[Iscussion on the use of hexane extract of Serenoa repens for combination therapy in patients with LUTS/BPH].

Based on literature data, feasibility of combined therapy with Serenoa repens extracts (including Permixon) and 1-adrenoblocators in patients with LUTS/BPH based on the pathogenesis of these drugs and clinical results was analyzed. The composition and biological activity of various SRE is influenced by the extraction method, as well as the production technology used by the manufacturer, which can lead to different results of experimental and clinical studies. The mechanism of action of SRE, including hexane extract Permixon, is multicomponent, which combines an antiandrogenic effect, influence on neurogenic regulation of urinary tract function (-adrenoreceptors, M-holinoreceptors, vanilloid receptors), anti-inflammatory and anti-edematous actions. At the same time, the effect of these preparations is not limited to the influence on the prostate gland, but can directly affect the bladder, helping to reduce functional disorders. A wider range of mechanisms of action and a possible direct effect of SRE on the bladder provides the same clinical effect as other traditionally used drugs (-blockers, 5-reductase inhibitors) with a significantly lower frequency of side effects of therapy. A number of publications demonstrate the feasibility of combined therapy with 1-adrenoblockers and SRE in patients with LUTS/BPH, especially with a high degree of urination dysfunction. Futher investigations are needed. The role of Serenoa repens extracts in the combination therapy of LUTS/BPH is still under discussion. Serenoa repens extracts monotherapy demonstrates similar effectiveness in patients with LUTS as 1-adrenoblockers and 5-reductase inhibitors. Recent studies indicate the advantages of combining Serenoa repens extracts with 1-adrenoblockers, especially in patients with moderate or severe symptoms. These advantages are associated with the multicomponent action of Serenoa repens extracts, which complements the blockade of 1-adrenergic receptors with other mechanisms of action (in particular, anti-inflammatory). The combination of drugs with different mechanisms of action, in particular, Serenoa repens extracts (Permixon) and 1-adrenoblockers has certain pathophysiologically based advantages, which allows to increase the efficiency of therapy. In addition, combination therapy is not associated with an increased rate of side effects.

[An influence of herbal plant based on the combination of natural terpenes, vitamin and essential oil on the spontaneous stone passage after extracorporeal shock-wave lithotripsy].

INTRODUCTION: There are more than 20 drugs, that are widely used as medical expulsive therapy after extracorporeal shock wave lithotripsy (ESWL). Herbal plants are actively used along with the drug therapy in order to improve the efficiency of the treatment. PURPOSE OF THE STUDY: to evaluate the efficiency of the drug "Renotinex" in patients with kidney stones, as medical expulsive therapy. MATERIALS AND METHODS: A total of 41 patients with kidney stones who undergone ESWL were included in the study. Patients were divided into two groups of 21 patients. In the main group, patients received the dietary supplement "Renotinex" 2 capsules 2 times a day for 1 month, along with standard medical expulsive therapy (NSAIDs [Diclofenac suppositories 50 mg in case of pain] + alpha blockers [Tamsulosin 0.4 mg in the morning for 1 month). The efficiency of treatment was evaluated after 2 and 4 weeks by means of ultrasound and x-ray. A presence and mean size of the stone and dilatation of the collecting system were assessed. In addition, complete blood count (hemoglobin, level of red blood cells and white blood cells), as well as urinalysis (microhematuria and leukocyturia) were performed. For statistical analysis, Student's criterion and the Fishers method were used. RESULTS: After 2 weeks of treatment, a decrease in the hemoglobin level, number of leukocytes and erythrocytes in urine, as well as a significant decrease in pelvis size and the average size of the urinary stone were seen in the main group. In the control group, there was also a slight decrease in the hemoglobin and a significant increase in the grade of leukocyturia and microhematuria. After 4 weeks, significant intergroup differences were documented in the level of microhematuria, pelvis size and the presence of stone in the collecting system, as confirmed by ultrasound and X-ray study. Stone-free rate in the main group was 47.6%, compared to 20% in the control group. CONCLUSION: Medical expulsive therapy in combination with dietary supplements "Renotinex" after ESWL is more efficient than standard medical expulsive therapy (NSAIDs and -blockers) as monotherapy.

Stimulation of Structural and Functional Recovery of the Kidney in Rats with Postischemic Acute Renal Failure of Different Severity by Embryonic Protein-Peptide Complex Therapy.

