48-week treatment period. The maximum urinary flow increased frombaseline values after 24 weeks by 1.9 (5.6) milliliter(mL)/second with PRO 160/120 andby 2.4 (6.3) mL/second with finasteride. There was not a statistically significantdifference between the two groups (p=0.52). Patients with small prostates (less than orequal to 40 mL) had similar improvements, with mean values of 1.8 (5.2) mL/second

with PRO 160/120 and 2.7 (7.4) mL/second with finasteride. The outcome for men withprostates of greater than 40 mL was similar, at 2.3 (6.1) and 2.2(5.3) mL/second,respectively. The improvement in the International Prostate Symptom Score (IPSS) wassimilar in both groups, but the PRO 160/120 had better tolerability and less adverseeffects than finasteride. Results of this study suggest that the efficacy of treatment withfinasteride or PRO 160/120 cannot be predicted by the patients' baseline prostatevolumes (Sokeland, 2000).i)A 50% reduction in residual urine volume, a 6.1 mL/sec increase in peak urine flow,and a lower rate of deterioration in the treated patients was reported in a prospective,multicenter study completed over 3 years. A hexane extract (320 mg/day) wasevaluated in 435 patients with benign prostatic hyperplasia (Bach & Ebeling, 1996).j) Saw palmetto significantly reduced the International Prostate Symptom Score (IPSS)in 46 evaluable patients with lower urinary tract symptoms (LUTS) resulting from benign

prostatic hypertrophy. Patients received saw palmetto 160 milligrams twice daily for sixmonths in this non-randomized, open-label trial. A significant improvement in mean IPSSwas evident at two, four, and six-month evaluations (p less than 0.001) and 85% ofpatients showed improvement. A greater than 50% improvement in IPSS was observedin 21% at two months, 30% at four months, and 46% of patients at six months. Nosignificant change in peak urinary flow rate, post void residual urine volume, bladderpressure, or serum prostate specific antigen (PSA) was observed. The investigatorsnoted that changes in IPSS may be due to a placebo effect, considering the study designand that urodynamic changes may not have been detected due to patient selection(58% without bladder obstruction) and/or sample size (Gerber et al, 1998).k)Almost 75% of 38 benign prostatic hyperplasia (BPH) patients who were treated withsaw palmetto extract for a year reported improved subjective complaints, an increase inflow rates from 10.36 milliliters/second (mL/s) to 14.44 mL/s, a 10.6% reduction in the

size of the prostate, and a reduction of 47 milliliters of residual urine. Ninety percent ofthe patients reported that urinary retention decreased or disappeared. The study wasopen and uncontrolled and results were confirmed by Student t test. The dose was 320milligrams of the extract IDS89/day (Kondas et al, 1996).l) Saw palmetto extract was significantly more effective than placebo in a double-blind,randomized, placebo-controlled, multicenter study of 176 benign prostatic hyperplasia(BHP) patients who were non-placebo responders in other studies. The patients weregiven either 160 milligrams of the extract twice a day or placebo. Results of the studyare listed below: Symptom/saw palmetto group/placebo group. Decreased dysuriaseverity/31.3%/16.1% decrease; daytime urinary frequency/31% decrease/unchanged;decreased nocturnal urinary frequency/32.5%/ 17.7; and increased mean peak urinary


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flow/28.9%/8.5% (Descotes et al, 1995).m) Some improvement was observed in benign prostatic hyperplasia (BPH) symptomsafter 45 days and 90 days in another study. About 88% of the patients and 88% of thephysicians considered the treatment to be beneficial. Five hundred and five patients withmild to moderate symptoms of BPH were treated with oral Prostaserene(R) (sawpalmetto extract) 160 mg twice daily. The final number of patients evaluated after 90days of treatment was 305. Patients were evaluated for urinary flow rates, residualvolume, prostate size, and subjective improvement (patients and physicians). Subjective

evaluations of treatment made by patients after 45 and 90 days of treatment were quitefavorable. After 45 days, 83% of patients estimated the drug was effective. After 90days, the percentage increased to 88%. Similarly, global evaluations made by physiciansafter 45 and 90 days demonstrated 81% and 88% effectiveness, respectively. Theobjective evaluations demonstrated remarkable improvements in all measurements.Maximum urinary flow increased from 9.8 to 12.2 mL/sec, mean urinary flow increasedfrom 5.8 to 7.4 mL/sec, prostatic volume decreased from 40,348 to 36,246 mm(3), andthe international prostate symptom score decreased from 19 to 12.4. Serum PSAconcentrations were not altered during treatment. Only 5% of patients experienced sideeffects (Braeckman, 1994).n) Reduction in edema and congestion of the prostate was reported in a prospective,randomized, double-blind study of eight benign prostatic hyperplasia (BPH) patients whowere evaluated by open prostatectomy. Prostate morphological changes occurred in

