Lipido-sterolic extract of Serenoa repens (LSESr, Permixon) treatment affects human prostate cancer cell membrane organization.

The molecular mechanism by which the lipido-sterolic extract of Serenoa repens (LSESr, Permixon) affects prostate cells remains to be fully elucidated. In androgen-independent PC3 prostate cancer cells, the LSESr-induced effects on proliferation and apoptosis were evaluated by counting cells and using a FACScan cytofluorimeter. PC3 cells were stained with JC-1 dye to detect mitochondrial membrane potential. Cell membrane lipid composition was evaluated by thin layer chromatography and gas chromatographic analysis. Akt phosphorylation was analyzed by Western blotting and cellular ultrastructure through electron microscopy. LSESr (12.5 and 25 microg/ml) administration exerted a biphasic action by both inhibiting proliferation and stimulating apoptosis. After 1 h, it caused a marked reduction in the mitochondrial potential, decreased cholesterol content and modified phospholipid composition. A decrease in phosphatidylinositol-4,5-bisphosphate (PIP2) level was coupled with reduced Akt phosphorylation. After 24 h, all of these effects were restored to pre-treatment conditions; however, the saturated (SFA)/unsaturated fatty acid (UFA) ratio increased, mainly due to a significant decrease in omega 6 content. The reduction in cholesterol content could be responsible for both membrane raft disruption and redistribution of signaling complexes, allowing for a decrease of PIP2 levels, reduction of Akt phosphorylation and apoptosis induction. The decrease in omega 6 content appears to be responsible for the prolonged and more consistent increase in the apoptosis rate and inhibition of proliferation observed after 2-3 days of LSESr treatment. In conclusion, LSESr administration results in complex changes in cell membrane organization and fluidity of prostate cancer cells that have progressed to hormone-independent status.

Effects of long-term treatment with Serenoa repens (Permixon) on the concentrations and regional distribution of androgens and epidermal growth factor in benign prostatic hyperplasia.

BACKGROUND: The n-hexane lipido-sterol extract of Serenoa repens (LSESr, Permixon, Pierre Fabre Medicament, Castres, France), a phytotherapeutic agent used in the treatment of benign prostatic hyperplasia (BPH), has a multisite mechanism of action including inhibition of types 1 and 2 5alpha-reductase and competitive binding to androgen receptors in prostatic cells. Here, the response of testosterone (T), dihydrotestosterone (DHT), and epidermal growth factor (EGF) in BPH tissue of patients treated with LSESr (320 mg/day for 3 months) is analyzed. METHODS: BPH samples were sectioned in periurethral, subcapsular, and intermediate regions: in each region T, DHT, and EGF were determined by radioimmunoassay after purification on celite columns or Sep-pak C18 cartridges. RESULTS: In the untreated group, T, DHT, and EGF presented the highest concentrations in the periurethral region (615 +/- 62 (SE) pg/g tissue, 7,317 +/- 551 pg/g tissue, and 20.9 +/- 3.3 ng/g tissue, respectively) with respect to the peripheral subcapsular region (425 +/- 45 pg/g tissue, 4,215 +/- 561 pg/g tissue, and 10.8 +/- 1.4 ng/g tissue, respectively). In the LSESr-treated group, a statistically significant reduction was observed, mainly in the periurethral region of DHT (2,363 +/- 553 pg/g tissue, P < 0.001) and EGF (6.98 +/- 2.48 ng/g tissue, P < 0.01), with increased T values (1,023 +/- 101 pg/g tissue, P < 0.001). CONCLUSIONS: The decrease of DHT and the rise of T in BPH tissue of patients treated with Permixon confirms the capacity of this drug to inhibit in vivo 5alpha-reductase in human pathological prostate. A marked decrease of EGF, associated with DHT reduction, was also observed. These biochemical effects, similar to those obtained with finasteride, are particularly evident in the periurethral region, whose enlargement is responsible for urinary obstruction, with respect to the subcapsular region. A possible speculation is that the preferential reduction of DHT and EGF content in the periurethral region is involved in the clinical improvement of the obstructive symptoms in BPH during LSESr therapy.

Effects of the lipidosterolic extract of Serenoa repens (Permixon) on human prostatic cell lines.

