• Deakos

MINERVA UROLOGICA E NEFROLOGICA




A PROSPECTIVE STUDY TO EVALUATE THE EFFICACY

OF CISTIQUER IN IMPROVING LOWER

URINARY TRACT SYMPTOMS IN FEMALES

WITH URETHRAL SYNDROME


G. PALLESCHI 1, A. CARBONE 1, A. RIPOLI 1, L. SILVESTRI 1

V. PETROZZA 2, P. P. ZANELLO 3, A. L. PASTORE 1


Aim. The aim of the study was to compare Cistiquer, a new phytotherapeutic product developed for chronic bladder inftammatory diseases, and intra-vesical administration of gentamicin plus betametasone, in females with urethral syndrome.

Methods. Between september 2013 and may 2014, 60 women with urethral syndrome and trigonitis were incuded in this study. Patients were randomly assigned to treatment with intra-vesical administration of betametasone 8 mg plus gentamicin 80 mg (group A), and oral administration of Cistiquer (group B) for 7 weeks. Before and after the therapeutic protocol, symptoms were assessed by three days voiding diary, the overactive bladder questionnaire short form and a ten points visual analogic scale adopted to assess the micturition discomfort. Histologic ftndings were assessed by the examination of speci- mens obtained by cold bladder biopsies of the bladder trigone at baseline in all the sub- jects.

Results. The two groups had signiftcant and comparable symptoms improvement. How- ever, the score obtained from the visual ana- logic scale decreased signiftcantly only in the group submitted to oral therapy. Further- more, in the group treated with endovesical approach, higher drop out rate and higher incidence of urinary infection were observed. Conclusion. Patients with urethral syndrome and trigonitis improved symptoms either with oral therapy with Cistiquer and with in- tra-vesical administration of gentamicin plus betametasone. However, treatment adherence resulted higher for patients treated by oral therapy and rate of adverse events resulted higher for those submitted to endovesical treatment.

Key words: Lower urinary tract symptoms -

Ure- thral syndrome is an ill-understood disease affecting females and respon- sible for lower urinary tract symptoms (LUTS), as urinary frequency, urinary ur- gency, burning micturition, hematuria, and pelvic pain associated with negative urine cultures.1 Cystoscopic examination of indi- viduals suffering from urethral syndrome reveals an inflammatory status of the blad- der neck and trigone, described as trigoni- tis, whose histologic pattern reveals many layers of stratified squamous epithelium.2 To cure urethral syndrome, therapies today available are symptomatic but most of them

are not effective and do not contribute to significantly improve quality of life of pa- tients. This is also the consequence of the fact that urethral syndrome has had several sobriquets, which have led to much confu- sion over its existence and the useful op- tions in the care of the afflicted patients.3 Urethral syndrome is refractory to antibiosis and patients often do not respond to oral administration of conventional therapy, represented by steroidal and non-steroidal anti-inflammatory drugs.

