Serenoa repens (Permixon®)
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Serenoa repens (Permixon®)1 has been available for several years for the treatment of men with benign prostatic hyperplasia (BPH). The drug is the n-hexane lipidosterolic extract of the dwarf American palm (also known as Serenoa repens ) and is a complex mixture of various compounds. A number of pharmacodynamic effects have been demonstrated with the lipidosterolic extract of Serenoa repens (LSESR), suggesting multiple mechanisms of action including in vitro inhibition of both type 1 and type 2 isoenzymes of 5α-reductase and interference with binding of dihydrotestosterone to cytosolic androgen receptors in prostate cells.
In controlled clinical trials in men with BPH, oral administration of Serenoa repens 160mg twice daily for 1 to 3 months was generally superior to placebo in improving subjective symptoms, such as dysuria, as well as objective parameters. The frequency of nocturia was reduced by 33 to 74%, while urinary frequency during the day decreased by 11 to 43% and peak urinary flow rate increased by 26 to 50% with Serenoa repens. Corresponding values for placebo were 13 to 39%, 1 to 29% and 2 to 35%. The only large comparative trial conducted to date, in which >1000 men with moderate BPH were randomised to receive Serenoa repens 160mg twice daily or finasteride 5mg once daily for 6 months, demonstrated similar efficacy between the two drugs. No statistically significant difference was demonstrated between treatment groups for improvement in patient self-rated quality-of-life scores and the primary end-point of objective symptom score; International Prostate Symptom Score improved by 37% with Serenoa repens compared with 39% with finasteride. In much smaller comparative trials, few significant differences were demonstrated between Serenoa repens and α1-receptor antagonists, and larger randomised trials of adequate duration are required to better compare the clinical efficacy of these drugs. The most frequently reported adverse events in clinical trials with Serenoa repens have been minor gastrointestinal problems (e.g. nausea and abdominal pain).
In conclusion, Serenoa repens is well tolerated and has greater efficacy than placebo and similar efficacy to finasteride in improving symptoms in men with BPH. Although there is a need for further comparative studies, particularly with α1-receptor antagonists, available data indicate that Serenoa repens is a useful alternative to α1-receptor antagonists and finasteride in the treatment of men with BPH.
The precise mechanism of action of Serenoa repens has not been fully elucidated; however, important in vitro effects of the lipidosterolic extract of Serenoa repens (LSESR) include inhibition of 5α-reductase, the enzyme responsible for conversion of testosterone to dihydrotestosterone (DHT), and inhibition of binding of DHT to androgen receptors in the cytosolic component of prostate cells. Two 5α-reductase isoenzymes, type 1 and 2, appear to be expressed by cultured human prostate cells. Although there is some controversy whether the type 1 isoenzyme is expressed, it is generally agreed that the type 2 isoenzyme predominates. LSESR has been shown to inhibit both isoenzymes in a eukaryotic expression system, whereas finasteride primarily inhibits 5α-reductase type 2. LSESR also inhibited binding of the ligand [ H]methyltrienolone to androgen receptors in the cytosolic component of rat prostate cells and inhibited binding of [ H]DHT to its receptor in human foreskin fibroblasts.
Data from other in vitro studies and in vivo trials conducted in various animal models suggest additional mechanisms by which the drug may exert its effects. These include inhibition of prolactin- and growth factor-induced prostatic cell proliferation, an antioedematous effect and interference with mediators of inflammation.
Studies in men with benign prostatic hyperplasia (BPH) receiving Serenoa repens 320 mg/day for 3 months also suggest an antiestrogenic effect of the drug, and a comparative trial demonstrated reductions in prostatic tissue levels of DHT similar to those observed with finasteride 5 mg/day.
