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Whatdoweknowaboutphytotherapyofbenignprostatichyperplasia?

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Life Sciences 126 (2015) 42–56

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Review article

What do we know about phytotherapy of benign prostatic hyperplasia?

Olta Allkanjari, Annabella Vitalone ⁎Department of Physiology and Pharmacology, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy

⁎ Corresponding author at: Department of Physiology afax: +39 06 49912480.

E-mail address: annabella.vitalone@uniroma1.it (A. Vi

http://dx.doi.org/10.1016/j.lfs.2015.01.0230024-3205/© 2015 Elsevier Inc. All rights reserved.

a b s t r a c t

a r t i c l e i n f o

Article history:Received 13 November 2014Accepted 21 January 2015Available online 20 February 2015

Chemical compounds studied in this article:β-Sitosterol (PubChem CID: 222284)Palmitic acid (PubChem CID: 985)Tamsulosin (PubChem CID: 129211)Finasteride (PubChem CID: 57363)Stigmasterol (PubChem CID: 5280794)Kaempferol (PubChem CID: 5280863)Lycopene (PubChem CID: 446925)Rooperol (PubChem CID: 6438989)N-Docosanol (PubChem CID: 12620)Selenium (PubChem CID: 6326970)

Keywords:Benign prostatic hyperplasiaPhytotherapySaw palmettoClinical efficacySafety profileReview

Benign prostatic hyperplasia (BPH) is one of the most common urological diseases in aging men. Because of itslong latency, BPH is a good target for prevention. The aim of the study has been to review the various optionsof treatment, currently available, in the field of phytotherapy. Watchful waiting, pharmacological therapy, andsurgery are also helpful, depending on the severity of the disease. Although drug therapy (alpha1-blockers,5alpha-reductase inhibitors) and surgery (prostatectomy, transurethral resection, etc.) seem to bemost effectivefor patients with moderate-severe BPH, herbal medicines (i.e., Serenoa repens, Pygeum africanum, Urtica dioica)are also commonly used in patients with mild–moderate symptoms. On the basis of preclinical studies severalmechanisms of action have been postulated, including 5alpha-reductase inhibition, alpha-adrenergic antago-nism, dihydrotestosterone and estrogen receptor inhibition. Randomized clinical trials indicate significant effica-cy in improving urinary symptoms and mild adverse effects for some phytotherapeutic agents, while furtherclinical evidence is needed for others (e.g., Epilobium spp., Secale cereale, Roystonea regia). Healthcare profes-sionals should be constantly informed about BPH phytotherapy, taking into account the risk/benefit profile ofthe use of medicinal plants in the management of BPH.

© 2015 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43Cucurbita pepo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Epilobium spp. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45

Hypoxis rooperi . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Lycopersicum esculentum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46

Pinus pinaster . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

nd Pharmacology “V. Erspamer”, Sapienza University of Rome, Piazzale AldoMoro 5, 00185 Rome, Italy. Tel.: +39 06 49912904;

talone).

43O. Allkanjari, A. Vitalone / Life Sciences 126 (2015) 42–56

P. africanum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Roystonea regia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

Secale cereale . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48

S. repens . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49

Urtica dioica . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Preclinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Clinical studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50Other medicinal plants (less) used in BPH . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51

Conclusions and perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51Conflict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52

Introduction

Benign prostatic hyperplasia (BPH) is one of the most commonurological diseases in aging men. It typically develops after the age of40 years and ranges in prevalence from over 50% at 60 years to ashigh as 90% by 85 years of age [1]. BPH is characterized by highmorbid-ity and lowmortality rate, and is considered a public health problem [2].The BPH natural history can be divided into the pathological and clinicalphases. The first phase is asymptomatic, and occurs at the periurethrallevel with nodular hyperplasia [3]. The clinical phase occurs when theenlarged prostate gland compresses the urethra, this results in an in-crease of urine flow resistance associated with the loss of elasticity oftensile organ, and sometimes with the presence of inflammation (pros-tatitis). The condition determines symptoms associated with a clinicalpicture named “prostatism” [4] that is characterized by dynamic andstatic components. The first one affects stromal tissue and it is due toan increase of the smooth muscle tone of the bladder neck and of pros-tate stromal portion. The alpha1-receptors seem to be the mediators ofthis process. The obstructive symptoms induced by the dynamic com-ponent are terminal dribbling, sense of incomplete bladder emptyingdue to urinary retention, decreased force of the stream, urinary hesitan-cy or urinary flow intermittency. The other factor of the clinical phase(i.e., static component) involves the epithelial tissue which is affectedby androgen-induced proliferation leading to prostate hypertrophy.The irritative symptoms caused by the static component are nocturia,incontinence, hematuria, urgency and increased frequency of voidingacts [5]. The symptoms described above can lead to anxiety, sleep dis-turbance [6], reduced mobility, difficulty in sexual relations and a com-promised feeling of well-being, resulting in interruption of work andsocial activities, with a negative impact on the quality of life (QoL) [7].

The origin of BPH is not clearly defined. Three theories have beenproposed to explain the causes of BPH development. The first one isbased on the role of androgens, estrogens and growth factors. Theprostate cells are able to convert about 90% of testosterone (TE) todihydrotestosterone (DHT) by 5alpha-reductase. The latter binds toandrogen receptors with higher affinity than TE, and it appears to actdirectly by stimulating protein synthesis, differentiation and prostatecell growth [8,9]. DHT accumulates in prostate even when TE levelsare low [10]. The binding of DHT to its receptor further stimulates thetranscription and transduction of DNA specific segments, coding forgrowth factors (e.g., epidermal growth factor— EGF; insulin like growthfactor— IGF), leading to abnormal prostate cell proliferation [11]. More-over, estrogens act in synergy with androgens in the development ofBPH. Particularly, an increase in the expression of aromatase (an en-zyme that catalyzes the peripheral conversion of androgens into

estrogens) and estrogen receptors at the transition zone of hypertrophicprostate tissue has been observed [12]. The second postulate about BPHdevelopment is based on the presence of a small percentage of prostatecells androgen-independent that can self-renew in androgen-deficientconditions [3]. The third theory concerns the interactions between stro-ma and epithelium. Both of them are able to convert TE into DHT,allowing the production of various growth factors (fibroblast growthfactor — FGF; endothelin-1 — ET1; transforming growth factor — TGF-β1; etc.), responsible for modulation, proliferation, apoptosis and secre-tory activities of both stromal (autocrine transmission) and epithelialportions (paracrine secretion) [3,13,14].

In the pathogenesis of BPH some risk factors should also be takeninto account, since this disease is more common in patients fromNorth America and Europe, with large baseline prostate, with positivefamily history [15], and with previous inflammation of the prostategland. Prostatitis, aswell as oxidative stress, stimulates the inflammato-ry cascade associated with nuclear factor kappa-B (NF- B), induciblenitric oxide synthase (iNOS), and 5-lipoxigenase (5-LOX) activation,cyclooxygenase-2 (COX-2) over-expression, and cytokine and leukotri-ene production [16].

Therapeutic approaches currently available for the treatment of BPHconsist of: watchful waiting, surgery, pharmacological therapy and theuse of medicinal plants. The choice of treatment should be decidedtogether with the patient and should be individualized, according tohis personal preference and to the disease severity [17]. The main aimis to relieve symptoms and to improve patient's QoL.

Watchful waiting (i.e., periodic revaluations of clinical conditions)and some changes in lifestyle are recommended for patients with mildsymptoms who are not at risk of acute urinary retention [18]. In thecase of worsening of symptoms and as the post-void residual volumeincreases, pharmacological therapies are proposed. The two mainclasses of drugs are alpha1-antagonists (prazosin, doxazosin, terazosin,alfuzosin, tamsulosin, silodosin) and 5alpha-reductase inhibitors(finasteride, dutasteride), often effectively used in combination as a rec-ommended option for the treatment of patients at risk of BPH progres-sion [19]. The target of alpha1-adrenergic antagonists is the dynamiccomponent and they are considered as the mainstay of therapy [20].The alpha1-blockers increase the volume and the stream force, improv-ing symptoms and consequently patient's QoL. The most common sideeffects are dizziness, tachycardia, postural hypotension [21], retrogradeejaculation (reversible after discontinuation of therapy) [19,22]. The5alpha-reductase inhibitors reduce the static component causing an-drogen reduction. They are more effective in patients with a significantenlargement of the prostate gland [23]. The use of finasteride increasesthe stream of urine and reduces BPH-related symptoms [24]. However,

44 O. Allkanjari, A. Vitalone / Life Sciences 126 (2015) 42–56

it causes numerous side effects such as decreased libido, decreasedvolume of ejaculate, impotence and skin rash. Cases of gynecomastiahave been also reported [25]. The antimuscarinic drugs (tolterodine,fesoterodine) may also be used, in association with the two previouslymentioned drug classes, in severe conditions related to storage symp-toms [22]. A more recent long-term pharmacological treatment of BPHof moderate degree consists in prostate antigen-specific antibodies(known as afala). This preparation promptly and effectively reducesirritative and obstructive symptoms and post-void residual volume,while increase urine flow [26]. Other recent and, in some cases,promising pharmacological therapies include the use of: β3-agonist(i.e., mirabegron); the association of 5-phosphodiesterase inhibitors(i.e., tadalafil) and alpha1-adrenergic antagonists; lonidamine (capableof inhibiting glycolysis and of causing cell apoptosis) and botulinumneurotoxin [27–29]. The latter approach, consisting of an intraprostaticinjection of botulinum toxin, is still of doubtful efficacy and safety andfurther studies are needed to determine its use in the management ofpatients with urologic conditions [30].