BACKGROUND: Permixon is a drug used in the treatment of benign prostatic hyperplasia. We studied its androgenic and antiandrogenic effects in the prostatic cell lines LNCaP and PC3, respectively responsive and unresponsive to androgen stimulation. METHODS: We performed FACScan analysis to investigate toxicity, 3H thymidine and 35S methionine incorporation to determine antiproliferative and metabolic effects, electron microscopy to study ultrastructural changes and cotransfection experiments to elucidate the role of wild type androgen receptor. RESULTS: In LNCaP cell line, Permixon induced a double proliferative/differentiative effect, not observed in PC3 cells. In PC3 cells cotransfected with wild-type androgen receptors and CAT reporter genes under the control of a androgen responsive element, the drug inhibited androgen-induced CAT transcription. CONCLUSIONS: Our data indicate a role of the androgen receptor in mediating the effects of Permixon in LNCaP cells. Cotransfection experiments in PC3 cells support a clear antiandrogenic action of the drug.

Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: a randomized international study of 1,098 patients.

BACKGROUND: Controversy regarding the relative efficacy of treatments for the relief of the symptoms of benign prostatic hyperplasia (BPH). METHODS: This was a 6-month double-blind randomized equivalence study that compared the effects of a plant extract (320 mg Permixon) with those of a 5 alpha-reductase inhibitor (5 mg finasteride) in 1,098 men with moderate BPH using the International Prostate Symptom Score (IPSS) as the primary end-point. RESULTS: Both Permixon and finasteride decreased the IPSS (-37% and -39%, respectively), improved quality of life (by 38 and 41%), and increased peak urinary flow rate (+25% and +30%, P = 0.035), with no statistical difference in the percent of responders with a 3 ml/sec improvement. Finasteride markedly decreased prostate volume (-18%) and serum PSA levels (-41%); Permixon improved symptoms with little effect on volume (-6%) and no change in PSA levels. Permixon fared better than finasteride in a sexual function questionnaire and gave rise to less complaints of decreased libido and impotence. CONCLUSIONS: Both treatments relieve the symptoms of BPH in about two-thirds of patients but, unlike finasteride, Permixon has little effect on so-called androgen-dependent parameters. This suggests that other pathways might also be involved in the symptomatology of BPH.

Comparative efficacy of sparfloxacin versus ciprofloxacin in the treatment of complicated urinary tract infection.

A total of 686 adult patients with complicated urinary tract infections were enrolled in a double-blind, randomised, multicentre study to compare sparfloxacin (200 mg loading dose on day 1 followed by 100 mg daily) with ciprofloxacin (500 mg orally twice daily) for 10 to 14 days. Urinary tract infection was defined as pyuria and bacteriuria (cfu > or = 10(5)/mL). Evaluations were performed at four time-points. The clinical efficacy of the two antibacterial agents was equivalent at the end of treatment: clinical cure in 88.6% of the intent-to-treat population and 87.3% in the evaluable population treated with sparfloxacin compared to 85.4% and 84.8% of the intent-to-treat and evaluable populations, respectively, treated with ciprofloxacin. The clinical results were also equivalent at follow-up. The bacteriological efficacy of the two agents was not equivalent. At the end of treatment, bacteriological cure was observed in 72.6% of the intent-to-treat and 72.1% of the evaluable populations treated with sparfloxacin and in 81.4% and 80.8% of the intent-to-treat and evaluable populations, respectively, treated with ciprofloxacin. The difference was primarily because of a higher number of persisting pathogens, which included Enterobacteriaceae other than Escherichia coli, Pseudomonas aeruginosa and enterococci, which exhibited moderate susceptibility to sparfloxacin. Tolerability was similar in the two treatment groups.

[Prevention of renal calculosis: efficacy of Fiuggi water cure. Research Group on Renal Calculosis]. / Profilassi della calcolosi renale: efficacia della terapia idropinica con l'acqua di Fiuggi. Gruppo di Ricerca per la Calcolosi Renale.

