Comparison of three artificial intelligence algorithms for automatic cobb angle measurement using teaching data specific to three disease groups.

Spinal deformities, including adolescent idiopathic scoliosis (AIS) and adult spinal deformity (ASD), affect many patients. The measurement of the Cobb angle on coronal radiographs is essential for their diagnosis and treatment planning. To enhance the precision of Cobb angle measurements for both AIS and ASD, we developed three distinct artificial intelligence (AI) algorithms: AIS/ASD-trained AI (trained with both AIS and ASD cases); AIS-trained AI (trained solely on AIS cases); ASD-trained AI (trained solely on ASD cases). We used 1612 whole-spine radiographs, including 1029 AIS and 583 ASD cases with variable postures, as teaching data. We measured the major and two minor curves. To assess the accuracy, we used 285 radiographs (159 AIS and 126 ASD) as a test set and calculated the mean absolute error (MAE) and intraclass correlation coefficient (ICC) between each AI algorithm and the average of manual measurements by four spine experts. The AIS/ASD-trained AI showed the highest accuracy among the three AI algorithms. This result suggested that learning across multiple diseases rather than disease-specific training may be an efficient AI learning method. The presented AI algorithm has the potential to reduce errors in Cobb angle measurements and improve the quality of clinical practice.

Decomposed Multilateral Filtering for Accelerating Filtering with Multiple Guidance Images.

This paper proposes an efficient algorithm for edge-preserving filtering with multiple guidance images, so-called multilateral filtering. Multimodal signal processing for sensor fusion is increasingly important in image sensing. Edge-preserving filtering is available for various sensor fusion applications, such as estimating scene properties and refining inverse-rendered images. The main application is joint edge-preserving filtering, which can preferably reflect the edge information of a guidance image from an additional sensor. The drawback of edge-preserving filtering lies in its long computational time; thus, many acceleration methods have been proposed. However, most accelerated filtering cannot handle multiple guidance information well, although the multiple guidance information provides us with various benefits. Therefore, we extend the efficient edge-preserving filters so that they can use additional multiple guidance images. Our algorithm, named decomposes multilateral filtering (DMF), can extend the efficient filtering methods to the multilateral filtering method, which decomposes the filter into a set of constant-time filtering. Experimental results show that our algorithm performs efficiently and is sufficient for various applications.

Automatic measurement of the Cobb angle for adolescent idiopathic scoliosis using convolutional neural network.

This study proposes a convolutional neural network method for automatic vertebrae detection and Cobb angle (CA) measurement on X-ray images for scoliosis. 1021 full-length X-ray images of the whole spine of patients with adolescent idiopathic scoliosis (AIS) were used for training and segmentation. The proposed AI algorithm's results were compared with those of the manual method by six doctors using the intraclass correlation coefficient (ICC). The ICCs recorded by six doctors and AI were excellent or good, with a value of 0.973 for the major curve in the standing position. The mean error between AI and doctors was not affected by the angle size, with AI tending to measure 1.7°-2.2° smaller than that measured by the doctors. The proposed method showed a high correlation with the doctors' measurements, regardless of the CA size, doctors' experience, and patient posture. The proposed method showed excellent reliability, indicating that it is a promising automated method for measuring CA in patients with AIS.

Upper End Vertebra of Proximal Thoracic Curve At T1 is a Novel Risk Factor of Postoperative Shoulder Imbalance in Lenke Type 2 Adolescent Idiopathic Scoliosis.