In the worst cases of symptomatic BPH, invasive surgery (openprostatectomy — OP) or minimally invasive procedures (transurethralresection, transurethral microwave thermotherapy, laser ablationendoscopic, etc.) may be required. The type of surgery is based on thesize of the prostate, the presence of painful symptoms and/or otherconcomitant diseases. OP is considered as the most effective as well asthe most invasive procedure [5]. The incidence of its complicationscan range from retrograde ejaculation (81%) to urinary tract infections(3%) [31]. In recent years, the transurethral resection of the prostate(TURP) has become the “gold standard” in patients with BPH, becausethis surgical approach allows obtaining an immediate removal ofthe obstruction and long-term improvement of the symptoms.However, this procedure has also been associated with side effects(e.g., incontinence, impotence, hemorrhages. The latter could be obviat-ed by the use of intermittent clotting) [32]. Other minimally invasiveprocedures that improve the symptoms quickly and have a good cost/efficacy have been developed and the most practiced included thefollowing: transurethral incision of the prostate (TUIP) that reducedthe urethral compression and it is recommended when the glandweight is about 30 g; transurethral electrovaporization of the prostate(TUVP) that represents TURP modifications, consisting in the destruc-tion of the hypertrophic prostate tissue; transurethral microwavetherapy (TUMP), transurethral needle ablation (TUNA), and varioustypes of endoscopic ablation by laser (ELAP). All of the abovementionedapproaches are, in different extent, responsible for side effects such as:ineffectiveness or failure in the short term, high incidence of complica-tions, need for a prolonged catheterization, retrograde ejaculation, etc.[32]. Because of many side effects of drug therapy and surgicalprocedures, and since the high morbidity and the long latency of BPHmake it a good target for prevention [32], herbal medicines (alsoknow as botanicals) are becoming a popular option in the treatmentof this disease. Herbal products are usually derived from roots, berriesor fruits of various plants, and are commercialized as extracts, thatcontain a wide range of chemical compounds (e.g., phytosterols, fattyacids, flavonoids). The most commonly used herbal remedies formild–moderate BPH are Serenoa repens fruit extracts and Pygeumafricanum bark extract [33,34]. The herbal treatments generally showgreat tolerance and plural numbers of action sites, many of which arein common with drugs such 5alpha-reductase inhibitors and alpha1-receptor antagonists. Many of the herbal products currently used forBPH are sold in health food stores and are often, but not always,available as dietary supplement without medical prescription [32]. Inparticular, in the United States medicinal plants are regulated by theDietary Supplement Health and Education Act as dietary supplementsand are usually available without medical prescription [35]. In Italy,some of these herbal preparations are also registered as drugs andrequire prescription. In Germany and Austria, phytotherapy is thefirst-line treatment of mild to moderate urinary symptoms and

represents more than 90% of all the drugs prescribed for BPH treatment[36]. Phytotherapy is generally less used in other countries, includingIreland, UK, Denmark, Norway, Finland, Sweden, Italy, Greece andPortugal. On the contrary, thenumber of phytotherapeutic prescriptionsis particularly high in Belgium [37].

This review summarizes the preclinical and clinical evidences of themedicinal plants most widely used in the treatment of BPH. Particularattention was also devoted to their safety profile.

Cucurbita pepo

C. pepo L. belongs to the Cucurbitaceae family. It is an annual herba-ceous plant native of South-Central America, also known as pumpkin orDubba. In traditional medicine, the oil of pumpkin seeds has been usedfor its antioxidant and anti-inflammatory actions in the treatment ofBPH and its urinary related problems [38].

Preclinical studies

The chemical composition of pumpkin seeds consists of alpha-tocopherol, proteins, carbohydrates, fatty acids (palmitic, stearic, oleicand linoleic), non-essential amino acids (cucurbitine) and Δ5-Δ7-Δ8-phytosterols (including sitosterol, stigmasterol, etc.) [38,39]. The Δ7-sterols have a chemical structure similar to DHT and can competitivelyinhibit the binding of DHT to its receptors. However, the active ingredi-ent has not been yet identified and the data related to themechanism ofaction are limited and not conclusive. Some studies carried out in ratsshow that pumpkin seed extracts can block the increase of prostateweight and protein synthesis induced by testosterone/prazosin [40],inhibiting testosterone-induced hypertrophy [41], and improves thefunction of the bladder (i.e. tonic action, sphincter relax action) andurethra [42,43]. The mechanism of action of pumpkin seed oil issupposed to be the 5alpha-reductase inhibition [41].

Clinical studies

From a multicenter clinical trial conducted on thousands of pa-tients with BPH treated with capsules of pumpkin seed extract(500 mg), there was a decrease in the International Prostate Symp-toms Score (IPSS) and an improvement of QoL [44]. A significant de-crease in the levels of DHT, and a significant improvement in BPHurinary flow symptoms (i.e., time of the bladder emptying, residualvolume, daily frequency of urination and nocturia) were also foundin patients using a combination of pumpkin seeds and S. repens[38]. This association (320 mg/day of each medicinal plant) wasalso effective in prostatic Korean patients in the amelioration ofIPSS, QoL, PSA serum levels and maximum urine flow, while therewere no differences in the prostate volume [45]. Other more recentmultiple association involves the use of C. pepo seed oil (160 mg),Epilobium parviflorum extract (500 mg of dry herb), lycopene(2.1 mg), P. africanum (15 g of dry stem) and S. repens (660 mg ofdry leaf). This herbal preparation, during three months of treatment,induces a significant reduction in IPSS, and day- and night time uri-nary frequency, in patients who presented medically diagnosedBPH [46]. However, further studies to confirm the efficacy ofC. pepo in the treatment of BPH are needed. Regarding the safety ofthis plant, there is no indication of serious side effects, though itcould be responsible for mild gastrointestinal problems(e.g., indigestion, diarrhea) [42], electrolyte loss (possibly due toits diuretic properties) [47], and alteration of the International Nor-malized Ratio (INR, an indicator of prothrombin time). The last effectmakes cucurbita contraindicated in the case of anticoagulant con-comitant therapies [38].

45O. Allkanjari, A. Vitalone / Life Sciences 126 (2015) 42–56

Epilobium spp.

Epilobium L. is a perennial herbaceous plant that belongs to theOnagraceae family. It consists of more than 200 species distributed inEurope, Asia, Africa, Australia, America, Tasmania and New Zealand[38]. The most common species include E. parviflorum, Epilobiumhirsutum, Epilobium rosmarinifolium and Epilobium angustifolium (com-monly known as willow herb). The part of the plant commonly usedin various products is derived from the aerial flowered one. Traditionalmedicines consider the willow herb useful for fever, rheumatic compli-cations, headache, and as a general pain relief, even if such uses are notsupported by scientific evidence [38].