High fluid intake is the only nutritional modification that is universally agreed to be useful in all forms of nephrolithiasis. Particularly the use of oligomineral waters seems to be important as they can obtain a high urine volume with a low electrolytes concentration. The aim of this study was to evaluate the effects of an oligomineral water (Fiuggi) on some urinary parameters on different regimens of therapy. Out of 200 patients (118 M., 82 F., mean age 53 +/- 13 years), arrived to our outpatient Kidney Stone Center in Fiuggi, a random of 100 was submitted to water cure with more than 1500 ml/die of Fiuggi water for a period of 7 and 14 days, the other 100 patients to less than 1500 ml/die for the same periods. All the patients had a history of stone disease. Urinary values of calcium, phosphate, uric acid, magnesium, potassium, pH and density were measured in all groups of patients before and after water cure. Data were analyzed in unvaried method and were presented as mean +/- S.D. To evaluate the statistical differences between the values before and after therapy, the paired t test was used. Moreover, the percent changes of the considered parameters in relation to their basal values was considered. The 50-70% of all patients showed a reduction of the considered urinary parameters, with a statistical significance in patients who drunk more than 1500 ml of water. Urinary pH and Mg+/Ca++ ratio increased significantly in both groups of patients. The sex and the length of therapy didn't show any significant power on these results.

Chlamydia trachomatis genitourinary infections: laboratory diagnosis and therapeutic aspects. Evaluation of in vitro and in vivo effectiveness of azithromycin.

Chlamydia trachomatis (C.t.) cell culture represents a sensitive method for the diagnosis of chlamydial infection and the only one which makes it possible to determine the susceptibility of an isolate to antibiotics so that an appropriate drug can be selected for individual treatment. In 11 patients, affected by urethroprostatitis and suspected of treatment failure with standard drug regimens, either due to lack of compliance with therapy or antibiotic resistance, C.t. was isolated in McCoy cell culture from urethral swabs, after prostatic massage. The in vitro activity of azithromycin against these isolates and the in vivo efficacy of the drug in the patients treated with a single 1 g dose have been evaluated. All the C.t. strains tested were susceptible to the action of azithromycin (MIC range 0.125-1.0 microgram/ml). Bactericidal values were one dilution higher (MBC range 0.25-2.0 microgram/ml). These in vitro results are consistent with clinical observations as all the patients treated had negative culture at a 4-week follow-up visit.

Cost effectiveness in the management of benign prostatic hyperplasia: Italian data.

Several works in literature demonstrate that in some countries the economic considerations are as important as the clinical aspects of a disease; economic evaluation may be of help for decision making. The exact cost of the diagnosis and treatment of benign prostatic hypertrophy (BPH) patients is difficult to estimate. The total number of males in Italy is 27,982,144 (1991 data). In the last year 2,200,000 patients have been treated for BPH in Italy (surgically and pharmacologically); the overall cost for the therapy of BPH exceeded 46 million dollars per year. Currently surgery represents the standard treatment of BPH. In the USA alone over 350,000 surgical procedures are performed annually. In USA the cost per TURP is 12,000 dollars. In Italy the minimum direct cost is 3681 dollars; in most cases, however, the cost per TURP is over 5000 dollars. It is estimated that about 80% of patients with micturion problems prefer an alternative treatment before surgery. In our country 4,338,000 diagnoses of BPH have been performed in 1991. The number of prescriptions for BPH has been 4,867,000 and the number of drugs per prescription 1.16. It may be of interest to compare costs associated with different pharmacological therapies for BPH. Considering the direct costs, it has been estimated that the cost of 1 year's treatment with finasteride is 1833 dollars, while that of 1 year with plant extracts is 1151 dollars. The existing literature is deficient in defining the cost related to the therapeutical options for BPH.(ABSTRACT TRUNCATED AT 250 WORDS)

Plant extracts in BPH.

In Italy plant extracts represent 8.6% of all pharmacological prescriptions for Benign Prostatic Hyperplasia (data from 1991). This review evaluates all the suggested mechanisms of action for plant extracts. Recently we demonstrated an antiestrogenic effect of Serenoa Repens in BPH patients. Clinical trials with plant extracts have yielded conflicting results. In a recent review by Dreikorn and Richter, only five placebo controlled studies were found. Moreover, as opposed to chemically defined drugs, it is possible that for these extracts the active ingredients are not known; consequently pharmacodynamic and pharmacokinetic data are often missing. The International Consultation of Benign Prostatic Hyperplasia (Paris, June 1991) concluded that, to date, phytotherapeutic agents must be considered as a symptomatic treatment. Now more adequate pharmacological and clinical studies, placebo controlled, should determine the exact role of these drugs in the treatment of BPH.