STUDY DESIGN: Retrospective single-center study. OBJECTIVE: We investigated the risk factors of postoperative shoulder imbalance (PSI) in patients with Lenke type 2 adolescent idiopathic scoliosis (AIS) including the position of preoperative upper end vertebra (UEV). METHODS: Seventy-five patients with Lenke type 2 AIS who underwent posterior correction and fusion surgeries from 2008 to 2018 were included. We included only patients whose upper instrumented vertebrae were at T2. The patients were divided into 2 groups based on radiographic shoulder height (RSH) at final follow-up, namely PSI group and non-PSI group, and PSI was defined as RSH > 10 mm. UEV, RSH, Cobb angle, curve flexibility, T1 and T2 tilt, correction rate, Risser grade, Scoliosis Research Society-22 scores, and demographic data were compared between the groups using independent t-tests or chi-square tests. Variables with P value < 0.20 in univariate analysis were assessed in logistic regression analysis. RESULTS: Thirty-four patients in the PSI group and 37 patients in the non-PSI group were analyzed. Univariate analysis revealed that there were more patients with UEV at T1 (PSI: 85%, non-PSI: 54%, P < 0.01) and Risser grade ≥ 3 (PSI: 88%, non-PSI: 62%; P < 0.05) in the PSI group than in the non-PSI group. Logistic regression analysis revealed that UEV at T1 (odds ratio [OR] = 4.1 [1.2-14.4], P < 0.05) and Risser grade ≥ 3 (OR = 3.9 [1.1-14.5], P < 0.05) are significantly associated with PSI. CONCLUSIONS: UEV at T1 and Risser grade ≥ 3 at the time of surgery are significant risk factors of PSI.

Multispectral near-infrared imaging for wetness estimation.

Estimation of the wetness of objects is an important technique for recognizing states in the real world. In this paper, we propose a non-contact method for estimating the wetness of objects using multispectral near-infrared (NIR) imaging. In contrast with a previous method that requires hyperspectral (110-band) images taken with fine spectral resolution (5 nm intervals) to estimate the degree of wetness, our method enables accurate wetness estimation using few-band NIR images with coarse spectral resolution (40 nm intervals). In general, water absorbs a substantial amount of incident light at wavelengths around 1000 nm and a smaller amount at wavelengths around 900 nm. This phenomenon indicates that the light absorption coefficient of water particularly varies over the NIR spectral band. These differences in the light absorption coefficients of water in the NIR bands are exploited in the model we derived for the appearance of a wet object surface, facilitating accurate wetness estimation. The effectiveness of the proposed method is demonstrated experimentally.

Does cognitive behavioral therapy for anxiety disorders assist the discontinuation of benzodiazepines among patients with anxiety disorders? A systematic review and meta-analysis.

Long-term use of benzodiazepines (BZD) is not recommended for the treatment of anxiety disorders. Cognitive behavioral therapy (CBT) is an effective treatment option for discontinuation of BZD in patients with anxiety disorders. This systematic review and meta-analysis sought to clarify whether CBT is effective for discontinuing BZD anxiolytics in patients with anxiety disorders. This study was preregistered with PROSPERO (registration number: CRD42019125263). A literature search of major electronic databases was conducted in December 2018. Three randomized controlled trials were included in this review, and meta-analyses were performed. The proportion of discontinuing BZD anxiolytics was significantly higher in the CBT plus gradual tapering group than in the gradual tapering alone group, both in the short term (3 months after allocation; number needed to treat: 3.2, 95% confidence interval [CI]: 2.1 to 7.1; risk ratio: 1.96, 95%CI: 1.29 to 2.98, P = 0.002, three studies) and long term (6 to 12 months after allocation; number needed to treat: 2.8, 95%CI: 1.9 to 5.3; risk ratio: 2.16, 95%CI: 1.41 to 3.32, P = 0.0004, three studies). CBT may be effective for discontinuing BZD anxiolytics, both in the short term and in the long term after the allocation. Further studies with larger sample sizes are necessary to draw definitive conclusions regarding the efficacy and safety of CBT for discontinuing BZD anxiolytics in patients with anxiety disorders.

Investigation of appropriate semi-quantitative index for assessment of esophageal and breast cancer treatment response in Japanese patients using 18F-FDG PET/CT findings.