Preclinical studies

The various species of this family are rich in flavonoids(myricitrin, isoquercitrin, quercitrin, guaiaverin, quercetin-3-O-β-D-glucuronide, etc.), dimeric macrocyclic ellagitannins (oenotheinA and B) and sterols (β-sitosterol and its esters) [48,49]. The com-mon element in the various species of Epilobium is the presence ofoenothein B which seems to play an important role in the inhibitionof DNA synthesis, although other components may contribute to thiseffect [50]. The commercial Epilobium containing products, usually,consist of different plant species association, so that the pharmaco-logical standardization of this plant remains difficult. A study carriedout by Bazylko et al. [51] has developed a simple, fast and selectivemethod for the separation and quantitative determination ofoenothein B and quercetin glucuronide of the E. angustifolium aque-ous extract. Several studies confirm that the main tannic componentof E. parviflorum is oenothein B, while the main flavonoid ismyricitrin (myricetin-3-O-ramnoside). The presence of caffeic,chlorogenic, ellagic and gallic acid derivatives and myricitrin,quercitrin, kaempferol and their glycosides [52] was also found.Epilobium is one of the various medicinal plants used in the treat-ment of BPH, although the exact mechanism of action has not yetbeen clarified. The activities observed in the experimental studiesconsist of: high radical-scavenger, antioxidant activity [53], anti-inflammatory effect, analgesic property, anti-proliferative effect, in-hibition of the activity of hyaluronidase and myeloperoxidase,lipoxygenase release possibly due to oenothein B content, and inhib-itory effect on aromatase and 5alpha-reductase type 2 enzymes [49,50,54,55]. The radical-scavenger and antioxidant activities havebeen found for both ethanol and aqueous extract of E. parviflorum;these were higher (greater than that of Trolox® and ascorbic acid,used as positive controls), dose-dependent, and seem to be due tothe presence of flavonoids [56]. The same finding was also confirmedby other studies for other Epilobium species [53,57]. Regarding theanti-inflammatory activity, a potent inhibition of COX-1 and COX-2has been found in vitro for the ethanolic (rather than aqueous)extract of E. parviflorum [56]. Furthermore, in vivo study oncarrageenan-induced rat paw edema has confirmed its high anti-inflammatory property, probably due to the inhibition of prostaglan-din synthesis [58]. As regard the antiproliferative effect, an aspecificeffect on the inhibition of cell proliferation has been found forvarious Epilobium species (E. angustifolium, E. rosmarinifolium,E. tetragonum) [50,59]. This activity appeared to be related to inter-ference on cell cycle progression from the G0 to the G1 phase, ratherthan to a cytotoxic effect [60]. Other results that may offer an expla-nation of the pharmacological use of willow herb in traditional med-icine have shown an inhibition of 5alpha-reductase [61] and theinduction of neutral endopeptidase (NEP) in prostate cells [59].Moreover, antitumor activity due to the immune response enhance-ment mediated by macrophage activation was found [62]. All of thepreviously mentioned activities indicate a key role of oenothein B[50,59,61,62].

Clinical studies

Although all the preclinical results could support the traditionaluse of different species of Epilobium for the treatment of BPH, andthis plant is widely present in dietary supplements and cosmeticproducts used against androgenetic alopecia, further researches areneeded, in particular those regarding the inhibition of prostatic cellproliferation and the anti-androgenic, anti-inflammatory and anal-gesic properties that may be useful in the treatment of the symptomsassociated with BPH. In the literature, as previously discussed (seethe Epilobium spp. section), there is only one clinical study regardingE. parviflorum, used in associationwith various medicinal plants [46],whereas there are no published data regarding clinical efficacy andsafety of Epilobium spp. when used alone. Although the lack ofhuman studies, Epilobium extracts appear to be harmless to animals,but this data cannot be directly traduced in terms of clinical evidence[49].

Hypoxis rooperi

H. rooperi Moore belongs to the Hypoxidaceae (Amaryllidaceae)family. This is a perennial herbaceous plant native of South-EastAfrican regions, particularly of KwaZulu Natal and of Transkei. It is alsoknown as Hypoxis hemerocallidea, African potato or yellow star. Thepart of the plant usually used is made from a dark brown or blacktuber which presents a yellow pulp [43]. H. rooperi is traditionallyknown as a “miracle” medicinal plant because it has been used for awide array of human ailments, including cancers, diabetes, infections,nervous disorders, immune-related illnesses, heart weaknesses andurinary tract infections [63].

Preclinical studies

The tuber contains mainly sterols (β-sitosterol and β-sitosterolglycoside), polysaccharides and lignans (mainly hypoxoside thatshould be converted to rooperol, its biologically active glycone)[38,64]. The pharmacological effects of Hypoxis could be attributedto sterols [43]. In particular, β-sitosterol seems responsible for theincrease of TGF-β1 expression and protein kinase C-alpha activity,in the stromal cells of the human prostate [43]. However, this specif-ic effect doesn't appear clinically relevant in vivo, though an im-provement of BPH related symptoms (post-void residual volume,increase of urine flow) has been found [65]. Themechanism of actionof this herb is not well known. From preclinical studies it doesn'tseem to inhibit 5alpha-reductase [66]. In vitro, rooperol has beenshown to have anti-inflammatory activity, by inhibiting cytokineproduction and COX-1 and COX-2 activity (the ethanolic extract ap-peared to be more potent than the aqueous one), by reducing the ac-tivity of transcription factors [56], and it might interfere with thesynthesis of inflammatory mediators, such as prostaglandins [42,67,68]. The anti-inflammatory effect was also recently confirmed atthe intestinal level, in mice, by an inhibition of epithelial cell prolif-eration and by a reduction in the expression of NF- B in the colonicmucosa [69]. It has also been shown to have radical scavenger activ-ity (that was equal for both ethanolic and aqueous extracts) [56]. Asregards the safety of the Hypoxis extract, an in vivo study in mice,treated with 2000 mg/kg of Hypoxis for 2 weeks, did not show anytoxicity on various vital organs (brain, heart, lungs, liver, spleen, kid-ney and intestine), also confirmed at the histomorphological level[68]. On the other hand, the possibility of a negative interaction ofHypoxis with various isoforms of CYP450 (i.e., CYP1A2, 2A6, 2B6,2C8, 2C9, 3A4 and 3A5) should be kept in mind. Indeed, the inhibi-tion of presystemic metabolism could be achieved in the gastrointes-tinal tract when traditional doses of Hypoxis are taken [70].

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Clinical studies

There is not enough data about the efficacy and safety of H. rooperi.Clinical evaluations comparedwith placebo after 6months of treatmentwith the whole plant extract, reported an increase in urinary flow, sig-nificant improvement in subjective complications, and a decreasedpost-void residual volume in patients with BPH [38]. Improvements inthe IPSS score, with mild and infrequent adverse events were alsofound [71]. Those affect gastrointestinal (i.e., nausea, diarrhea) andcardiovascular (i.e., ventricular tachycardia) systems, and appear to bedue to hypoxoside and rooperol, respectively [72]. In the recent years,the entire extract, phytosterols and other constituents of Hypoxis arefinding new applications in the antioxidant, anti-inflammatory, anti-diabetic, and anti-convulsant fields [73].

Lycopersicum esculentum

L. esculentumMill. (also known as Solanum lycopersicum L.) belongsto the Solanaceae family. The tomato is an annual herbaceous plant thatis native of the area between Mexico and Peru. It is commonly used asfood (tomato-based food: tomato paste, tomato sauce, tomato soups,etc.). Generally the tomato fruit and tomato-based products provide tothe human body about 85% of lycopene, while the remaining 15% isusually obtained from the consumption of watermelon, apricot, peach,papaya and red berries [74].

Preclinical studies

L. esculentum contains glycoalkaloids (alpha-tomatine), salicylates,flavones (apigenin and luteolin), polyphenolic compounds (quercetin,myricetin, kaempferol, naringenin and chlorogenic acid) and other ca-rotenoids (phytoene and phytofluene) [75]. All green parts are toxic,as they contain solanine, a steroidal glycoalkaloid, which is not eliminat-ed even by cooking processes. The ripe fruit is rich in nutrients, amongwhich are amino acids, minerals (e.g., potassium) and vitamins (A, B,C, D, E, K, and folate). A substance that has generated great interestamong researchers is a polyunsaturated long-chain acyclic carotenoid,which is called lycopene. It contains 11 conjugateddouble bonds, linear-ly arranged in the trans configuration [76], while most of the lycopenethat have been found in the prostate tissue has cys conformation [77].The cys form is preferentially captured by benign and malignant pros-tate tissues and it is produced during cooking [77]. As lycopene hasbeen correlated with a low frequency of adenocarcinoma [78], from2003 it was added to most multivitamin products as an agent for theprevention of cancer and has become themost commonly used caroten-oid, amongmen of 45–65 years old [79]. In addition to lycopene, tomatocontains lycopene cyclase (the enzyme that catalyzes the conversion oflycopene to β-carotene). The number of the mechanisms of action thathave been proposed for the control of adenocarcinoma, as well asadenoma, is various, including: inhibition of growth factor-inducedcell proliferation, interferences in the progression of the cell cyclefrom the G0/G1 to the S phase, modulation of the COX pathway,down-regulation of 5alpha-reductase type 1, pro-apoptotic activity(potentially due to alpha-tomatine) [80], inhibition of the synthesis ofthe androgen receptor (which leads to a PSA reduction), and antioxi-dant activity [74,76–78,81]. The latter property consists of the highcapacity of lycopene (compared to other carotenoids) to capture oxygenradicals otherwise responsible for DNA damage [76]. Other substancesinvolved in the antioxidant effect are the tomato aglycone polyphenols(quercetin, naringenin and kaempferol), also responsible for the anti-carcinogenic effects and the inhibition of cell proliferation, in a dose-dependent manner [77].