In male rats, acute renal failure was simulated by clamping the vascular pedicle of the left kidney for 60 or 90 min and right-sided nephrectomy. In the control series, no therapy was performed. In the experimental series, the animals were daily injected subcutaneously with Cellex, a protein-peptide complex (PPC) chromatographically isolated from the brain tissue of pig embryos with a molecular weight of its components from 10 to 250 kDa. PPC was administered 5 times a week (10 injections) in a dose of 0.1 ml/kg (0.1 mg active substance per 1 kg body weight). Ischemia of a single kidney led to the development of acute renal failure, more severe after 90-min ischemia. PPC therapy reduced the severity of functional disorders mainly at the early stages (3 and 7 days) with normalization of blood concentrations of urea and creatinine, creatinine clearance, tubular reabsorption of sodium and calcium, including the cases with 90-min ischemia, which did not occur in the control series. PPC therapy also contributed to hypertrophy of many glomeruli, prevented the development of glomerulosclerosis, and reduced damage to the epithelium of the renal tubules. At the same time, neither pronounced lymphohistiocytic infiltration, nor focal nephrosclerosis typical of control series were observed.

[Prediction of the effectiveness of the therapy of LUTS/BPH by Serenoa repens extracts].

INTRODUCTION: For the treatment of LUTS/BPH is used a wide range of drugs that patients have to take for a long time. Therefore, it is important to develop methods for predicting long-term results of therapy. The purpose of this work is to evaluate the possibility to predict long-term results of drug therapy of LUTS/BPH using mathematical modeling on the example of treatment with Serenoa repens extract (ESR - Permixon). MATERIALS AND METHODS: For prediction using the methods of predictive analytics of the therapeutic ESR effect in the long term, materials from the open study "Clinical and biological long-term tolerance of a lipidosterolic extract of Serenoa repens (Permixon) in patients with symptomatic benign prostatic hypertrophy" (No. P0048 95 GP 401) were used. The study took place in 1995-1999 in 3 Moscow medical centers: Research Institute of Urology of the Ministry of Health of the Russian Federation, Urological Clinic of the Moscow Medical Academy named after Sechenov and the urology department of Moscow Clinical Hospital No 60. The study included 155 patients aged 52 to 87 years (65.3) who received the drug in 320 mg capsules per day for two years. The target indicators of the prognosis identified key clinical parameters: a decrease IPSS of>25% or>3 points and an increase in Qmax>25% at 12 and 24 months of treatment. When evaluating the results, a binary approach was used: improvement achieved (1), not achieved (0). RESULTS: Using the methods of predictive analytics, mathematical models were built to predict the long-term results of treatment according to the most significant 7 initial criterias (predictors): IPSS; Qmax; average urine flow rate; urination volume, urination time, residual urine volume, prostate volume. For each target field and time interval, mathematical models were built using ensembles from 7 selected machine learning algorithms with the best predictive qualities: BNet; C5.0; SVM; KNN; NNet; CHAID; C&RT. Verification of models on internal randomized samples showed their high prognostic properties: sensitivity 82.4-99.0; specificity 75.0-96.1; AUC 0,864-0,965. CONCLUSION: The potential for effective prediction by the methods of predictive analytics and data mining of the separated results of drug therapy of LUTS / BPH according to the main clinical criteria was demonstrated. It is necessary to continue training and testing the model with the inclusion of new clinical observations in the data set. This approach is applicable to the creation of similar models for predicting the effect of other drugs.

[The features of pathogenesis of urolithiasis in patients with diabetes mellitus type 2].

INTRODUCTION: In recent years, a large number of studies has been published that proved a very significant role of diabetes mellitus type 2 for development of urolithiasis. The aim of our work was to conduct a comparative study of biochemical parameters of blood and urine as well as chemical composition of urinary stones in urolithiasis patients in the general population and in patients with diabetes mellitus type 2. MATERIALS AND METHODS: The work was divided into 2 stages. During the first stage an analysis of chemical composition of urinary stones in the general population (n=5669) and in patients with diabetes mellitus type 2 was carried out (n=350). During the second stage an analysis of biochemical parameters of blood and urine in urolithiasis patients in the general population (n=101) and in patients with diabetes mellitus type 2 was conducted (n=350). RESULTS: In the general population calcium oxalate stones was predominated (56.8%), while phosphate (24.9%) and urate (17.4%) stones were less frequent. In a subgroup of patients with diabetes mellitus type 2 uric acid stones were predominated (74.3%), significantly exceeding calcium oxalate (15.1%) and calcium phosphate (10.6%) stones. In the general population of patients with urolithiasis, hypercalciuria, hyperuricosuria, hyperuricemia and hypomagnesiuria was detected in 60.4%, 42.6%, 26.7% and 43.5% of cases, respectively. In patients with concomitant diabetes mellitus type 2, hypercalciuria, hyperuricosuria, hyperuricemia was observed in 9.4%, 26.7% and 42.5%, respectively. In 60.3% of patients with diabetes mellitus type 2 marked acidity of the morning urine was detected (pH<6.0). CONCLUSION: Correction of metabolic disorders in patients with urinary stone disease and diabetes mellitus type 2 should be aimed at increasing of urine pH and reducing the level of uric acid in the blood and urine.