OBJECTIVE: To examine the correlation of the quantitative indexes standardized uptake value (SUV), SUV corrected for lean body mass (SUL) and SUV corrected for Japanese lean body mass (SULj) with body weight to develop an appropriate quantitative index independent of body weight fluctuation for assessment of response to cancer treatment in Japanese patients. SUBJECTS AND METHODS: Fifty-six males with esophageal cancer and 30 females with breast cancer underwent fluorine-18-fluoro-2-deoxy-D-glucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) scans, once before and once after, receiving neoadjuvant chemotherapy prior to planned surgical resection. The maximum value, peak value, and average value of SUV, SUL and SULj were calculated by setting a spherical volume of interest (3cm diameter) in a normal area of the liver. The correlation between each index and body weight was obtained from the correlation coefficient (r) and the significance of the correlation was tested. RESULTS: Analyses were conducted with all patients (P<0.01), as well as after dividing into those with only esophageal (P<0.05) or breast (P<0.01) cancer. Regarding the correlation coefficient between each index and body weight, a significant difference was seen for SUVmax, SUVpeak and SUVmean. In contrast, there was no correlation with body weight for SULmax, SULpeak, SULmean, SULjmax, SULjpeak, or SULjmean in any of the 3 groups. CONCLUSION: Based on the correlation with body weight, we concluded that both SUL and SULj (SUL corrected for Japanese lean body mass) is useful for assessment of cancer treatment response in Japanese patients.

[Simulation at Incomplete Acquisition on Stress-rest Cerebral Blood Flow Quantitative Values One Day Method].

The QSPECT dual table autoradiography (DTARG) method can be used for quantitative determination of cerebral blood flow. We verified the influence on quantitative values obtained for cerebral blood flow in the case when usual acquisition was impossible and evaluated those values. Results obtained with an acquisition time of 30 min were considered to be true values, and the correlation and consistency with results of other times were evaluated. Values obtained with a shortened acquisition time showed a high correlation with the true value. As for consistency, there were differences among the various data collection intervals. Nevertheless, regardless of the use of a shortened acquisition time and the data acquisition interval, values obtained with the QSPECT program showed a high correlation with the true value. Based on our findings showing a high correlation, a quantitative evaluation of cerebral blood flow can be performed with the QSPECT DTARG method, even with complications, such as examination interruption, thus, it is considered to be a flexible method.

C5a receptor expression is associated with poor prognosis in urothelial cell carcinoma patients treated with radical cystectomy or nephroureterectomy.

Patients with aggressive urothelial cell carcinoma (UCC) that undergo radical cystectomy or nephroureterectomy exhibit markedly high rates of disease recurrence and mortality. To select appropriate adjuvant thxerapies in addition to radical surgery, the identification of predictive prognostic markers for UCC patients is required. The aim of the present study was to identify such markers, by evaluating the association of UCC complement component 5 (C5) fragment a (C5a)receptor (C5aR) expression, detected using immunohistochemistry, with clinicopathological parameters and survival outcomes of UCC patients. The results revealed that C5aR was expressed in cancer cells, particularly at the invasive front, but not in noncancerous urothelial cells or adjacent cells. The UCC C5aR-positive rate of patients treated with radical surgeries was 73% (38/52) and the rate was 83% (20/24) at stages I-II of disease. No correlation between C5aR expression and any of clinicopathological parameters, which included gender, tumor location, World Health Organization grade, T stage, vessel invasion and stage of disease, was identified. However, univariate and multivariate analyses revealed that C5aR-positive UCC patients exhibited significantly lower overall survival rates [hazard ratio (HR), 3.14; 95% confidence interval (CI), 1.03-9.60; P=0.035 and HR, 3.92; 95% CI, 1.15-13.4; P=0.029, respectively] and 5-year survival rates (0.42 vs. 0.83) compared with C5aR-negative UCC patients. Furthermore, 5-year survival and disease-specific survival rates were lower in patients with C5aR-positive UCC (0.51; 95% CI, 0.30-0.71) than patients with C5aR-negative UCC (0.83; 95% CI, 0.62-1.00). These results indicate that UCC C5aR expression is predictive of poor patient outcomes and thus may lead to the appropriate selection of adjuvant therapies at earlier UCC stages, which could improve patient prognosis.