However Tait J. et al. identified a micro- biological cause in 4 patients of a cohort of 31 individuals referred to their attention with a diagnosis of recurrent urethral syn- drome.4 Cystoscopy hardly contributes to diagnosis cause it reveals hyperemia and squamous aspect of the bladder mucosa at trigone level. In his population, Tait noted trigonitis at cystoscopy in 26 of the 31 pa- tients and bladder biopsies showed squa- mous metaplasia in 15 and lymphocytic in- filtration of the lamina propria in 29. These findings give support to an inflammatory aetiology of this enigmatic condition and confirm the hard association between ure- thral syndrome and trigonitis5. Further evi- dence of this association is provided by Car- reras, who reported 68% of urethritis alone or combined with trigonitis in a cohort of 350 women presenting LUTS.6 In addition, this author specified that urine examination and cultures resulted negative in 80% of this population. Bladder histology in these patients shows pathological findings. Nor- mal trigonal urothelium consists of 3 cell layers (basal, intermediate and superficial), whereas trigonitis constitutes many lay- ers of stratified squamous epithelium. The basal cells contain prominent nuclei with condensed chromatin, nucleoli and nuclear bodies. The cytoplasm of these cells is rich in mitochondria. The profiles of the urothe- lial cells become progressively elongated, their nuclei increasingly smaller and their content of cell organelles gradually reduced as the luminal surface is approached. The squamous surface cells, linked by desmo- somes, retain many longitudinally arranged fine filaments, together with an occasional degenerate nucleus.7 Similar findings have been reported by our pathologists in pa- tients enrolled in this protocol. These al- terations are usually not found in the lateral wall of the bladder, as clearly showed by Pacchioni et al., who showed also clear cor- respondence between the presence of ster- oid receptors at the squamous metaplasia of the trigonum speculating about a possible endocrine pathogenesis of trigonitis.8 This observation is also supported by Stephen- son TJ et al. who found the selective ex- pression of nuclear estrogen receptor in trigonal epithelium of 10 women affected by trigonitis, in a distribution similar to that reported in vaginal epithelium by other workers. In this case the authors suggest an oestrogen mediated aetiology of trigonitis speculating that it could be consistent with an embryological derivation of the trigone, distinct from that of the rest of the blad- der.9 An association has been found among trigonitis, intestinal disorders, and inflam- matory lesions of the genital tract (uterine cervix). Since 1956 J.E. Semple of the St. Paul’s Hospital, London, reporting his ex- perience in 43 females with trigonitis, has described that 11 subjects presented with lesions of the large intestine (diverticula and radiologic appearances of inflamma- tion).10 However, he suggested that the cor- relations between bowel inflammation and trigonitis was not so strong as the associa- tion that he found with alteration of the cer- vix and genital tract (in 66% of patients). In his experience, Semple firstly suggested the chance of treating these patients by endoscopic fulguration of the bladder or urethral calibration.10-12 However, urethral calibration is not useful in patients with normal micturition parameters as the pa- tients enrolled in our protocol. Endoscopic treatment is considered invasive but it is still widely used for treating this condition by monopolar or bipolar fulguration of the inflammatory area of the bladder trigone. However, no randomized prospective trials have been developed on this therapeutic option and no level of evidence is therefore available regarding its efficacy and safety. Only Costantini et al. reported the results of a prospective randomized study on surgical treatment using Nd:yAG laser in 62 patients with trigonitis refractory to drugs.1 This study concluded that side-firing laser, which produces necrotic coagulation followed by reconstitution of normal functional epithe- lium, was significantly more successful than end-firing and was associated with a 78% success rate. These results are encourag- ing in patients who are usually refractory to medical therapy. Medical therapy options are represented by oral anti-inflammatory drugs which determine short-time relief of symptoms and are very often followed by recurrence. One of the most used treatment is represented by topic administration of drugs. Shirley Sw et al. reported favorable outcomes using Dimethyl sulfoxide. How- ever, this study included a large population of both sexes and suffering from various disorders, as prostatitis, intractable intersti- tial cystitis, radiation cystitis, chronic pros- tatitis, and chronic female trigonitis.13 Many physicians use topic administration of cor- tisone reporting satisfying results. However, for all these therapeutic options there are no large randomized trials available and some data come from old studies.14

Since many years various authors expe- rienced the effects on urethral syndrome symptoms exerted by drugs capable of re- ducing inflammation of the bladder.15 The high incidence of symptoms recurrence and the poor efficacy of these therapeutic choic- es, induce patients to receive mini-invasive treatments, consisting of intravesical instilla- tion of drugs, or surgical approaches, such as endoscopic resection or coagulation of the pathologic bladder mucosa. Obviously, invasive treatments are not well tolerated and furthermore they have variable efficacy, thus to prompt patients to search for alter- native options.

Several reports show encouraging out- comes provided by phytotherapic agents on chronic lower urinary tract inflammatory disorders. Recurrent cystitis and chronic prostatitis are the most important diseases that benefit from these therapies.