[Early diagnosis of risk for developing calcium oxalate urolithiasis].

AIM: To identify risk groups for calcium oxalate urolithiasis among healthy individuals and patients with urolithiasis in the Russian population using molecular genetics. MATERIALS AND METHODS: The study comprised 72 patients with calcium oxalate urolithiasis (study group) and 189 healthy adults from the general Russian population (control group). The study group consisted of 39 (54.2%) men and 33 (45.8%) women. The mean age of urolithiasis patients was 41.5+/-12.4 years. Analysis of polymorphic variants of 8 candidate urolithiasis genes: tumor necrosis factor 11B (TNFRSF11B, rs3134057), -subunit of the nuclear estrogen receptor (ESR1, rs851982), Cloto gene (KL, rs526906), vitamin D receptor (VDR, rs1540339 ), an extracellular calcium-sensing receptor (CASR, rs2202127), membrane anion transporter family 26 (SLC26A6, rs2310996), tumor necrosis factor 11 (TNFSF11, rs9525641), the calcium release-activated calcium modulator 1 (ORAI1, rs7135617) in two groups was performed by real-time PCR using Applied Biosystems test. Statistical analysis was performed using Fishers angular transformation and 2. RESULTS: In the polymorphism of the ORAI1 gene (rs7135617), the differences in the frequencies of the GG genotype and the G allele in the control sample and in the sample of patients with calcium oxalate urolithiasis were significant: p=0.0004 and p=0.001, respectively. No statistically significant differences in the genotype and allele frequencies were found in the remaining seven gene polymorphisms. CONCLUSIONS: Healthy individuals and patients with urolithiasis in the Russian population who have the GG genotype and/or the G allele of the polymorphism of the ORAI1 gene (rs7135617) represent risk groups for the formation of calcium oxalate stones.

[Hormone Resistance and Neuroendocrine Differentiation Due to Accumulation of Genetic Lesions during Clonal Evolution of Prostate Cancer].

Progression of malignant tumors is largely due to clonal evolution of the primary tumor, clones acquiring different sets of molecular genetic lesions. Lesions can confer a selective advantage in proliferation rate or metastasis on the tumor cell population, especially if developing resistance to anticancer therapy. Prostate cancer (PCa) provides an illustrative example of clinically significant clonal evolution. The review considers the genetic alterations that occur in primary PCa and the mechanism whereby hormone-refractory PCa develops on hormone therapy, including mutations and alternative splicing of the androgen receptor gene (AR) and intratumoral androgen synthesis. Certain molecular genetic lesions determine resistance to new generation inhibitors (AR mutations that block the antagonist effect or allow other hormones to activate the receptor) or lead to neuroendocrine differentiation (repression of the AR signaling pathway, TP53 mutations, and amplification of the AURKA or MYCN oncogene). Multistep therapy based on the data about somatic mutations associated with progression and metastasis of the primary tumor can be expected to significantly improve the survival of patients with advanced PCa in the nearest future.

[The incidence of acute urinary retention as an indicator of the quality of care for patients with benign prostatic hyperplasia].

AIM: To evaluate the incidence of acute urinary retention as an indicator of the quality of care for patients with benign prostatic hyperplasia by the example of "Urology" Program implemented in the Voronezh region. MATERIALS AND METHODS: As part of the program "Urology", the incidence of AUR was used as an indicator of quality of care for patients with BPH. Urological health care for patients with BPH was provided within a three-stage model. For each of the stages standardized packages of detailed methodological materials, including regional standards were developed. RESULTS: Over the 3 years of the program (2011-2013) questionnaire survey was conducted among 762 937 men 50-75 years old with 85.3-88.1% annual coverage of respondents. Over the past three years (2009-2012) there was consistent and statistically significant (p<0.05) decrease (from 11.27 to 1.5%) in the proportion of hospitalizations for AUR reaching a "plateau" (p>0.05) in 2012-2013. There was a significant correlation of AUR with the main indicators of effectiveness of BPH treatment: the structure of morbidity (prevalence of early BPH forms - groups 1 and 2), the number of surgical interventions, the frequency of complications (including surgical), general and specific costs for diagnosis and treatment of BPH. CONCLUSIONS: Acute urinary retention may be regarded as an integral indicator of the quality of care for patients with BPH.