Sorafenib enhances the antitumor effects of anti-CTLA-4 antibody in a murine cancer model by inhibiting myeloid-derived suppressor cells.

This antitumor effect of sorafenib is considered to be dependent not only on its direct cytotoxicity to cancer cells but also due to the inhibition of myeloid-derived suppressor cells (MDSCs). Recently, a novel antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4), which activates lymphocytes, is currently in clinical applications. The aim of the present study was to investigate the synergistic antitumor effects of anti-CTLA-4 antibody (Ab) and sorafenib in a murine cancer model. RENCA cells were subcutaneously inoculated into mice, which were randomly divided into 4 treatment groups: sorafenib plus anti-CTLA-4 Ab, sorafenib plus control Ab, vehicle plus anti-CTLA-4 Ab, and vehicle plus control Ab. Single therapy using anti-CTLA-4 Ab suppressed tumor growth, but no difference was noted when compared with the single therapy group using sorafenib. Notably, the greatest decrease in tumor size was noted with sorafenib plus anti-CTLA-4 Ab (combination therapy), and the highest rate of tumor rejection was observed in the combination therapy group. The number of infiltrating CD4- or CD8-positive lymphocytes was strongly increased in the combination therapy group. These in vivo data indicate that sorafenib increased the immunostimulatory effect of anti-CTLA-4 Ab even when sorafenib was used at a low dose. An in vitro study using MDSCs and CD8(+) T cells showed that the inhibitory effect of MDSCs on CD8(+) T cells was significantly abrogated by the combined use of sorafenib and anti-CTLA-4 Ab. Sorafenib suppressed the expression of immunosuppressive factors in MDSCs. These data indicate that combination therapy of sorafenib and anti-CTLA-4 Ab may be effective in advanced kidney cancer patients.

C5aR is frequently expressed in metastatic renal cell carcinoma and plays a crucial role in cell invasion via the ERK and PI3 kinase pathways.

The anaphylatoxin C5a is a chemoattractant for leukocyte migration via the C5a receptor (C5aR). We recently reported that C5aR was aberrantly expressed in a wide variety of human related cancers, while it also promotes cancer cell invasion by C5a stimulation. However, the biological significance of C5aR expression in renal cell carcinoma (RCC) has not yet been clarified. In the present study, we aimed to elucidate the biological role of C5aR in RCC progression. Clinical RCC specimens were analyzed for C5aR expression and its relationship with baseline demographic data and clinicopathological parameters was analyzed. Moreover, renal carcinoma Renca cells stably expressing C5aR were generated and used to assess the effects of C5a-C5aR axis activation on various cellular phenomena in culture. Immunohistochemistry revealed that 96.7% of the metastatic RCCs (mRCCs) showed C5aR expression, whereas only 50.5% of the non-metastatic RCCs expressed C5aR (P<0.001). Although C5a stimulation did not significantly alter anoikis of C5aR­expressing Renca cells, C5a elicited cell morphological change and scattering of those cells accompanied with dynamic actin rearrangement, which was not observed in the Renca cells harboring the empty vector only. Moreover, C5a triggered ERK and PI3K­dependent invasion of the C5aR-expressing renal carcinoma cells. These results are consistent with the idea that the C5a-C5aR axis plays a crucial role in renal carcinoma cell invasion, which may be one of the key steps for RCC metastasis. The present study provides proof­of­concept that the C5a-C5aR axis may be a useful therapeutic target for preventing RCC progression.