Cistiquer is a phytotherapeutic agent composed by natural elements which may

contribute to reduce inflammation and pain, and to preserve the integrity of urothelium and connective tissue of the bladder. quer- citin, the principal, is a flavonoid, a plant pigment with a molecular structure like or derived from flavone. It is found in fruits, vegetables, leaves and grains. It can be used as an ingredient in supplements, beverages, or foods. Several laboratory studies show quercetin may have anti-inflammatory prop- erties and it is being investigated for a wide range of potential health benefits.16, 17 A study with rats showed that quercetin effec- tively reduced immediate-release niacin (vi- tamin B3) flush, in part by means of reduc- ing prostaglandin D2 production.18 A pilot clinical study of four humans gave prelimi- nary data supporting this.19 quercetin may have properties of a calcineurin inhibitor, similar to cyclosporin A and tacrolimus, ac- cording to one laboratory study.20 Moreover, quercetin has been found to provide sig- nificant symptomatic improvement in most men with chronic prostatitis, a condition also known as male chronic pelvic pain syn- drome.21 Cistiquer contains also Condroitin Sulphate, a glycosaminoglycan (GAG) acting by the inibition of NO synthesis providing ef- fective outcome on inflammatory symptoms, and glucosamine, which contributes both to restore physiological properties and ana- tomical integrity of urothelium, as already shown by previous studies which also dem- onstrated efficacy and safety of these agents on chronic bladder conditions, as trigonitis and interstitial cistytis.22 Another agent con- tained in Cistiquer is bromelin, which is an extract derived from the stems of pineap- ples, although it exists in all parts of the fresh plant and fruit, which has many uses and also anti-inflammatory properties.23-25 An antioxidant and anti-inflammatory activ- ity has been also shown for another compo- nent of Cistiquer, Centella, a genus of 2 or 3 species of flowering plants in the subfamily Mackinlayaceae which has also revealed im- portant antibacterial properties in microbio- logical studies.26, 27 Other extracts included in Cistiquer are from Rhodiola, a plant of the Crassulaceae family which has shown effects on relieving mental and physical fatigue,28

and from Scutellaria barbata, a species of flowering plants in the mint family whose English common name is Barbed skullcap. It is used as a herbal remedy for inflammation and traumatic injury and has been tested in clinical trials for the treatment of metastatic breast cancer; moreover, its extracts induced apoptosis in prostate cancer cells in labo- ratory studies.29 The properties of all these natural agents appear intriguing for treating bladder modifications observed in urethral syndrome associated with trigonitis. The ac- tion of quercetin combined with the other natural extracts and the precious contribute of condroitin sulphate and glucosamine may provide hard synergic favorable effects re- ducing irritative symptoms as a consequence of lower inflammation and of better bladder mucosa integrity. Considering these charac- teristics, the aim of this investigation was to compare the efficacy and tolerability of oral administration of Cistiquer with intravesical administration of gentamicin and betameta- sone in females with urethral syndrome.

Materials and methods

A total of 98 females with urgency-fre- quency syndrome were prospectively re-

cruited for this study after informed consent was read by the investigator, signed and dat- ed by the patients. All subjects were evalu- ated at the Urology Unit of the Department of Medico-Surgical Sciences and Biotech- nologies of Sapienza University of Rome, by means of history, comorbidities assess- ment, physical and genital examination in- cluding stress test, microbiological tests on vaginal swab to exclude genital infections (Chlamydia, Mycoplasma, Ureaplasma, Tri- chomonas), urinanalysis and urine culture, renal and pelvic ultrasound, three days void- ing diary, urinary cytology, pregnancy test, uroflowmetry with ultrasound evaluation of bladder residual volume, and flexible cys- toscopy combined with multiple cold biop- sies of bladder mucosa at trigone level (six for each patient). Symptoms were assessed by the overactive bladder questionnaire screener short form (OAB-SF, Figure 1). Fur- thermore, all patients were invited to indi- cate the grade of micturition discomfort on a ten visual analogic scale (VAS), from 0=no discomfort to 10=severe discomfort. Inclu- sion criteria were represented by presence of irritative symptoms as urinary urgency and urinary frequency combined with a his- tological diagnosis of trigonitis. Exclusion criteria were considered: urinary and/or