Limited pharmacokinetic data are available for Serenoa repens, primarily because the drug is a complex mixture of several compounds. In healthy young men, mean peak plasma drug concentration (second component; retention time 26.4 minutes on high performance liquid chromatography assay) was 2.6 mg/L and time to achieve peak concentration was 1.5 hours after oral administration of Serenoa repens 320mg. Elimination half-life was 1.9 hours and mean value of area under the concentration versus time curve was 8.2 mg/L • h. Tissue distribution studies in the rat indicate that the drug achieved higher concentrations in the prostate gland than the liver or genitourinary tissues other than the prostate.
The effects of Serenoa repens 160mg twice daily on urinary frequency and peak urinary flow rate were superior to placebo in 3 of 4 larger (i.e. >50 patients) controlled clinical trials lasting 1 to 3 months in men with BPH. Serenoa repens was associated with reductions in urinary frequency at night ranging from 33 to 74% (13 to 39% with placebo) and urinary frequency during the day ranging from 11 to 43% (1 to 29% with placebo); peak urinary flow rate was increased by 26 to 50% (2 to 35% with placebo) in placebo-controlled trials. Some studies evaluated additional parameters and demonstrated that Serenoa repens was more effective than placebo in improving dysuria (difficult or painful urination), reducing postmicturition residual urinary volume and improving subjective symptoms of BPH according to patient and physician global assessment.
Clinical efficacy of Serenoa repens 160mg twice daily was compared with that of finasteride 5mg once daily for 6 months in a large randomised double-blind study. The study was conducted in 9 European countries and is the largest international trial comparing 2 drugs in the treatment of men with BPH. Intention-to-treat analysis included 1069 men with moderate BPH and demonstrated similar results between treatment groups. At the end of the treatment period, symptoms [as assessed using the well-accepted International Prostate Symptom Score (I-PSS)] were reduced by 37% among Serenoa repens recipients compared with 39% among finasteride recipients, and the difference between treatment groups was not statistically significant. A marked improvement in patient self-rated quality-of-life scores was noted with both Serenoa repens and finasteride (69 vs 73%; no statistically significant difference between groups). Results of a separate questionnaire demonstrated that Serenoa repens produced a modest improvement in sexual function score, whereas a deterioration was reported with finasteride, and the difference between treatment groups achieved statistical significance. Both drugs improved peak urinary flow rates and reduced prostate volume, although changes were significantly greater with finasteride. However, the proportion of patients with a 30% or 3 ml/sec increase in peak urinary flow rate was similar between treatment groups. Unlike finasteride, Serenoa repens did not significantly affect serum prostate specific antigen (PSA) levels.
In two smaller comparative trials, Serenoa repens 160mg twice daily and α1-receptor antagonists improved overall symptoms, reduced urinary frequency and postmicturition residual urine volume and increased urinary flow rate. In general, clinical efficacy tended to favour the α1-receptor antagonists (alfuzosin 2.5mg 3 times daily and prazosin titrated to 2mg every 12 hours); however, few significant differences were observed between treatment groups. Moreover, studies included relatively small numbers of patients and one of the trials was only 3 weeks in duration.
In general, Serenoa repens is well tolerated, with only 2% of patients spontaneously reporting adverse events in a large noncomparative trial of 500 men with BPH receiving the drug for 3 months. Similar results were noted in smaller placebo-controlled trials, and discontinuation of Serenoa repens because of poor tolerability occurred only rarely. The most common adverse events in clinical trials have been minor gastrointestinal complaints, such as nausea and abdominal pain. In a large comparative trial with finasteride, Serenoa repens tended to be associated with a higher incidence of hypertension, headache, urinary retention and back pain, whereas gastrointestinal complaints, impotence, dysuria and decreased libido tended to be more frequently reported among men receiving finasteride. Clinically significant changes in laboratory parameters did not occur with Serenoa repens in clinical trials.
Dosage and Administration
For the treatment of men with BPH the recommended dosage of Serenoa repens is 160mg twice daily by oral administration. The drug should be taken with morning and evening meals to minimise possible gastrointestinal disturbances.
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