In vivo results indicated conflicting evidence related to the effect oftomato (or pure lycopene) on the reduction of plasmatic testosteronelevel. This could be explained by the duration of treatment, the differ-ences in animal species or in the lycopene content [82]. However, as

experimental studies indicate that the tomato extract is more effectivein inhibiting carcinogenesis than lycopene alone, [83], this carotenoiddoes not appear to be the only constituent of tomato that has effectson the prostate [75].

In vivo pre-clinical assessment of lycopene showed a good safetyprofile with a LD50 greater than 5000 mg/kg of body weight, and noacute dermal toxicity up to 2000 mg/kg of body weight. These dosesare about 300 times higher than those usually consumed by humans[84]. Indeed, it was estimated a consumption of daily amount oflycopene about 8mg [84], with benefits that become evident at approx-imately 7–35 mg/day [85,86].

Clinical studies

Regarding the clinical efficacy of tomato juice and in particular lyco-pene, a decrease in blood levels of PSA and in oxidative DNA damage,and an increase of cell apoptosis in patients with adenocarcinomahave been found [85,87,88]. To reach these effects, lycopene should betaken (at an average of 15mg/day) for 3–6months [88]. A good efficacyof low doses of lycopene (5 mg/day) was also found when it was asso-ciated with S. repens [89]. The common adverse effects induced by dietcontaining tomato products rich in lycopene are mild and reversibleafter discontinuation of therapy, and consist of gastrointestinal prob-lems (dyspepsia, flatulence, etc.) [87] and dermatologic effects (itchyskin, etc.). In this context, it should be highlighted that chronic exposureto high doses of tomato products can induce lycopenemia, a reversiblealteration consisting of yellow–orange skin discoloration. This adverseeffect could be also associated with fatty hepatic cysts due to depositsof lycopene, which can cause abdominal pain and morphological andhistological changes of liver parenchyma [84,90].

The Scientific Committee on Food of the European Commission hasconsidered the use of lycopene synthetic preparations unacceptable asfood, because of their high sensitivity to oxygen and light, which formdegradation products with mutagenic activity [74]. Moreover, lycopeneinduces phase and metabolism enzymes and, even if helpful for theelimination of carcinogens and toxins from the body, particularattention must be devoted to the concomitant use of pharmaceuticalproducts [74].

In conclusion, though the data is very encouraging, the use oflycopene in the prevention or treatment of prostatic diseases is stillpremature.

Pinus pinaster

P. pinaster Sol. belongs to the Pinaceae family. It is also known as theMaritime pine and lives spontaneously in the Western Mediterraneanbasin. The parts commonly used are the gems, twigs and resin, fromwhich the essential yellow oil with characteristic smell and resinoustaste could be obtained, by distillation in steam.

Preclinical studies

The essential oil contains alpha- and beta-pinenes with antisepticproperties, esters of borneol, D-limonene, aldehydes and oleoresin(or turpentine) that by distillation provides turpentine and rosinresin which is a transparent solid. It also contains diterpenes, cou-marins and flavonoids. The needles are rich in vitamin C and flavo-noids. The main and active component is the β-sitosterol, with achemical structure similar to that of cholesterol, which is also com-monly found in legumes and vegetables and in particular in plantslike Hypoxis, Pygeum or other genus. In vitro experiments haveshown the effectiveness of β-sitosterol in inhibiting prostate cellproliferation [91,92].

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Clinical studies

A randomized, double-blind and placebo study was conducted toevaluate the efficacy and safety of β-sitosterol (130 mg/day, for6 months). In treated patients there was a significant improvementin the quality of life, in post-void residual volume, in the IPSS andin Qmax [91]. A systematic review also found a significant improve-ment of the urinary symptoms due to β-sitosterol [93]. Other authorshave reported contradictory results regarding the efficacy of β-sitosterol, also in association with other plants and substances,where a slight improvement was found though not statistically sig-nificant, therefore further clinical studies are needed [94]. The sideeffects induced by β-sitosterol are generally mild; however, impo-tence and gastrointestinal problems are presented to a greater ex-tent compared to patients in the placebo group [93,17].

P. africanum

P. africanum Hook belongs to the Rosaceae family. It is an evergreentree native of the Central and South American mountains, theMadagascar and Comoros islands and the Gulf of Guinea. This plant isknown even as: African Plum, Prunus africana and African cherry.P. africana is the only member of the genus widespread on the Africancontinent and may be chemically distinctive. The major exporters ofits bark (the part of the plant used) include Cameroon, Madagascar,Equatorial Guinea, and Kenya [95]. Young trees have smooth, reddishbark whereas older trees have dark, resinous bark with an intensesmell of hydrocyanic acid. It has the rare ability to regenerate its bark,as long as the vascular cambium is not destroyed [95,96].

Preclinical studies

P. africanum composition consists of phytosterols (β-sitosterol,β-sitosteryl glucoside, β-sitostenone), fatty acids, triterpenoidpentacyclic acids (ursolic, oleanolic and their homologs), alcohols (n-docosanol and its derivatives), esters of ferulic acid, linear acetogenins,nonacosane, hentriacontane, glucopyranosyl ester of benzoic acid andβ-D-glucopyranoside of diphenyl methyl alcohol, lignan isolariciresinol-9-hydroxy-7,8-dimethyl ether and proanthocyanidins [43,97]. Twoother important constituents isolated from the bark of Pygeum are N-N-butylbenzenesulfonamide (NBBS) with anti-androgenic activity, andatraric acid, whose mechanism of action is to inactivate the androgenreceptor by inhibiting its nuclear translocation [98]. Pygeum inhibits theandrogen and progesterone receptors, but not those of glucocorticoidsand estrogens; it inhibits endogenous PSA expression and prostate can-cer cell growth [98]. Furthermore, the isolation of derivatives ofdocosanol from other plants (e.g.,Myoschilos oblongum), but also presentin Pygeum, has contributed to highlight the inhibition of cell proliferationof human prostatic cells [99]. To confirm this mechanism of action,other studies evidenced a downregulation of TGF-β1 expression, andan inhibition of the proliferation of human prostatic fibroblasts andmyofibroblasts [100]. Its antiproliferative effect has been demonstratedalso in rats through treatment with Tadenan® (P. africanum extract),before and after administration of DHT [101]. Other studies performedwith Tadenan® support the hypothesis that it might prevent the activa-tion of metabolizing enzymes (or the formation of free radicals) orprotect intracellular membranes against the destructive effects of freeradicals reducing significantly the severity of both urinary bladderdysfunctions [43,102].

In animal models, Pygeum regenerates the secretory activity ofthe prostate epithelium, modulates the contractility of the bladderand has anti-inflammatory activity related to the inhibition of 5-lipoxygenase, with a consequent decrease of leukotriene productionand other 5-lipoxygenase metabolites [103]. The anti-phlogistic actionof Pygeum could partially depend on its ability to reduce the numberof neutrophils and the TGF-β expression in these cells [104].

Finally, P. africanum has been demonstrating in vivo a significantreduction of the incidence of prostate cancer, providing a preliminaryevidence of its use as a supplement in persons who have a high risk ofdeveloping prostate cancer [105].

Clinical studies

P. africanum extract taken at a daily dose of 100–200 mg, for about1–2 months, significantly improves urinary symptoms (nocturia, fre-quency of micturition, etc.), flow parameters (i.e., maximum urinaryflow rate and post-void residual urine), spermogram, the IPSS andconsequently the QoL [106–109]. These benefits seem to remain almostunchanged even after 30 days of treatment, indicating a persistentclinical activity with long term benefits [107]. It is also established thata single or fractionated doses of 100 mg/day are equivalent [109].Regarding the effects of P. africanum lipid–sterol extract on the glandsize, there are conflicting results indicating its reduction [106,107].

Despite the different works mentioned above, a meta-analysisassessed that the clinical trials on Pygeum are of short duration, per-formed on very small groups of patients [110], and have often been con-ducted with different evaluation methods and on different extracts.However, it indicates that this drug is significantly more effective thanplacebo in relieving the symptoms of BPH patients. Further clinical trialsare needed on a single type of standardized extract, for longer time andwith validatedmethods in order to obtain conclusive information [111].It has been reported that P. africanum compared to watchful waiting,seems to improve significantly the urologic symptoms, and might beequally effective as S. repens [17]. No information about the preventionof BPH long-term complications (such as acute urinary retention, renalfailure or the need for surgery) has been reported. Finally, all clinicalstudies have concluded that Pygeum-induced adverse effects are mildand comparable to placebo in frequency and type [107,108,111], andconsisted in gastrointestinal problems (diarrhea, abdominal pain, con-stipation, nausea) and headache [43].