[Genetic risk factors for recurrence-free urolithiasis in the russian population].

PURPOSE: Search for and identification of possible associations of recurrence-free urolithiasis with polymorphisms of urolithiasis candidate genes in the Russian population. MATERIALS AND METHODS: The study involved 43 patients with recurrence-free urolithiasis, 13 (30.2%) women and 30 (69.8%) of men (main group) from Central Russia, and 189 healthy adults (control group) from the same region. The mean age of the main group was 42.5+/-13 years. The venous blood samples were used for the evaluation. Real-time PCR using the "Applied Biosystems" test systems was performed to determine the spectrum and frequency of eight urolithiasis candidate genes polymorphisms: tumor necrosis factor receptor gene (TNFRSF11B (rs3134057), vitamin D receptor gene (VDR, (rs1540339), extracellular calcium-sensing receptor gene (CASR, (rs2202127), calcium release-activatedcalcium modulator 1 gene (ORAI1, rs7135617), Klotho gene (KL, rs526906), nuclear estrogen receptor alpha-subunit gene (ESR1, rs851982), tumor necrosis factor 11 gene (TNFSF11, rs9525641), and 26 gene family anionic membrane transporter gene (SLC26A6, rs2310996). Fishers angular transformation and 2 test were used for statistical analysis of the data. RESULTS: For ORAI1 gene, differences in genotype and allele frequencies in the control and main groups are significant: p=0.0001 and p=0.013, respectively. For polymorphisms of the other seven genes studied, the differences in genotype and allele frequencies are non-significant. The results indicate the presence of the association between recurrence-free urolithiasis and calcium release-activatedcalcium modulator 1 gene polymorphism (ORAI1, rs7135617), both in genotypes and alleles. CONCLUSIONS: In Russian population, genetic factors, in particular, ORAI1 (rs7135617) gene polymorphism, can play the role in the development of recurrence-free urolithiasis.

[GENETIC RISK FACTORS FOR MULTIPLE KIDNEY STONE FORMATION IN THE RUSSIAN POPULATION].

This study examines the association of multiple kidney stones with polymorphisms of urolithiasis candidate genes in the Russian population. A total of 75 adult patients with multiple stones (the main group) residing in the Central Russia and 189 healthy adults (control group) from the same region underwent genetic testing. The study group consisted of 41 (54.7%) males and 34 (45.3%) females with mean age 44.5 ± 14 years. The material for the study was samples of venous blood. Spectrum and frequency of polymorphic variants of four urolithiasis candidate genes were determined using real time PCR: the Klotho gene (KL, rs526906), vitamin D receptor gene (VDR, rs1540339), gene of the extracellular calcium-sensitive receptor (CASR, rs2202127), calcium release-activated calcium modulator 1 (ORAI1, rs7135617). Fisher angular conversion and χ2 tests showed association between the genetic polymorphisms of ORAI1 and multiple kidney stone formation in the Russian population. No association was found between multiple kidney stones and polymorphisms of genes encoding KL, VDR, CASR. These results indicate that genetic factors, in particular polymorphic variants of the ORAI calcium release-activated calcium modulator 1 (ORAI1, rs7135617), may affect multiple kidney stone formation in the Russian population.

[PCA3 AND TMPRSS2:ERG GENES EXPRESSION IN BIOPSIES OF BENIGN PROSTATE HYPERPLASIA, INTRAEPITHELIAL NEOPLASIA, AND PROSTATE CANCER].