Figure 1.—The overactive bladder questionnaire short form (OABq SF). This questionnaire has been specifically developed to diagnose OAB, is easy to fill and is self-administered.



genital tract infection, evidence of organic disease at renal and pelvic ultrasound, geni- tal prolapse, stress urinary incontinence at history or revealed by physical examination,

neurogenic diagnosis, previous genital and/ or urological surgery, previous pelvic ra- diotherapy, maximum flow rate <18 mL/s, bladder residual volume >50 mL, any evi- dence of genital dystrophy, or any anatomic alteration at genital assessment such as hyp- ospadias, positive pregnancy test. Basing on these criteria, from the preliminary cohort,

61 patients were histologically diagnosed suffering from trigonitis and satisfied the inclusion criteria. The histological diagnosis was achieved by optical microscopy. Two different pathologists evaluated independ- ently the specimens and provided the same diagnosis. Patients eligible for the protocol basing on inclusion and exclusion criteria were randomized 1:1 to two different treat- ments: 30 individuals were submitted to en- do-vesical administration of gentamicin 80 mg plus betametasone 8 mg (twice/week for 7 weeks, group A) while the other 30 as- sumed oral therapy with Cistiquer, one tab- let/day/7 weeks (group B). One patient was excluded from the protocol to obtain the same number of individuals in both groups. The outcomes provided by the reported in- vestigational measures were assessed 7 days before and 7 days afer therapeutic protocol. Statistical analysis was performed to evalu- ate the outcomes: c2 test and odds ratios for categorical variables, and Student’s t test to evaluate differences of continuous measurements.

Results

Clinical findings

Mean age, mean body mass index, meno- pausal status and comorbidities distribution did not significantly differ between the two groups compared in the study (Table I). In order of prevalence, comorbidities were represented by: type II diabetes, dyslipi- demia, blood hypertension, dysthyroidism. All diabetic patients assumed only oral therapy. None of these patients presented polyuria at voiding diary examination.

Protocol development

Three patients of group A spontaneously dropped out from the protocol. One of them due to severe hematuria cured in 48 hours with bladder catheterism; 2 patients refused further catheterism after 6 and 8 procedures respectively due to pain; furthermore, these 2 patients reported no symptom improve- ment. One patient of the group A and 2 pa- tients of group B needed antibiosis due to acute urinary infection during the first week of treatment and were therefore excluded from the study. Final evaluable cohort at the end of protocol resulted of 26 patients in group A and 28 patients of group B. 19/26 subjects of group A and 19/28 subjects of group B reported to be sexually active. Base- line data achieved by three days voiding di- ary showed severe increase of micturition episodes in the population and significant number of urinary urgency episodes. None patient suffered from polyuria (considered as voided urine volume > 3000 mls per 24 hours). VAS scores did not significantly dif- fer between the two groups at baseline. Par- ticularly, patients in group A scored at VAS a median 8, mean 6.5±2.3; patients in group B scored a median 8, mean 6.3±2.2.

Three patients of group A and 2 patients of group B presented also urinary urgency incontinence episodes. After the protocol was concluded, the examination of voiding diary data and of OAB-q SF scores showed a significant improvement of symptoms and significant reduction of urinary frequency and urgency episodes in both groups. Al- though the results appeared better for the group B, this outcome did not reach sta- tistical significance (Table II). None of the patients of group B reported any adverse event secondary to drug assumption. A sig- nificant decrease of VAS score was reported by females of group B, whilst no signifi- cant modification of this parameter was ob- served in patients of group A. In fact, after treatment, patients in group A scored at VAS a median 5, mean 3.5±2.3, while patients in group B scored a median 0.8, mean 1.1±1.7 (P=0.001, Figure 2). In group B, 55% of

Figure 2.—Comparison of VAS before and after treatment between the two groups shows a significant higher decrease of score in group B respect to group A



patients referred no micturition discom- fort (VAS=0) while all patients in the other groups experience the persistence of some degree of discomfort. At the end of the pro- tocol the number of individuals who re- ported to be sexually active increased only in group B, from 19 to 21 women. Urinary urgency incontinence episodes disappeared in 1 patient of group A and 1 of group B.