Roystonea regia

R. regia Cook is a palm tree that belongs to the Arecaceae family. It isnative of South Florida, Mexico and parts of Central America. In Cuba, itis also called palm criollo, while in India, where it is widely cultivated, itis called Vakka [112]. The drug used for BPH is constituted by its maturefruits.

Preclinical studies

The extracts from its fruits contain amixture of free fatty acids (oleic,lauric, palmitic and myristic acids in abundance), also known as D-004.Other acids (caprylic, capric, palmitoleic, stearic, linoleic and linolenicacids) are also found in lower concentrations. Preclinical studies haveshown that the lipid extract of D-004 produced antioxidant effects inprostate tissue [113], competitively inhibits the prostatic 5alpha-reductase [114] and the simpatic-induced contraction of the smoothmuscle in rat-isolated deferens tube [115]. In vivo studies have shownthat oral treatment for 14 days with the lipid extract of R. regia fruitscould prevent and improve benign prostatic hyperplasia induced bytestosterone, in rats. Experimental data indicate an antagonism ofalpha1-adrenoceptors, and a decrease of prostate enlargement thatseems dose-dependent and more efficient than that obtained withS. repens, but largely less effective than tamsulosin [116–118]. On theother hand, the combination of D-004 and tamsulosin has resulted tobe much more effective (71%) than each of the monotherapies (57%)in preventing the urodynamic changes induced by phenylephrine inrats [119]. However, the mechanism leading to these effects requiresfurther studies.

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Clinical studies

It is not yet possible to attribute clinical efficacy to Roystonea, evenif the family to which it belongs and the antagonism of alpha1-adrenoceptors offer good basis for further studies. A randomized,double-blind study on healthy volunteers indicated a significant antiox-idant effect on plasmatic oxidative markers of D-004 (320 mg/day),taken for 6 weeks [120]. Information in the literature concerning thesafety of Roystonea are currently very limited; only 2 cases of dyspepsiawere reported [120].

Secale cereale

S. cereale L. is an annual or biannual herbaceous plant that belongs tothe Graminaceae family and is widespread in temperate zones. It is alsoknown by the names of rye, common rye and rye pollen. The drug ismade from the pollen and the extract is obtained from a microbialdigestion of pollen of various plants, especially from S. cereale fromSweden and Switzerland. The extraction process involves the sequentialuse of water and organic solvents [43].

Preclinical studies

The common presence of proteins, carbohydrates, vitamins, min-erals and β-sterols (in the acetone-soluble fraction) has been reported[121], however the active ingredient is still not known. Moreover, thecomposition of commercial products (tablets and capsules) is highlyvariable, making it difficult to interpret the results. One of the mostfamous products, used by millions of people, prepared from theS. cereale pollen extract is Cernilton® (each dose is standardized in60 mg of cernitina T60 — the water soluble fraction, and 3 mg ofCernitina GBX— the acetone soluble fraction). It is registered as a herbaldrug throughout Western Europe (i.e., Switzerland, Austria, Germany,Spain, Greece), Japan, Korea and Argentina; while in the U.S. it is usedas a dietary supplement. Several mechanisms of action have been pro-posed for pollen extracts, including: relaxation of urethral sphinctericsmooth muscle tone [122], increase of the bladder muscle contraction[123], increase of the apoptosis in epithelial cells of the prostate gland,inhibition of 5alpha-reductase, increase of the serum and prostaticlevels of zinc, blockage of the alpha-adrenergic receptors and inhibitionof prostaglandin and leukotriene biosyntheses [43]. From an in vivostudy, it has been suggested that therapy with S. cereale pollen extractmay retard the growth of prostate cancer by increased apoptosis oftumor cells in animal models [124], but it can't yet be recommendedas a successful treatment for prostate disorders.

Clinical studies

The pollen of S. cereale seems useful in relieving the urinary symp-toms of BPH and prostatitis, but the improvement is modest and theevidence is limited [42,93]. Two systematic reviews have comparedthe activity of Cernilton®with placebo or other types of herbal prepara-tions used in BPH. A modest and subjective improvement in urologicsymptoms was found when pollen is used for 24 weeks. However, itdid not improve urinary flow, prostate size or the residual urine volumecompared with placebo [43,125]. Although results suggest thatCernilton offers modest benefits to patients with BPH, the studies eval-uated in this review were limited by several factors, as reported below[126,127]. The duration of treatmentwas short (i.e., 24weeks). The dos-ages of Cernilton®have not been reported in all of these studies and thestandardization of the preparation is unknown. Other studies, that haveevaluated the clinical efficacy and safety of pollen extract, havesuggested that it is well tolerated and improves modestly all urologicsymptoms including nocturia. However, the administration oftamsulosin hydrochloride alone and in combination with pollen extractappearedmore effective than the administration of pollen extract alone,

in patientswith urinary symptoms associatedwith BPH [128]. The long-term efficacy, safety and the capacity of S. cereale pollen extract to pre-vent the complications of BPH are not known. One recent randomizedclinical trial indicated that the long-term administration of 750 mg ofCernilton (Prostate®) may improve the symptoms of BPH and preventits clinical progression better and faster than only 375 mg of the sameproduct [129]. A total of 240 patients who presented values of IPSSgreater than 7, were treated orallywith 750mg of Prostate® (Cernilton)for the first year and 375 mg for the next three. After the first year oftreatment with Cernilton, the volume of the prostate, the incidence ofurinary retention and the need for surgery were reduced. On the otherhand, many other parameters (i.e., IPSS, prostate volume, residualurine, post-urination, Qmax) improved only after 4 years of treatment[129]. However, no adverse effects were observed. A previous multi-center, randomized clinical trial conducted versus placebo in 906 pa-tients with BPH, have highlighted that, after 6 months of treatment,Cernilton® has the same efficacy of alpha1-antagonists and 5alpha-reductase inhibitors in improving IPSS, QoL, Qmax and residual urine.This effect was greater in patients with a high IPSS baseline. Conversely,Cernilton® was less effective than 5alpha-reductase inhibitors in thereduction of prostate size [130]. The pollen extract is also efficaciousinmenwith inflammatory prostatitis and chronic pelvic pain syndromein improving total symptoms, pain and QoL, without significant side ef-fects [131]. The common side effects in using pollen extracts are of theallergic type,which includes respiratory reactions, skin hypersensitivity,and gastrointestinal symptoms [42,93].

S. repens

S. repens Small. is a small palm, of the Aricaceae family. It is alsoknown as Sabal serrulata, saw palmetto, Ju-zhong and Dwarf palm. Itshabitat is in West India and in the Southeastern part of the UnitedStates, especially in South Carolina, Florida, and Southern California.The drug consists of the dried ripe fruits; these drupes of soapy andunpleasant taste are similar to black olives which, in therapy, uses thelyposterolic extract. Traditional medicine describes the use of dwarfpalm since the 1800s for the treatment of a variety of problems of theprostate and, without any scientific evidences, for other indicationsincluding breast enlargement, sperm production, and sexual potency[132]. From the twentieth century, the fruit of Serenoa has beenrecommended by many urologists to treat difficulties in micturitionassociated with BPH, so that it became one of the 10 top-selling drugsin the United States [133]. Only in this country, in 2002, about 2.5million adults have been using saw palmetto [134].

Preclinical studies

The liposterolic extract of S. repens consists of a complex mixture oflong-chain alcohols, fatty acids and their glycerides (oleic, caprylic,myristic, lauric, stearic, palmitic, linoleic acids), carbohydrates (galac-tose, arabinose and uronic acid), phytosterols (beta-sitosterol, beta-sitosterol-3-O-glucoside, beta-sitosterol-3-O-diglucoside, campestrol,cycloartenol), flavonoids (isoquercetin, kaempferol-3-O-glucoside),resins, tannins, pigments, essential oils and organic acids (caffeic,chlorogenic and anthranilic acids) [133]. The SPE (sawpalmetto extract,also known as S. repens purified extract) contains predominantly satu-rated and unsaturated fatty acids (90%), amongwhich themain constit-uents are oleic and lauric acids; both representingmore than 50% of thecontent of SPE. In addition, there are also myristic, palmitic and linoleicacids [135]. It is thought that the phytosterols and free fatty acids are thepharmacologically active constituents. In vitro results suggest two prob-able mechanisms: the non-competitive inhibition of 5alpha-reductase(both isoforms and ), which leads to decreased prostatic DHT contentand inhibition of DHT binding to the androgen receptors, present in thecytosol of prostate cells [136]. The anti-androgenic effects of lipophilicextract also consist of inhibiting the 3-ketosteroid reductase responsible