Morphological analysis of the biopsies for prostate cancer (PCa) often is a difficult task due to heterogeneity and multifocality of tumors. At the same time, a lot of data exist about the potential molecular genetic markers of PCa. The aim of our study is to determine of PCA3 and TMPRSS2:ERG genes expression in benign hyperplasia (BPH), low and high grade intraepithelial neoplasia (PIN), PCa for revealing of diagnostic value of those genes expression in benign and precancerous changes in prostate. Total RNA was isolated from 53 biopsies, reverse transcription was performed, gene expression was determined by real time PCR (RT-PCR) then deltaCt index was determined as Ct(PCA3)--Ct(KLK3). Average deltaCt and its SD in BPH were 8.28 ± 3.13, low PIN--8.56 ± 2.64, high PIN--8.98 ±1.69, PCa--1.08 ± 2.36. We have demonstarted that deltaCt did not differ in patients with BPH, low and high grade PIN, whereas significantly increased in PCa relative to any of the three groups listed above (p < 0.0001). Expression of TMPRSS2:ERG was absent in BPH, PIN, but it was detected in 40% (4/10) of PCa cases. ROC-analysis showed that the AUC (area under ROC-curve with 95% CI, p < 0.0001) was 0.98 ± 0.02 in the analysis of a combination of overexpression of PCA3 and TMPRSS2:ERG. Thus, the expression analysis of the PCA3 and chimeric oncogene TMPRSS2:ERG in biopsy cannot be used for differential diagnosis of BPH, low and high grade PIN. However, overexpression of PCA3 and expression of TMPRSS2:ERG are characteristic in PCa. Expression analysis of these genes by the proposed RT-PCR modification at the threshold level deltaCt 3,22 has diagnostic accuracy 90% to detect PCa in biopsy specimens.

[Markers for non-invasive molecular genetic diagnosis of oncourological diseases].

Currently, there is accumulated mass of data on the molecular-genetic disorders in prostate cancer (PCa), bladder cancer (BC) and renal cancer (RC). Tumor cells in these diseases are present in the urine sediment; their number is sufficient for molecular genetic analysis that makes possible the development of noninvasive diagnosis of oncourological diseases. A characteristic feature of PCa includes the overexpression of the PCA3 gene; assay kit Progensa™ to quantify such overexpression has been developed; approximately 50% of tumors express a TMPRSS2-ERG chimeric oncogene. Combined analysis of PCA3 and TMPRSS2-ERG allows to detect PCa with a diagnostic accuracy of 84%, which is significantly higher than that of prostate specific antigen test. As a potential markers of BC, there are somatic mutations in FGFR3, PIK3CA, TERT genes in urine sediment, which are found in this disease with a frequency of about 60, 30 and 50%, respectively. The basis of the test system for DNA diagnosis of BC in urine sediment may include a definition of a combination of mutations in these genes with microsatellite instability. Aberrant methylation of the 5'-regulatory regions of tumor suppressor genes, integrated in the panel, also is considered as a tool in the diagnosis of RC (VHL, RASSF1, RARB2, CDH1), PCa (GSTP1, PTGS2, LGALS3) and BC (RASSF1, APC, SFRP2) after standardization of panels of loci investigated, sample preparation methods, bisulfite conversion, and the design of primers and probes. Thus, a test systems for molecular genetic diagnosis of oncourological diseases in urine sediment are currently available or may be developed in the near future.

[Results of open multicenter study of the safety of doxazosin in combination with indigal in men with stages I-II prostatic adenoma].

The article presents a method of conservative treatment of men with I-II stage prostatic adenoma using a combination of doxazosin and indigal, which has antioxidant, antiproliferative and anti-inflammatory properties, that allowed improving urodynamic parameters and reducing the progression prostate adenoma, minimizing the adverse effects of treatment.

[Selzink plus study in patients with chronic non-infectious prostatitis and abnormal fertility].

Correction of subnormal spermatogenesis caused by chronic prostatitis is made with application of different therapeutic schemes. Our aim was to investigate efficacy of selzink medicine which corrects deficiency of trace elements Se and Zn in ejaculate and thus improves spermatogenesis. One-month course of therapy produced no side effects, had a positive effect on low fertility of ejaculate. Therefore, selzink can be recommended in combined treatment of male infertility.

[A comparative clinical randomized trial of cernilton efficacy and safety in patients with chronic abacterial prostatitis].

The trial of efficacy and safety of two doses of the drug cernilton in patients with chronic abacterial prostatitis made in the Research Institute of Urology and I.M. Sechenov Medical Academy in 2008 gave evidence for subjective (NIH-CPSI, Sex-4, IPSS and other scales, QOL) and objective (leucocyte count in prostatic secretion) pronounced anti-inflammatory effects of the drug which persist for at least 6 months. Comparison of the two doses of cernilton showed significant differences in subjective response of the patients (NIH-CPSI and Symptom Frequency Scale). Cernilton is recommended as a medication of choice for treatment of patients with chronic abacterial prostatitis.