patients on Sabal extract IDS89. All types of prostate hypertrophy were found, includingpredominately stromal, predominately glandular, and mixed type. The placebo group (10patients) had marked edema and mucoid degeneration of the periglandular stroma orstromal nodules and intraglandular congestion. The study group (eight patients)demonstrated significant improvement in mucoid degeneration, intraglandularcongestion, congestive prostatitis, and glandular stromal edema. The study lasted 12weeks and the dose was 320 milligrams of Sabal extract (IDS89) three times a day(Helpap et al, 1995).o) Obstructive symptoms, residual volume, and mean and maximum urine flow rateswere significantly improved in a study of 42 patients with stage two or three benignprostatic hyperplasia who were treated for 12 months with a daily dose of 320milligrams. Routine laboratory examinations, rectal digital examination, duration ofurination, duration of urination until maximum flow, maximum flow rate, urine volume,

suprapubic ultrasound examination, nocturia, feeling of urine residual, dribbling, andhesitancy were measured at three, six, and twelve months. Improvement was observedin all areas (Romics et al, 1993).p) In a drug monitoring study, 1334 outpatients with benign prostatic hyperplasia (BPH)were treated for 12 weeks with an extract from the fruits of Sabal serrulata. Under thistreatment, the volume of residual urine decreased on average by 37% and nocturiadecreased by 54%. The percentage of patients with dysuric pain decreased from 75% to37%. The efficacy of the drug was rated good to excellent in more than 80% of thecases. Good to excellent tolerability was reported by more than 95% of the patients. Theimprovement in the irritative symptoms may be considered relevant in terms ofimprovement in the quality of the life of the patients and justifies this form of treatment(Vahlensieck et al, 1993).

COMPARATIVE EFFICACY

ALFUZOSIN

1) SUMMARY:

a) Comparable treatment results of maximum and mean urine flow, residual urinevolume, and bladder irritability were obtained in a double-blind study of Serenoa repensand alfuzosin (Grasso et al, 1995).

2) BENIGN PROSTATIC HYPERTROPHY (BPH):


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a)Alfuzosin was statistically better in producing a rapid onset of action concerningobstructive symptoms, but in other measures, such as irritative score, maximum andmean urine flow, and residual urine volume, the two methods of treatment werecomparable. This was a study of 63 BPH patients who participated in a 3-week, double-blind, comparative parallel-group study. One group took alfuzosin 2.5 mg 3 times a daywhile another group took Serenoa repens 160 mg twice a day. Efficacy was determinedby clinical symptoms, urinary flow rates, and residual urinary volume (Grasso et al,1995).

CYPROTERONE

1) SUMMARY:

a) In a double-blind investigative study of Serenoa repens and cyproterone, a reductionin prostate volume was noted (DiSilverio et al, 1993).


a)A statistically significant difference in prostate volume reduction was noted between acombination therapy group and two other groups who used monotherapy with Serenoarepens extract or cyproterone. The study was a multicenter, double-blind investigation ofBPH patients who were using Serenoa repens plus cyproterone acetate (DiSilverio et al,1993).

FINASTERIDE

1) SUMMARY:

a) Finasteride demonstrated a significant reduction in prostate size and lowered serumdihydrotestosterone more effectively in several comparison studies with Permixon(R)(extract of Serenoa repens) (Carraro et al, 1996; Strauch et al, 1994; Rhodes et al,1993).b)A combination of saw palmetto and stinging nettle extract was better-tolerated andequivalent in efficacy for BPH symptoms to finasteride in a double-blind, randomized,multicenter trial (Sokeland, 2000).


a)A combination of saw palmetto and stinging nettle extracts was equivalent in efficacyto finasteride but was better-tolerated. In a multi-center, double-blind, randomizedstudy, after a two-week placebo run-in period, men 50 to 88 years received either PRO

(Prostagutt forte(R), a combination of saw palmetto 160 milligrams (mg) and stingingnettle 120 mg) two capsules and one placebo daily or finasteride 5 mg with two placebocapsules daily for 48 weeks. Subjects were examined at baseline, 48 weeks, and at six-week intervals during the study. Maximal urine flow, mean urine flow rate, voidedvolume and duration, time to flow rate increase, prostate volume via ultrasonography,quality of life, and International Prostate Symptom Scores (IPSS) were measured at eachexamination. At the end of the study, prostate volume in the PRO group had decreasedfrom 42.7 to 42.4 milliliters (mL) and in the finasteride group it decreased from 44 to37.2 mL (p=0.52). In subgroup analysis by prostate size, mean scores decreased withno significant differences between the treatment groups or for differing prostate size.The maximal urine flow rate increased in both treatment groups, without a significantdifference between groups. IPSS scores also decreased in both groups during the study,with no significant difference between groups. In the PRO group, 52 patients

