Effects of Protoves-M1^® and IPB-tre^® on the prevention and the treatment of irritative symptoms after REZUM therapy of benign prostatic hyperplasia (BPH)

The median age was 64.1 years old (interquartile range IQR 46–79) with a median ASA of 2 (IQR 1–3) and a median PSA of 3.79 (IQR 0.41–23). Median prostate volume was 68.6 mL (IQR 40–160) and a middle lobe was presented in 70% of the patients.
Before the treatment, all patients received treatment with alpha-blockers (AB) for a period of a minimum of 1 year and 5 patients (10%) received combination therapy with 5-alpha reductase inhibitors (5-ARI), but without a clinical benefit (median IPSS 27.1; IQR 14–35). Nevertheless, no patients referred pain at baseline.
At preoperative uroflowmetry, the preoperative median Q_max was 10.1 (IQR 3.5–16.4) with a median PVR of 101.3 mL (IQR 33–250). Two patients (4%) had acute urinary retention (AUR) and an indwelling catheter was preoperatively inserted (Table 2).

The median operative time from the instrument transurethral insertion to patient catheterization was 11.44 (IQR 7–16) minutes. Patients received a median of 7.2 (IQR 4–14) PEEK vapor needle injections and the median time for dismissal was 1.5 hours after the procedure (IQR 1–2). The indwelling urinary catheter was removed after a median of 11.7 (IQR 10–30) days.
Patients reported a significant decrease of IPSS from baseline at first [27.1 (IQR 14–35) vs 16.8 (IQR 7–32), p = 0.03], third [27.1 vs 9.6 (IQR 2–22), p < 0.02] and sixth [27.1 vs 5.3 (IQR 0–12), p < 0.0001] month after surgery. Nevertheless, at a 3-month follow-up, 4 patients (8%) maintained a pharmacological therapy with AB.
The median VAS on 1^st postoperative day was 2.9 (IQR 2–4). After the interruption of anti-inflammatory therapy with ibuprofen, we assisted in a significant decrease of VAS on the 10^th postoperative day, with a median value of 1.6 (1–3). At 1 postoperative month, only 3 patients (6%) referred a VAS of 1.
Median TSQM scores on effectiveness, side effects, convenience, and satisfaction were 75.2, 100.0, 82.5, and 85.9, respectively. Any grade of toxicity was reported (Table 3).