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for the DHT conversion to another androgenic metabolite [137]. Inhibi-tion of 5alpha-reductase by Serenoa extract depends, at least in part, toits free fatty acid content. Currently, there are no accepted guidelines fora standardized content of saw palmetto extracts in commercial prod-ucts, even though the WHO has recommended that its compositionshould be 80–95% of fatty acids and sterols combined, or 85–95% offatty acids and more than 0.2% sterols [134]. In order to analyze thebinding affinity of fatty acids of SPE to various receptors (i.e., alpha1-adrenergic, muscarinic and dihydropyridine 1.4 calcium channels), itwas shown that fatty acids inhibited prazosin and isradipine binding,in the central nervous system, in a dose-dependentmanner. The affinityof oleic, linoleic and myristic acids for each receptor was higher thanthat of the SPE. The results suggest that the oleic and lauric acids antag-onize receptors in a non-competitive manner [138]. Another importantrole of the fatty acid content (with the exception of palmitic acid) isthe inhibition of both type 1 and 2 isoenzymes of 5alpha-reductase.This is the most noticeable effect of whole SPE, and occurs in a dose-dependent manner [138]. A stronger inhibition of 5alpha-reductase inprostate cancer cells was also found when Serenoa berry extract wasassociated with astaxanthin (carotenoid) [139]. The inhibition of bothtypes of 5alpha-reductase was also confirmed by other studies, even ifwith very different potencies. The high variability in commercial prod-ucts appeared due to different extraction processes that lead to qualita-tive and quantitative differences in the active ingredients [140,141]. Inorder to obtain reproducible biological activity, the standardization ofevery product in the commercial processing is consequently necessary.Additionally in 5alpha-reductase inhibition, Serenoa seems to have anti-inflammatory effects by inhibiting the synthesis of pro-inflammatorymetabolites of arachidonic acid, through the blockade of COX and5alpha-lipoxygenase enzymes [136] and by modulating the expressionof inflammation related-genes [142]. A spasmolytic action on bladdermuscle has been also reported, by blocking calciumchannels, by activat-ing the Na+/Ca2+ exchanger [43], and through the antagonism ofacetylcholine-induced contraction [143]. All thesemechanisms supportthe clinical effectiveness of the SPE for the treatment of lower urinarytract symptoms, as they lead to significant relief of urodynamic symp-toms, increasing bladder capacity and extension of the time of urination[144]. Othermechanisms of action of SPE include: inhibition of estrogennuclear receptors and growth factors involved in prostate cell prolifera-tion (EGF, FGF), anti-edematous effects and alpha-adrenergic receptorblockade through a non-competitive antagonism [133]. About the lasteffect, unexpectedly, it has also been reported that Serenoa stimulatesnoradrenaline release causing the contraction of the prostate smoothmuscle. This sympathomimetic effect could be due to the constitutivepresence of some amines, even if it is not been confirmed neitherin vivo, nor in clinical trials probably because of the metabolism ofthese substances by hepatic enzymes [145]. Several studies havefound that SPE suppresses the growth and induces the apoptosis ofprostatic epithelial cells, by inhibition of signal transduction pathwaysIGF1-activated and through the inactivation of the STAT 3 signals[146]. An increase in the Bax/Bcl-2 ratio, caspase-3 activity and expres-sion of p53 protein and a decrease in the expression of p21 and p27 pro-teins appear to be also involved [147,148]. However, contrastingevidence regarding apoptosis has been reported, as the reduction ofprostate size was achieved only at high doses [132,149]. Regarding thesafety of Serenoa, an in vivo study has shown no signs of liver toxicity[150] and no significant differences in body weight, enzymatic activityand levels of malondialdehyde, compared to placebo [150]. In order toincrease the therapeutic activity in BPH, S. repens is frequently associat-edwith lycopene and selenium (an element able to promote an optimalantioxidant/oxidant balance). An association containing lycopene, sele-nium and S. repens, commercialized as a dietary supplement namedProfluss®, has been studied in vitro and in vivo for its efficacy in BPH.An inhibition of COX-2, 5-lipoxygenase, inducible nitric oxide synthase,and a reduction of NF- B andmRNA that synthetize TNF-alpha, has beenfound. The association of lycopene, selenium and S. repens had more

powerful anti-inflammatory and antiproliferative effects, compared toeither compound alone, in reducing prostate weight and hyperplasia,in the suppression of cell proliferation induced by various growthfactors (e.g., EGF, VEGF, TNF-alpha) [151], and in promoting apoptosis[152].

Clinical studies

In relation to the clinical efficacy, S. repens seems useful in the treat-ment of mild and moderate BPH if patients are treated with standard-ized products (90% free fatty acids), at a dose of 160 mg twice daily,for at least three months [132]. On the other hand, it is contraindicatedin advanced BPH with severe urinary retention and should not be usedwithout consulting the physician [133]. The clinical efficacy of S. repensappeared superior to placebo and comparable to 5alpha-reductaseinhibitors and alpha1-antagonists. Various studies are discussed below.

A meta-analysis of 18 controlled clinical studies conducted forperiods ranging from 4 to 48 weeks, showed the therapeutic efficacyof Serenoa extracts to be significantly superior to placebo and identicalto finasteride [153]. Favorable effects on IPSS, LUTS, urine flow, nocturiaand dysuria, have been also reported [154]. However, other studies havenot reached the same conclusion, pointing negative results on theimprovement of urinary symptoms associated with BPH [134]. Further-more, S. repens does not seem to reduce prostate size and urinary flowmeasures [155], nor change the levels of prostate-specific antigen(PSA), testosterone, DHT, follicle stimulating hormone (FSH), estradiol,and luteinizing hormone (LH) [133,156].

Compared to finasteride (5 mg/g), S. repens (320 mg/day) producessimilar improvements in urinary flow, IPSS, and quality of life. Finaste-ride seemed to have a slightly higher effect on the peak urinary flow,whereas saw palmetto extract affected libido and impotence in a signif-icantly lower manner [157].

As regards the alpha1-antagonists, Serenoa seems to have compara-ble efficacy to tamsulosin in improving bladder function [17]. On theother hand, the efficacy of prazosin in improving urine flows, micturi-tion nocturnal frequency and post-void residual volume appeared supe-rior than that of saw palmetto [149]. The combination therapies ofSerenoa with tamsulosin and Serenoa with lycopene, selenium andtamsulosin increase Qmax and decrease IPSS, resulting to be moreeffective than the single therapies [158,159].

As mentioned above, it is noteworthy that Serenoa is often associat-ed with other medicinal plant extracts and/or elements, and a lot ofclinical studies have been confirming its efficacy in improving themaximum urine flow, urinary resistance, IPSS score, quality of life,pain, urgency and nocturia [160–164]. These studies regard combina-tions as: Prostataplex® (Serenoa plus vitamin A, plant sterols, lycopene,pumpkin seedoil, palmoil and selenium) [160], amixture of 320mg/dieof Serenoa and 240 mg/die of nettle root extracts [161], IPB-tre®(320 mg of S. repens, 120 mg of Urtica dioica and 5 mg of P. pinaster)[162], Pluvio® (160 mg of fluid lipid-sterolic extract of S. repensstandardized in 85% of fatty acids, 300 mg of dry extract of U. dioicastandardized in 0.8% of β-sitosterol, 167 mg of avocado and soyastandardized in 30% of phytosterols, 1mg of vitamin B1, 5mg of vitaminE and 7.5 mg of zinc) [163] and Profluss® (5 mg of lycopene, 50 μg ofselenium and 320 mg of S. repens oil extract) [164].

The randomized studies compared with placebo (320 patients;30 days–1 year) [162], finasteride (543 patients; 48 weeks) [161],watchful waiting (120 patients; 6 months) [163], and Serenoa alone(108 patients; 8 weeks) [164] have been reporting either positive re-sults in the reduction of prostate volume [160,162,163] or improvementin menwith LUTS associatedwith BPH or chronic nonbacterial prostati-tis [160–164]; although conflicting results have been found about theireffect on PSA level [163,164]. Regarding the safety of the associationsmentioned above, most of the studies have reported no serious and/ormedium side effects [156,162,163,164].

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Recently, an association of S. repens, Pinus massoniana bark extract(PMBE) and Crocus sativus (named IDIProst® Gold), has been shownto better improve urinary and sexual function when compared withS. repens alone [165]. Probably, the association of PMBE and Crocussativus to Serenoa produced a synergistic effect due to pharmacologicalproperties of the other medicinal plants, including: nitric oxide activity,antioxidant effect and free radical scavenging properties of PMBE, in-crease of eNOS activity and promotion of the diffusion of oxygen intotissues induced by C. sativus [165].