Severe bleeding tendency caused by a rare complication of excessive fibrinolysis with disseminated intravascular coagulation in a 51-year-old Japanese man with prostate cancer: a case report.

INTRODUCTION: Disseminated intravascular coagulation causes thrombotic tendency leading to multiple organ failure and occurs in a wide variety of diseases including malignancy. Disseminated intravascular coagulation is a latent complication in people with prostate cancer. CASE PRESENTATION: A 51-year-old Japanese man with advanced castration-resistant prostate cancer was admitted to our hospital because of extensive purpura and severe anemia. Prolonged plasma coagulation time, hypofibrinogenemia and normal platelet count suggested that a decrease in fibrinogen induced a bleeding tendency causing purpura. However, elevated plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers, with positive fibrin monomer test, manifested disseminated intravascular coagulation and subsequent fibrinolysis. Plasma levels of thrombin-antithrombin complex, fibrin and/or fibrinogen degradation products and D-dimers decreased after administration of low-molecular-weight heparin. However, low fibrinogen and α2-antiplasmin levels were not improved and plasmin-antiplasmin complex did not decrease, which revealed excessive fibrinolysis complicated with disseminated intravascular coagulation. We suspected that prostate cancer cell-derived urokinase-type plasminogen activator caused excessive fibrinolysis. Administration of tranexamic acid for fibrinogenolysis was added together with high-dose anti-androgen therapy (fosfestrol) for prostate cancer. Thereafter, prostate-specific antigen and plasmin-antiplasmin complex decreased, followed by normalized fibrinogen and α2-antiplasmin levels, and the patient eventually recovered from the bleeding tendency. Immunohistochemical staining of the biopsied prostate tissue exhibited that the prostate cancer cells produced tissue factor, the coagulation initiator, and urokinase-type plasminogen activator. CONCLUSION: This patient with rare complications of disseminated intravascular coagulation and excessive fibrinolysis is a warning case of potential coagulation disorder onset in patients with prostate cancer. We propose that combined administration of tranexamic acid and low-molecular-weight heparin together with high-dose anti-androgen therapy is a useful therapeutic option for patients with this complicated coagulation disorder.

Two identical nonylphenol monooxygenase genes linked to IS6100 and some putative insertion sequence elements in Sphingomonas sp. NP5.

Sphingomonas sp. NP5 can degrade a wide range of nonylphenol (NP) isomers that have widely contaminated aquatic environments as major endocrine-disrupting chemicals. To understand the biochemical and genetic backgrounds of NP degradation, a gene library of strain NP5 was constructed using a broad-host-range vector pBBR1MCS-2 and introduced into Sphingobium japonicum UT26. Several transformants accumulated reddish brown metabolites on agar plates dispersed with a mixture of NP isomers. Two different DNA fragments (7.6 and 9.3 kb) involved in the phenotype were isolated from the transformants. Sequence analysis revealed that both fragments contained an identical 1593 bp monooxygenase gene (nmoA), the predicted protein sequence of which showed 83 % identity to the octylphenol-4-monooxygenase of Sphingomonas sp. PWE1. The nmoA gene in the 7.6 kb fragment was surrounded by an IS21-type insertion sequence (IS) and IS6100, while another in the 9.3 kb fragment was adjacent to an IS66-type IS, suggesting that they have been acquired through multiple transposition events. A fast-growing recombinant Pseudomonas putida strain harbouring nmoA was constructed and used for degradation of a chemically synthesized NP isomer, 4-(1-ethyl-1-methylhexyl)phenol. This strain converted the isomer into hydroquinone stoichiometrically. 3-Methyl-3-octanol, probably originating from the alkyl side chain, was also detected as the metabolite. These results indicate that these two nmoA genes are involved in the NP degradation ability of strain NP5.

Blood kinetics of four intraperitoneally administered therapeutic candidate bacteriophages in healthy and neutropenic mice.