In the last decade, novel MISTs-like Rezum System have represented an effective and safe procedure in the treatment of BPH. McVary et al. [7] reported a double-blind Rezum RCT, suggesting a significant and long-term mean IPSS score improvement. Mean IPSS improvement from baseline remained significant from the early response at 3 months (49.9%) to 1 year (52.2%), 2 years (50.7%), 3 years (49.7%), and 4 years (46.7%), p < 0.0001. Moreover, IPSS quality of life (QoL) (42.9%, p < 0.0001) and Q_max (49.5%, p < 0.0001) improved significantly at a 4-year follow-up. An improvement of urinary outcomes [median Q_max of + 8.9 mL/s (IQR 5–13), median IPSS of –12 (p < 0.01), and a median PVR of –65.6 cc (p < 0.001)] was also reported in another recent study [20].
The physical principle of REZUM is based on the convective properties of water, releasing large amounts of stored thermal energy (540 calories/mL H₂O) as the vapor contacts prostate tissue and condenses back to the water. In this way, the vapor disrupts prostatic hyperplasic cells and shrinks the obstructive treated tissue. No thermal effects occur outside the targeted treatment zone [7]. Nevertheless, the high temperature of the water vapor at 103℃ and its injection by a needle can determine an inflammation of the treated prostatic tissue, which is responsible for postoperative irritative urinary symptoms such as urgency and dysuria [17].
In the last years, the role of phytotherapy in the treatment of prostatic inflammation and BPH has increased, and it has been well-defined [18]. In vitro, plant extracts can have anti-inflammatory, anti-androgenic, and estrogenic effects; they can decrease sexual hormone binding globulin, inhibit several enzymatic activities (aromatase, lipoxygenase, 5 α-reductase), growth factor-stimulated proliferation of prostatic cells, α-adrenoceptors, muscarinic cholinoceptors, dihydropyridine receptors, vanilloid receptors and neutralize free radicals [21]. A small trial by Shoskes et al. investigated the clinical efficiency of quercetin, a bioflavonoid with antioxidative properties. The daily use of Quercetin (500 mg 2 times per day) over a period of 4 weeks was associated with a significant improvement of urinary symptoms compared with placebo [22, 23]. Another clinical trial analyzed the therapeutic benefit of cernilton, a standardized pollen extract [24]. Even in this clinical experience, a 3-month therapy of cernilton (two capsules every 8 h) determined a significant improvement in the symptoms compared with a placebo. With only very few side effects, phytotherapeutic agents can be recommended as primary therapy or a combination in multimodal treatment regimens in the management of chronic prostatitis and chronic pelvic pain syndrome [22]. A recent Italian study evaluated the role of Protopine associated with Nuciferine in controlling adverse events during hyperthermic intravesical chemotherapy instillations, suggesting that Protopine and Nuciferine syrup can be an interesting alternative to anti-inflammatory and antimuscarinic agents to treat irritative and pain related symptoms of intravesical chemo/immunotherapy [25].
Several studies have suggested an anticholinergic and GABAergic action of Protopine and its capacity to positively influence some neurological systems responsible for bladder functions [25-29]. Moreover, its anti-acetylcholinesterase action gives it an anti-amnesic effect that alleviates certain memory deficiencies reported in dementia [30]. Protopine increases the p53-mediated transcriptional activity, resulting in the stabilization of the p53 protein. It exerts an antiproliferative activity and it is supposed to have a potential effect as a chemo-preventive agent for colon cancer [31]. Nuciferin is a partial antagonist of D2-like receptor and has a demonstrated regulatory action on the dopaminergic system affecting the bladder muscles and nerves [32]. Moreover, Nuciferin can reduce states of tension and anxiety with a pharmacologic profile similar to Chlorpromazine [33, 34]. Nuciferine also significantly inhibited the lipopolysaccharide (LPS)-induced inflammatory cytokine IL-6 and TNF-α production in RAW 264.7 cells having potential anti-inflammatory activities [35]. Its use significantly decreases the expression of TLR4 in a dose-dependent manner and potently improves LPSinduced mastitis by inhibition of the TLR4-NF-κB signaling pathway [36]. Finally, Nuciferine reduces fructoseinduced inflammation by blocking TLR4/PI3K/NF-κB signaling and NLRP3 inflammasome activation in rat renal cortex and HK-2 cells, which may contribute to the improvement of renal injury [37].
In our experience, Protopine associated with Nuciferine was adopted in combination of Serenoa repens, Pinus pinaster, and β-sitosterol, which are present in IPB-tre^®. Serenoa repens has a well-known anti-inflammatory, antihemogenic and anti-androgenic activity [38]. Pinus pinaster is a bark extract rich in Oligomeric proanthocyanidins (OPC) with strong anti-inflammatory and antioxidant properties [39]. β-sitosterol is an antagonist of DHT for the receptor located on the cellular membrane of prostate cells, thus lowering the hyperproliferation and stimulation by DHT that leads to BPH. Moreover, β-sitosterol does not interfere with 5-α-reductase, thus avoiding reports ofsexual dysfunction [40]. All patients underwent combined therapy with Protoves-M1^® and IPB-tre^® for a period including two weeks before REZUM and 3 months postoperatively. Interestingly, after interruption of anti-inflammatory therapy with ibuprofen and maintaining therapy with Protoves-M1^® and IPB-tre^®, we assisted in a significant decrease of VAS at the 10^th postoperative day, with a median value of 1.6 (1–3). At 1 postoperative month, only 3 patients (6%) referred a VAS of 1.
TSQM 1.4 is a validated questionnaire that evaluates global satisfaction with the performance of a medication. The combined therapy did not reveal significant sideeffect (median TSQM scores on side effects was 100%). All patients were satisfied concerning the effectiveness of the combined therapy (median TSQM scores of 75.2) but they were very satisfied with the convenience and results of the therapy (median TSQM scores on convenience and satisfaction were 82.5 and 85.9, respectively). Finally, any grade of toxicity was reported during the period of the combined therapy with Protoves-M1^® and IPB-tre^®. Nevertheless, the positive effect of Protoves-M1^® and IPB-tre^® on irritative symptoms in the early postoperative period was strengthened by the association with AB therapy.

Combined therapy with Protoves-M1^® and IPB-tre^® could be safe and efficient in reducing irritative symptoms after REZUM, even after the interruption of traditional antiinflammatory therapy. Moreover, all patients reported a high level of satisfaction with the therapy in the absence of side effects. Nevertheless, we suggest maintaining an AB therapy for the early 30 postoperative days to strengthen the positive effect of Protoves-M1^® and IPBtre^®. More observational studies with a greater cohort of patients and longer follow-up should investigate the possibility of replacing traditional anti-inflammatory therapy with combined phytotherapy for the treatment of irritative symptoms which can be reported after surgical therapy of BPH.

Financial support and sponsorship

None.

Conflicts of interest

Francesco Greco is a member of the editorial board of Uro-Technology Journal. The authors declare that they have no conflicts and were not involved in the journal's review or decision regarding this manuscript.

Ethical statement

This study was approved by the Institute Research Medical Ethics Committee of Centro Salute Uomo. All patients were informed of the procedures and provided written informed consent.