[Pharmacological combinations in the treatment of benign prostatic hypertrophy]. / Associations pharmacologiques dans le traitement de l'hypertrophie prostatique bénigne.

In the development of the obstructive symptomatology of benign prostatic hypertrophy (BPH), two components may be identified, mechanical and dynamic. In the mechanical component, the interaction of a stromal and a epithelial compartment determines prostatic mass growth. The dynamic component involves smooth muscle tone in the prostate and urethra. The consideration that prostatic disease is not only epithelial in origin, but also stromal, leads to the association of an antiandrogen (which acts on the epithelial component) and an antiestrogen (active on the stromal component) in the medical therapy of BPH. In 1985 we carried out a randomized study on 256 BPH patients treated with Cyproterone acetate (CPA) plus Tamoxifen (TAM). Recently, we performed a multicenter double blind study on BPH patients treated with the association CPA plus Serenoa Repens. A statistically significant difference in prostate volume reduction between the groups treated with the combinations and those with the monotherapies was observed. The development of new compounds, such as 5 alpha reductase and aromatase inhibitors, consents to introduce a combination therapy with less side effects. A second pharmacological association may be obtained with drugs acting on the mechanical and others acting on the dynamic (alpha blockers) component of BPH. This combination may associate the early symptomatic effect of alpha blockers with the long term results of a 5 alpha reductase inhibitor, antiestrogen or aromatase inhibitor.

Evidence that Serenoa repens extract displays an antiestrogenic activity in prostatic tissue of benign prostatic hypertrophy patients.

A double-blind placebo-controlled study was performed in 35 benign prostatic hypertrophy (BPH) patients never treated before. The patients were randomized into two groups, the 1st (18 cases) receiving Serenoa repens extract (160 mg t.d.) for 3 months up to the day before the operation of transvesical adenomectomy and the 2nd (17 cases) receiving placebo. Steroid receptors were evaluated in the nuclear (n) and cytosolic (c) fraction using the saturation analysis technique (Scatchard analysis or single saturating-dose assay) for androgen (AR) and estrogen (ER) receptors and the enzyme immunoassay (EIA) for ER and progesterone receptors (PgR). Scatchard analysis of ERc and ERn revealed the presence of two classes of binding sites, one with high-affinity low-capacity binding and the other with low-affinity high-capacity binding. In the untreated BPH group, ER were higher in the n than in the c fraction: ERn were positive in 14 cases and ERc in 12 of 17 cases. In the BPH group treated with S. repens extract on the contrary, ERn were negative for both binding classes in 17 cases and ERc in 6 of 18 cases. Using EIA, ERn and ERc were detected in all 15 samples examined, but in the treated group, ERn were significantly (p less than 0.01) lower than in the untreated group, whilst ERc remained almost unchanged. Similar results were obtained measuring PgR: the n fraction of the treated group prostatic samples was significantly (p less than 0.01) lower than that of the untreated group.(ABSTRACT TRUNCATED AT 250 WORDS)

[Etiology of bladder cancer]. / Eziologia del carcinoma vescicale.

Multiple agents have been suggested as urinary bladder carcinogens. Of these, certain aromatic amines and some tryptophan metabolites (Anthranilic acid, 3 hydroxy Anthranilic acid) have been proved to be carcinogenic. Others are suggested but are not conclusively proved as carcinogenic agents. Various animal species have been used as experimental models for the study of induction of cancer of the bladder and substantial progress has been made in the search for etiologic factors and pathogenesis of bladder tumors. A carcinogenic model of cancer bladder induction is proposed. However, knowledge of the tumorigenesis of cancer of the bladder is still limited and fragmentary. It appears, however, that Tryptophan dysmetabolism play a major role in this field and future experimental and epidemiologic studies should take this fact into consideration.