Due to multiple-drug resistant bacteria, phage therapy is being revisited. Although most animal experiments focus on therapeutic efficacy, the blood clearance kinetics of phages have not been well described. For further development of an efficient therapeutic strategy, information on phage blood kinetics is important. In this study, time-course concentration changes in peripheral blood of healthy and neutropenic mice were measured using four therapeutic phages (phiMR11, KPP10, phiEF24C, and KEP10). The results showed a two- to three-day rapid phage clearance, which fits a two-compartment model.

A new retainer using magnetic attachment.

PATIENT: A 58-year-old man with a complaint of masticatory disturbance presented. His mandibular left premolars and molars were missing, and the mandibular left canine, which was neighboring to the missing part, showed marked labial tipping. A cobalt-chromium removable partial denture was fabricated using a new magnetic attachment retainer because it seemed difficult to apply a conventional clasp for this case. This retainer is constructed from the buccal hook arm sliding bucco-lingually and the magnetic attachment which works to lock the movable part when it was closed. Six years after the delivery of this denture, both the abutment tooth and the periodontal tissue are healthy, and the denture is functioning well. DISCUSSION: As this retainer does not use the elasticity of clasp arms, block out area can be minimized, and the maximum area of the contacting surface of the hook arm brings about very positive retention and bracing. The function of attractive force is to resist the splitting force and not to become directly involved in the retention of the denture. Therefore, the attractive force for this system does not need to be very strong. This system also provides the advantages of a sectional denture, allowing protection of the abutment tooth and the use of the abutment tooth in its original form. CONCLUSION: The retainer described in this report has many advantages including, no hazardous lateral force, adequate retentive force, and application to natural teeth or tipped teeth.

Preventive effects of a Kampo medicine, Shosaikoto, on inflammatory responses in LPS-treated human gingival fibroblasts.

In the present study, we investigated the anti-inflammatory effects of a Kampo medicine Shosaikoto (TJ-9) using in vitro periodontal disease model, in which human gingival fibroblasts (HGFs) treated with lipopolysaccharide (LPS) from Porphyromonas gingivalis (PgLPS) produce IL-6, IL-8 and prostaglandin E2 (PGE2). Treatment with PgLPS (10 ng/ml), TJ-9 (up to 1 mg/ml) and their combinations for 24 h did not affect the viability of HGFs. Moreover, TJ-9 did not alter LPS-induced IL-6 and IL-8 productions. However, TJ-9 significantly suppressed LPS-induced PGE2 production in a dose-dependent manner but TJ-9 alone did not affect basal PGE2 level. Western blotting demonstrated that TJ-9 decreased cyclooxygenase-2 (COX-2) expression in a dose-dependent manner but not phospholipase A2. Moreover, TJ-9 selectively and dose-dependently inhibited COX-2 activity. These results suggest that TJ-9 decreased PGE2 production by inhibition of both COX-2 expression and activity and that TJ-9 may be useful to improve gingival inflammation in periodontal disease.

Pharmacological effects of solifenacin on human isolated urinary bladder.

To investigate the effects of solifenacin on human detrusor smooth muscles, we evaluate the effects of solifenacin on the contractions induced by carbachol, KCl, CaCl2 and electrical field stimulation (EFS), and the EFS-induced acetylcholine release from detrusor smooth muscle strips by using the muscle bath and microdialysis technique. The effects of solifenacin were also compared with effects of other antimuscarinic agents (atropine, oxybutynin and propiverine). Pretreatment with various antimuscarinic agents caused parallel shifts to the right of the concentration-response curves to carbachol. The pA2 value of the Schild plots for solifenacin was similar to that for oxybutynin. Atropine did not inhibit the KCl- and CaCl2-induced contractions, while solifenacin, oxybutynin and propiverine significantly inhibited these contractions. EFS-induced contractions were inhibited by various antimuscarinic drugs in a concentration-dependent manner. In the presence of atropine, solifenacin tended to inhibit the residual atropine-resistant contractions induced by EFS, but it was not significant. However, oxybutynin and propiverine inhibited them under the same conditions. Although pretreatment with atropine and propiverine did not cause significant changes in EFS-induced acetylcholine release, solifenacin and oxybutynin caused significant decreases in acetylcholine release. The present results suggest that solifenacin inhibits contractions of human detrusor smooth muscles mainly by the antimuscarinic action and that the high concentration of solifenacin has Ca2+ channel antagonist action. Moreover, solifenacin may block not only postjunctional receptors, but also prejunctional receptors to modulate acetylcholine releases in cholinergic nerve endings in human detrusor smooth muscles. The findings support that muscarinic-receptor-inhibitory actions in human bladder mainly contribute to the usefulness of solifenacin as a therapeutic drug for overactive bladder.