The adverse effects of Serenoa are generally mild and include head-ache, decreased libido, sexual dysfunction, ejaculation disorders andgastrointestinal problems (especially nausea and diarrhea if ingestedon an empty stomach or in large amounts, respectively) [17,133,153].The effects involving the sexual sphere are probably due to the Serenoaaction on 5alpha-reductase. Urinary tract infections, ejaculation prob-lems and impotence have been reported in 2% of patients treated inthe long-term with the dwarf palm, but in all cases its tolerability wasbetter than finasteride [133]. However, other studies have demonstrat-ed no negative impact onmale sexual function [166] and do not supportthe relationship between serious clinical adverse effects and the use ofdwarf palm extract [167]. The confirmation is given also by theCAMUS trial that showed no evidence of toxicity of sawpalmetto extractused at doses up to 3 times the usual clinical dose (160 mg, 2 times aday) during an 18-month period [168].

Other case reports of greater severity were reported in the literature,including: high risk of bleeding, hepatitis and pancreatitis. In particular,cases of hematuria and coagulopathy in patients taking Serenoawere re-ported [169], and a case of significant bleeding in aman hospitalized forsurgery of meningiomas [170]. However, Serenoa did not interfere inplatelet aggregation and there are no data about the increase of pro-thrombin time (PT) or partial thromboplastin time (PTT) [171]. Regard-ing the probable implication of Serenoa in acute hepatitis and pancreati-tis, a case of a 55 year oldmanwho had taken Serenoa intermittently forabout 4 years has been reported [172]. A second case of a 65 year oldman who had started, a week before, a treatment with saw palmetto(160 mg, 2 times a day) for difficulty in urination has documentedacute pancreatitis [173]. A case of liver injury (cholestasis and fattyliver) in a 58 year old male who had taken during the previous week aS. repens commercial preparation (900mgdry extract/day) has been re-ported [174]. The enrollment of specific patients in clinical trials, doesnot allow having unique information about potential drug interactions;among the exclusion criteria are men treated with alpha-blockers, di-uretics and other drugs [133]. Among the possible pharmacodynamicinteractions, an increase in bleeding time for the use of inhibitors ofCOX-2 and aspirin has been reported [97]. In addition, given its mecha-nism of action, S. repens can theoretically interact with all hormonaltherapies [43]. It is worth mentioning that S. repens was part of themedicinal plants present in PC SPES, sold in the United States for“prostate health”. In 2002, the California Department of Health Servicesreported that different lots of the product, in addition to presenting highvariability in the concentrations of its components were contaminatedby indomethacin, warfarin, alprazolam and diethylstilbestrol [175].Healthcare professionals should therefore carefully evaluate the qualityof herbal products, before recommending them to a patient.

Urtica dioica

U. dioica L. belongs to the Urticaceae family. It is also known by thenames of stinging nettle, common nettle and ortiga. It is a thorny herba-ceous plant that commonly grows all over the world, in regions wherethe climate is humid and temperate. The drug used in BPH is madefrom the roots, but fresh and dried flower parts are traditionally usedfor other purposes, such as joint pain and urinary tract infections andas diuretics. For external use the nettle is used as a remedy for hairloss, against seborrhea and dandruff of the scalp [38]. U. dioica hasbeen ranked among the 16 most commonly used medicinal plants in

the North of the Iberian Peninsula. Traditionally, it is used as adepurative, for acne, diarrhea and diabetes, and to improve circulationand low blood pressure [176].

Preclinical studies

The leaves contain sterols (beta-sitosterol, hydroxy-sitosterol),flavonoids (rutin, kaempferol, quercetin), minerals (calcium,potassium), tannins, acids (salicylic, malic acids) and amines(histamine) [43]. It has been reported that, in the root, theelements that are particularly important are lectines (mixtureof isolectines from 0.2 to 0.6%), polysaccharides (glucans,glucogalacturonans, arabinogalactan acid), hydroxycoumarins(scopoletin), ceramides, lignans (secoisolariciresinol-9-O-gluco-side, (−)-3,4-divanililtetraidrofuran, neo-olivile), sterols andtheir glycosides (beta-sitosterol, stigmasterol, campesterol),phenols (p-hydroxy benzaldehyde), monoterpendiols and theirglycosides, fatty triterpene, phenylpropane (homovanillyl alcoholand its 41-O-glycoside) [177].

In the treatment of BPH, a number of mechanisms of action of theroot have been postulated, including light diuretic and potent anti-inflammatory activities probably due to the presence of scopoletin.The root extract, in vitro, inhibits the binding of the sex hormone bind-ing globulin (SHBG) to its receptor in themembrane of the humanpros-tatic cells. The SHBG has the function of regulating the concentration offree androgens and estrogens in the plasma, and interference at itsreceptors on the membrane of prostate cells, would prevent thesehormones to interact, themselves, with their receptors [178]. Thelignans contained in the stinging nettle seem to have a high affinityfor SHBG [38]. The polysaccharides and lectins can block the bindingbetween the epidermal growth factor, secreted by the prostate tissue,and its receptors, with suppression of prostate cellular metabolismand its growth [43]. In addition, the lectines may contribute to theprostatic anti-proliferative and anti-inflammatory activities [38]. Thepolysaccharides stimulate the activity of T lymphocytes and the com-plement activation [179]. Both malic and caffeic acids show anti-inflammatory activity, in vitro and in vivo, through inhibition of COXand lipoxygenase. The nettle extract inhibits TNF activity [180], prostatecell proliferation [181], and aromatase activity [182]. The aqueous ex-tract of the leaves of the stinging nettle inhibits the activity of adenosinedeaminase (ADA), the key enzyme in nucleotide metabolism. Theinhibition is dose-dependent and it might be one of the mechanismsthat lead to improvements of the patients' symptoms [183].

Animal studies indicate that U. dioica inhibits markedly plateletaggregation and improves the lipid profile; the constituents responsiblefor this potent effect seem to be the flavonoids [184,185]. It was alsofound that the methanol extract of the stinging nettle significantlyinhibited the prostate growth induced experimentally [186,187]. Urticaseems to inhibit 5alpha-reductase activity, probably due to the presenceof scopoletin and beta-sitosterol, at least in vivo [188].

Clinical studies

A clinical study, randomized and double-blind, compared to placeboanalyzed the effect of U. dioica root aqueous extract (120 mg, 3 times/day). The results showed a significant improvement in LUTS, Qmax,and IPSS, after sixth months of treatment. These improvements werealso maintained after 18 months of treatment [189]. No significantdifference was observed between the groups in the levels of PSA andtestosterone, but the treated group showed a moderate reduction ofthe prostate size [189]. Another study carried out with a higher dosageof Urtica (459 mg), did not confirm the previous finding [190].

Other randomized trials have evaluated the effects of an associationcalled PRO 160/120 consisting in 160 mg of S. repens standardized fruitextract and 120 mg of U. dioica root extract. A total of 257 patients withmoderate and severe symptoms were treated with PRO 160/120 or

51O. Allkanjari, A. Vitalone / Life Sciences 126 (2015) 42–56

placebo (one capsule, 2 times a day, for six months). The efficacy of thetreatment was superior to placebo for attenuation of inflammatory andobstructive symptoms [191]. The same combination was tested on 140patients, for fifteen months, and was compared with tamsulosin(0.4 mg/day). This study found the effectiveness of PRO 160/120 andtamsulosin in the treatment of LUTS caused by BPH, and both treat-ments were well tolerated [192]. Another randomized, double-blindstudy, confirms the effectiveness and tolerability of PRO 160/120 versusfinasteride in increasing urine flow, improving symptoms related tobladder emptying, but not in reducing the prostate volume [193]. Thenettle (300 mg) has also been evaluated in combination withP. africanum (25 mg), in six months of treatment and no significantdifferences were found in various parameters (i.e., IPSS, QoL, Qmax)and clinical improvement [194].

The nettle extract is generally well tolerated [189] andmay result inonly occasionally mild gastrointestinal effects. There have been reportsof diarrhea and respiratory system diseases of moderate intensity, butthe effects do not differ from those observed in the placebo [191].Edema and urticaria related to allergic reactions induced by the planthave been rarely reported [38]. U. dioica contains tannins, which caninteract with a concomitant intake of iron, causing a reduction of theeffects in patients who need iron supplements. It is therefore, recom-mended to separate the times of administration of these componentsfor at least 2 h [38].