experienced a total of 74 adverse events and in the finasteride group, 54 patientsexperienced 96 adverse events (Sokeland, 2000).b) Finasteride may produce a reduction of prostate volume of up to 30% with a slightimprovement in uroflow and no significant change in urine residual volume. One study of1098 patients demonstrated a 37% reduction in the Prostate Symptom Score (IPPS) forfinasteride and a 39% reduction of IPPS for saw palmetto (Permixon(R)). Finasteridereduced prostate size by 18% while Permixon(R) only reduced prostate size by about6%. In other variables, they were about equal (Carraro et al, 1996).c)About 10.7% of patients discontinued treatment due to finasteride adverse effects. Inone 3-year, prospective, multicenter study, the adverse effects with saw palmetto wereonly 1.8%, while the residual urine volume was decreased by 50% and the peak urinary


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flow increased by 6.1 milliliters/minute (Bach et al, 1997).d) Thirty-two healthy males were randomized and given either finasteride (Proscar(R)) 5milligrams daily (n=10), saw palmetto (Permixon(R)) 80 milligrams twice daily (n=11),or placebo (n=11) for one week. The inhibition of 5-alpha-reductase was measured. Attwelve hours into the experiment and with only one dose being given, finasteridelowered the serum dihydrotestosterone level by 65%. After multiple doses, the rangewas minus 52% to minus 60%. No significant difference was observed betweenfinasteride and saw palmetto. No statistically significant difference was demonstrated

between finasteride and placebo except on day three and six (Strauch et al, 1994).e) In a seven-day clinical trial of 32 males, patients were divided randomly into groupsreceiving finasteride 5 milligrams/day, Permixon(R) (extract of Serenoa repens) 320milligrams/day, or placebo. Serum levels of testosterone and dihydrotestosterone werecompared. Finasteride exerted more potent inhibition of 5-alpha-reductase compared tosaw palmetto extract (Rhodes et al, 1993).

PRAZOSIN

1) SUMMARY:

a) Prazosin was slightly more effective in controlling symptoms of bladder irritation thanSerenoa repens (Semino et al, 1992).


a) Forty-five patients with BPH were entered into a comparative study of prazosin versusSerenoa repens extract. After 12 weeks, flow rates and various subjective measureswere evaluated. Prazosin was only slightly more advantageous in controlling the irritativesymptoms (Semino et al, 1992).

PYGEUM AFRICANUM EXTRACT

1) SUMMARY:

a) In patients with prostatic adenomas, a comparison of Serenoa repens and pygeumafricanum found the extract of Serenoa repens significantly more effective in improvingurologic parameters (Duvia et al, 1983).


a) The effectiveness and tolerability of Serenoa repens extract and pygeum africanumextract (EPA) were compared in 30 patients with prostate adenomas. Serenoa repens

therapy was superior in the clinical parameters measured, reducing dysuria, nocturnalfrequency, and prostate size, and increasing voiding rate. Those parameters weremeasured at the beginning of the study and at the end of the 30-day trial. Serenoarepens extract did not induce side effects while EPA created gastric disturbances in two(13%) patients (Duvia et al, 1983).

TAMSULOSIN

1) SUMMARY:

a) Permixon(R) and tamsulosin were equally effective in men with urinary tractsymptoms secondary to benign prostate hypertrophy (BPH) (Debruyne et al, 2002).


a) Permixon(R) and tamsulosin are well-tolerated and equally effective in men withlower urinary tract symptoms secondary to benign prostatic hypertrophy (BPH).Permixon(R) is a lipido-sterolic extract of Serenoa repens (LSESr; saw palmetto). It hasantiproliferative activity and is a non-competitive inhibitor of 5-alpha-reductase type oneand two. In this double-blind study, men (n=704; mean age 65.5 years) withsymptomatic BPH were randomized to receive either oral tamsulosin (0.4 milligram(mg)/day or oral Permixon(R) (320 mg/day). After 12 months, both treatments produceda similar decrease in total International Prostate Symptom Score (I-PSS). Patients withsevere symptoms experienced the greatest reduction in I-PSS total score. Tamsulosinachieved full activity at three months and this was maintained until study completionwhile continuous improvements were observed throughout the study for Permixon(R).No differences were observed between treatment groups in irritative and obstructivesymptom improvements. Peak urinary flow rate (Qmax) increased similarly in both


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treatment groups (50% of patients experienced a 20% increase). Prostate volumedecreased in the Permixon(R) group and increased in the tamsulosin group. Neithertreatment significantly affected total prostate-specific antigen (PSA) levels. Bothtreatments were well-tolerated with a similar overall incidence of adverse effects;however, ejaculation disorders occurred more frequently with tamsulosin than withPermixon(R) (4.2% versus 0.6%, respectively; p=0.001) (Debruyne et al, 2002).

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