Discussion

women with urethral syndrome present irritative symptoms which hardly lower their quality of life, limiting daily practises, social interaction and sexual activity. These pa- tients present negative urine examinations and cultures and are consequently refrac- tory to antibiosis. However, despite this evi- dence, they come to the attention of urolo- gists and gynecologists after many attempts of treatment with different antibiotics. Of course, urinary and genital tract infections (sexually transmitted diseases) must be ex- cluded to diagnose an inflammatory chronic abacterial condition of the bladder. In our clinical practice we use local administration of cortisone after endoscopic and histologic diagnosis of trigonitis: patients are submit- ted to 14 local instillations of betametasone 8 mg associated with gentamicin 80 mg to prevent acute urinary infection secondary to bladder catheterism. Patients who have no clinical improvement are then treated by bipolar electrovaporization of the inflamma- tory area of the trigone. In our experience, either catheterisms and endoscopic surgical treatment are not well tolerated by the pa- tients, so much that we need to find alterna- tive therapeutic strategies to improve symp- toms. Furthermore, many patients are willing to use therapeutic strategies derived from natural/herbal extracts, capable of lowering symptoms and curing chronic conditions as alternative and/or complementary therapy to glucocorticoids, non-steroidal antirheu- matics, and immunomodulators. Goals of therapy in trigonitis are: reducing the inflam- mation of the bladder, protecting the blad- der wall from damage of deeper layers and

restoring urothelium integrity. Cistiquer is a phytotherapeutic product containing various agents capable of reducing bladder inflam- mation and protecting urothelium. These possible advantages provided by Cistiquer seem to be supported by the outcomes of this investigation, which showed good symp- toms improvement of patients with favora- ble effects also on sexual activity. The results confirm that oral therapy is better tolerated than catheterism, as revealed by the higher rate of adverse events and higher drop-out rate observed in group A. In fact, as shown by VAS outcomes, urinary discomfort did not significantly change in patients submitted to intravesical therapy, although urinary fre- quency and urinary urgency were improved. Moreover, it has to be considered that natu- ral agents are characterized by a low rate of side effects inducing patients to well tolerate also long-term therapies, especially if associ- ated with symptoms improvement, as shown by Cistiquer in our experience.

Limitations of the study

Limits of the study are represented by the small population included and the absence of a placebo-controlled group. It should also be noticed that some data about ef- ficacy and therapeutical properties of some natural agents included in Cistiquer com- position are lacking of rigorously-designed, well-controlled randomized control trials. However, in the Literature the use of con- ventional drugs to treat trigonitis is also not commonly considered. Therefore, surely this topic needs better consideration with the aim to improve our knowledge on etio- pathoegeteic mechanisms and explore bet- ter therapeutic options. Basing also on this pilot experience, Cistiquer should be taken into consideration as one of the therapeutic options for treating urethral syndrome be- fore choosing invasive procedures.

Conclusions

Both oral treatment with Cistiquer and intravesical administration of betameta-

sone plus gentamicin improved symptoms of patients with urethral syndrome. How- ever, in the group treated with Cistiquer a lower rate of adverse events was observed and patients reported better improvement of urinary discomfort.

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Conflicts of interest.—Dr. Zanello is a scientific consult- ant for Deakos. The other authors do not have conflicts of interest to declare.

Received on July 6, 2014.

Accepted for publication on July 10, 2014.




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