Other medicinal plants (less) used in BPH

Other numerous medicinal plants have been proposed in thetreatment of benign prostatic hyperplasia-related symptoms, includingthe following: Zea mays (cornsilk), Allium sativum (garlic), Echinaceaspp., Althea officinalis (marshmallow), Equisetum arvense (horsetail),Lactuca scariola, Asteracantha longifolia, Argyreia speciosa and Parmelliaperlata for their antimicrobial activity, which is helpful in preventingchronic urinary infections [42, 195]; Arctostaphylos uva-ursi (uva-ursi)in the treatment of prostatitis; Opuntia ficus-indica (prickly pear) usefulin controlling prostate enlargement for its antioxidant and antiprolifer-ative activities on prostate cells [42,196]; Curculigo orchioides (blackmusli) for dysuria and polyuria, and in the management of prostaticenlargement [195]; Telfairia occidentalis for the inhibition of hormonalinduction of BPH [197]; Mucuna pruriens for its anti-inflammatorycapacity in various prostatic affections; Vaccaria segetalis for ameliorat-ing prostate pathomorphology and prostatic and testicular indexes[198]; etc. These medicinal plants and many others are of growingrecent scientific interest [199]. Most of the mentioned herbal remediesare probably more effective for prevention and/or for the treatment ofBPH-related symptoms, rather than for a direct effect on the prostategland. Moreover, the active ingredients and biochemical mechanismof action of some of the abovementioned plants still need investigation,and their clinical value is still unknown.

An overview of the medicinal plants described in this review isreported in Table 1.

Conclusions and perspective

Depending on the severity of the disease, the various treatment op-tions currently available are: watchful waiting, drug therapy, surgeryand the use of medicinal plants. Although drug therapy (alpha1-blockers, inhibitors of 5alpha-reductase) and surgery (prostatectomy,transurethral resection, etc.) seem to be the most effective choices forpatients with moderate to severe BPH, herbal medicine can be usefulin patients with mild to moderate symptoms. Medicinal plants mostcommonly used in BPH are: S. repens Small. (Arecaceae Family),P. africanum Hook (Rosaceae family), U. dioica L. (Urticaceae family),C. pepo L. (Cucurbitaceae family), Epilobium spp. L. (Onagraceae family),S. cereale L. (Graminaceae family), H. rooperi Moore (Hypoxidaceaefamily), R. regia Cook (Arecaceae family), P. pinaster Sol (Pinaceae

family) and L. esculentumMill. (Solanaceae family). The last twomedic-inal plants are primarily used for their extraction products, β-sitosteroland lycopene respectively. S. repens, P. africanum, Curcubita pepo, andU. dioica are the most prevalent plants used to treat BPH. The variousextraction procedures of plant based medicines, the different drugsused and their mechanism of action (sometimes poorly characterized),make difficult the comparison between the various products. At thesame time, whether in vitro or in vivo studies have reported some phar-macological actions of certain active substances, this does not necessar-ily mean that the same substances have beneficial effects in clinicalpractice. However, there is emerging evidence that various plant ex-tracts are well tolerated and allow for obtaining an improvement inthe symptoms BPH-related. S. repens in human studies shows an effec-tiveness higher than that of placebo, equivalent to tamsulosin and incombination with U. dioica reveals effects equal to finasteride in im-proving symptoms of lower urinary tract and with lesser side effects.Regarding the safety of Serenoa, gastrointestinal problems, headache,liver disease, pancreatitis, and sexual dysfunction have been reported.P. africanum as Serenoa is registered (at least in Italy) as a phytotherapicmedicine, and moderate evidence indicates that its use improves theparameters of the urinary stream. Pygeum seems a safe drug. U. dioicashows promising efficacy that is higher if it is taken in combinationwith othermedicinal plants and nutraceuticals such as Serenoa, pine, ly-copene, etc. The effectiveness of C. pepo is based on preliminary data andfurther confirmation is needed, especially in relation to long-term ef-fects. Pumpkin is safe enough except for some evidence which adviceagainst its associationwith anticoagulants. Because of the lack of clinicaltrials on the use of the various species of Epilobium, no data are currentlyavailable on its effectiveness and safety; although in experimental stud-ies they did not induce a particular toxicity. S. cereale seems effective inurinary symptomsof BPH, but its effects have to be confirmed by clinicalevidence. In relation to its adverse effects abdominal pain, nauseaand hypersensitivity, were found. Very limited data are availableabout the clinical use of H. rooperi and R. regia. Regarding lycopene,recent research confirms its ability in the prevention and progressionof BPH; the mechanisms of action could possibly be proposed in theprevention of adenocarcinoma. Furthermore, the effectiveness oftomato extract seems higher than that of lycopene alone. The tomatoconsumed in normal quantities of a Mediterranean diet can beconsidered, in the absence of specific allergic symptoms, a safe food.Regarding associationwith plants, they seem to be more effective thanthe plants alone; however, the use of a multi-component productdoes not play in favor of safety. Z. mays (cornsilk), A. sativum (garlic),Echinacea spp., A. officinalis (marshmallow), E. arvense (horsetail),L. scariola, A. longifolia, P. perlata, A. uva-ursi (uva-ursi), O. ficus-indica(prickly pear), C. orchioides (black musli), T. occidentalis, V. segatalisand many other plants are of growing scientific interest in the field ofBPH phytotherapy, but nowadays most of them result to be more effec-tive in the prevention and/or the treatment of BPH-related symptoms,rather than its effect on prostate gland enlargement. However, the effectobtainedwith drugs (as pure chemicals) is reached atmuch lower dosesthan those needed to obtain the same effect with the use of aphytocomplex. Moreover, regarding other plants, many products arenot standardized and, data relating to their safety are not always avail-able and their clinical efficacy is generally based on a short durationtreatment of a small number of patients. It should be also important toremember that in many cases the analytical, pharmacological and clin-ical markers are unknown, and the effects of some herbal productscould be unforeseeable. This disadvantage, along with thatphytotherapy usually requires at least fewweeks before to have any ef-ficacy, should be taken into account in the choice of treatment. In con-clusion, because of the impact of BPH symptoms on health and QoL, abetter communication between the patient and his doctor allows to fa-cilitate the diagnosis and to personalize the treatment, and healthcareprofessionals should try to be constantly informed about the possiblerisks and benefits of BPH herbal medicine.

Table 1Medicinal plants used in the treatment of benign prostatic hyperplasia, their mechanism of action, and clinical safety and efficacy (if known).

Botanical name(common name)

Postulated mechanism/s of action Clinicalefficacy

Safety

Cucurbita pepo(pumpkin, dubba)

Inhibition of DHT binding to the androgen receptor5alpha-reductase inhibition

+1 +

Epilobium spp.(willow herb)

Radical-scavenger and anti-oxidant activityAnti-androgenic activityAnti-inflammatory activityAnti-proliferative activityAnalgesic property

ND2 ND

Hypoxis rooperi(African potato, yellow star)

Anti-proliferative activityAnti-inflammatory activityRadical-scavenger activity

ND ND

Lycopersicum esculentum(tomato)

Anti-proliferative and pro-apoptotic activitiesOwn-regulation of 5alpha-reductaseAnti-oxidant activityAnti-inflammatory activity

ND ++3

Pinus pinaster(maritime pine)

Anti-proliferative activity +/−4 +/−

Pygeum africanum(prunus africanus, african cherry)

Inhibition of nuclear translocation of the androgen receptorInhibition of cell proliferationPro-apoptotic activityAnti-inflammatory activityAnti-oxidant activity

++ ++

Roystonea regia(palm criollo, vakka)

5alpha-reductase inhibitionAlpha1-adrenoceptor antagonismAntioxidant activity

ND ND

Secale cereale(common rye, rye pollen)

5alpha-reductase inhibitionPro-apoptotic activityAlpha-adrenergic receptor blockageAnti-inflammatory activitySpasmolytic activity

ND ++

Serenoa repens(Sabal serrulata, saw palmetto)

5alpha-reductase inhibitionInhibition of DHT binding to androgen receptorsAnti-inflammatory activitySpasmolytic activityAnti-proliferative activitySympathomimetic effectsAlpha1-adrenoceptor antagonism

++ +

Urtica dioica(stinging nettle, ortiga)

Anti-proliferative activityAnti-inflammatory activityInhibition of SHBGInhibition of aromatase

+ +

Zea mays (cornsilk), Allium sativum (garlic), Echinacea spp., Althea officinalis(marshmallow), Equisetum arvense (horsetail), Lactuca scariola,Asteracantha longifolia, Parmellia perlata, Arctostaphylos uva-ursi (uva-ursi),Opuntia ficus-indica (prickly pear), Curculigo orchioides (black musli),Telfairia occidentalis, Vaccaria segatalis.

Antimicrobial activityAnti-oxidant activityAnti-proliferative activityAnti-androgenic activityAnti-inflammatory activity

ND ND

1 : Efficacious/safe.2 : Not determined.3 : Very efficacious and/or very safe.4 : Contrasting evidences.

52 O. Allkanjari, A. Vitalone / Life Sciences 126 (2015) 42–56

Conflict of interest statement

The authors declare that there are no conflicts of interest.

Acknowledgments

This study was supported by the “Enrico and Enrica Sovena Founda-tion”, Rome, Italy.

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