Basic and clinical aspects of non-neuronal acetylcholine: expression of non-neuronal acetylcholine in urothelium and its clinical significance.

Recently, several reports demonstrate that non-neuronal acetylcholine (ACh) release may contribute to various pathophysiological conditions. In this review, we presented our experiments designed to evaluate the non-neuronal cholinergic system in human bladder. After insertion of the microdialysis probe, human bladder strips were suspended in an organ bath filled with Krebs-Henseleit solution, and Ringer solution was perfused into the probe. ACh release was measured by microdialysis and HPLC. The contribution of urothelium and the effects of age and stretch of bladder strips on non-neuronal ACh release were evaluated. Choline acetyltransferase (ChAT) immunohistochemical staining of bladder was also performed. Immunohistochemistry showed marked ChAT-positive staining in the urothelium. There was tetrodotoxin-insensitive non-neuronal ACh release and this was significantly higher in strips with urothelium than in strips without urothelium. The non-neuronal ACh release was increased with age. Stretch of bladder strips caused increases in non-neuronal ACh release. The stretch-induced release of non-neuronal ACh was increased with age. Our data demonstrate that there is a non-neuronal cholinergic system in human bladder and that urothelium contributes to non-neuronal ACh release. There was significant age-related and stretch-induced increase in non-neuronal ACh release. It is suggested that the non-neuronal cholinergic system may contribute to the physiology and pathophysiology of human bladder. We also discussed the clinical significance of the non-neuronal cholinergic system in human bladder.

Pharmacological effects of propiverine and its active metabolite, M-1, on isolated human urinary bladder smooth muscle, and on bladder contraction in rats.

OBJECTIVE: To investigate the effects of M-1, a major active metabolite of propiverine on the bladder. METHODS: We have evaluated the effects of M-1 on the contractions induced by carbachol, KCl, CaCl(2), and electrical field stimulation (EFS) in human detrusor smooth muscles, and pelvic nerve stimulation-induced bladder contractions in rats. The effects of M-1 were also compared with the effects of propiverine and tolterodine. RESULTS: Pretreatment with propiverine and tolterodine caused parallel shifts to the right of the concentration-response curves to carbachol. M-1 caused concentration-dependent reduction in the maximum contractile responses induced by carbachol. Although tolterodine did not inhibit the KCl- and CaCl(2)-induced contractions, M-1 and propiverine significantly inhibited these contractions. In the presence of atropine, M-1 and propiverine significantly inhibited the atropine resistant part of the contraction induced by EFS. On the other hand, tolterodine did not have significant inhibitory effects on atropine resistant contractions. Pelvic nerve stimulation induced bimodal phasic and tonic contractions in the rat bladder. M-1 mainly inhibited the phasic contraction. Tolterodine caused a significant inhibition in the tonic contraction, and propiverine had inhibitory effects on both contractions. CONCLUSIONS: The present results suggest that M-1 has inhibitory effects on the bladder smooth muscles through calcium antagonistic action. It is possible that the clinical effects of propiverine on the human bladder are based not only on the action of propiverine itself but also on one of its active metabolites, M-1.