Variables affecting new drug prices in South Korea's pricing system.

Objective: The price of pharmaceuticals is important from the economic and industrial perspectives but as well as patients' access to treatment. This study aimed to analyze the variables affecting the prices of new drugs in South Korea's pricing system. Methods: Data on 192 new drugs listed in South Korea from 2012 to 2022 were collected from the official website of the Health Insurance Review and Assessment Service. The independent variables included drugs for severe diseases, alternatives, number of patients, number of advanced 7 countries listed, budget impact, and listing period. The dependent variables included annual treatment cost and the price ratio to the advanced 7 country's average adjusted price. Descriptive statistics of variables, linear correlations between quantitative independent and dependent variables, and associations between independent and dependent variables were analyzed. Results: The mean annual treatment cost and price ratio to the advanced 7 country's average adjusted price were higher for drugs for severe diseases and those with no alternatives. Annual treatment cost and price ratio to the advanced 7 country's average adjusted price were negatively correlated with the number of patients and positively correlated with the number of advanced 7 countries listed. Annual treatment cost was affected by the variables drugs for severe diseases, alternatives, number of patients, number of advanced 7 countries listed, and budget impact. The price ratio to the advanced 7 country's average adjusted price was affected by drugs for severe diseases, alternatives, and the number of patients. Conclusion: This study revealed the effect of different variables on the prices of new drugs in South Korea, allowing for the development of a more effective assessment system to evaluate the prices of new drugs while ensuring profitability for pharmaceutical companies, sustainability of public insurance, and accessibility to drugs by patients.

Application of Machine Learning Algorithms to Predict Osteoporotic Fractures in Women.

BACKGROUND: Predicting the risk of osteoporotic fractures is vital for prevention. Traditional methods such as the Fracture Risk Assessment Tool (FRAX) model use clinical factors. This study examined the predictive power of the FRAX score and machine-learning algorithms trained on FRAX parameters. METHODS: We analyzed the data of 2,147 female participants from the Ansan cohort study. The FRAX parameters employed in this study included age, sex (female), height and weight, current smoking status, excessive alcohol consumption (>3 units/d of alcohol), and diagnosis of rheumatoid arthritis. Osteoporotic fracture was defined as one or more fractures of the hip, spine, or wrist during a 10-year observation period. Machine-learning algorithms, such as gradient boosting, random forest, decision tree, and logistic regression, were employed to predict osteoporotic fractures with a 70:30 training-to-test set ratio. We evaluated the area under the receiver operating characteristic curve (AUROC) scores to assess and compare the performance of these algorithms with the FRAX score. RESULTS: Of the 2,147 participants, 3.5% experienced osteoporotic fractures. Those with fractures were older, shorter in height, and had a higher prevalence of rheumatoid arthritis, as well as higher FRAX scores. The AUROC for the FRAX was 0.617. The machine-learning algorithms showed AUROC values of 0.662, 0.652, 0.648, and 0.637 for gradient boosting, logistic regression, decision tree, and random forest, respectively. CONCLUSION: This study highlighted the immense potential of machine-learning algorithms to improve osteoporotic fracture risk prediction in women when complete FRAX parameter information is unavailable.

Effect of permissive hypercarbia on lung oxygenation during one-lung ventilation and postoperative pulmonary complications in patients undergoing thoracic surgery: A prospective randomised controlled trial.

BACKGROUND: The effect of hypercarbia on lung oxygenation during thoracic surgery remains unclear. OBJECTIVE: To investigate the effect of hypercarbia on lung oxygenation during one-lung ventilation in patients undergoing thoracic surgery and evaluate the incidence of postoperative pulmonary complications. DESIGN: Prospective randomised controlled trial. SETTING: A tertiary university hospital in the Republic of Korea from November 2019 to December 2020. PATIENTS: Two hundred and ninety-seven patients with American Society of Anaesthesiologists physical status II to III, scheduled to undergo elective lung resection surgery. INTERVENTION: Patients were randomly assigned to Group 40, 50, or 60. An autoflow ventilation mode with a lung protective ventilation strategy was applied to all patients. Respiratory rate was adjusted to maintain a partial pressure of arterial carbon dioxide of 40 ±â€Š5 mmHg in Group 40, 50 ±â€Š5 mmHg in Group 50 and 60 ±â€Š5 mmHg in Group 60 during one-lung ventilation and at the end of surgery. MAIN OUTCOME MEASURES: The primary outcome was the arterial oxygen partial pressure/fractional inspired oxygen ratio after 60 min of one-lung ventilation. RESULTS: Data from 262 patients were analysed. The partial pressure/fractional inspired oxygen ratio was significantly higher in Group 50 and Group 60 than in Group 40 (269.4 vs. 262.9 vs. 214.4; P  < 0.001) but was not significantly different between Group 50 and Group 60. The incidence of postoperative pulmonary complications was comparable among the three groups. CONCLUSION: Permissive hypercarbia improved lung oxygenation during one-lung ventilation without increasing the risk of postoperative pulmonary complications or the length of hospital stay. TRIAL REGISTRATION: NCT04175379.

Efficacy of recombinant Bacillus Calmette-Guérin containing dltA in in vivo three-dimensional bio-printed bladder cancer-on-a-chip and ex vivo orthotopic mouse model.

PURPOSE: We investigated the efficacy and optimal dosage of recombinant Bacillus Calmette-Guérin-dltA (rBCG-dltA) in a high-throughput 3D bio-printed bladder cancer-on-a-chip (BCOC) and orthotopic bladder cancer mouse model. MATERIALS AND METHODS: We fabricated high-throughput BCOC with microfluidic systems, enabling efficient drug screening. The efficacy of rBCG-dltA was evaluated using BCOC by the cell viability assay, monocyte migration assay, and measuring cytokine levels. The anti-tumor effect was compared using the orthotopic bladder cancer mouse model. RESULTS: The cell proliferation rates of T24 and 253J bladder cancer cell lines (mean±standard error) were measured at three days after treatment. In T24 cell line, there was significantly decreased T24 cells compared to control at rBCG 1 multiplicity of infection (MOI) and 10 MOI (30 MOI: 63.1±6.4, 10 MOI: 47.4±5.2, 1 MOI: 50.5±7.5, control: 100.0±14.5, p<0.05). In 253J cell line, a statistically significant decrease in 253J cell count compared to control and mock BCG 30 MOI (30 MOI: 11.2±1.3, 10 MOI: 22.5±2.3, 1 MOI: 39.4±4.7, Mock: 54.9±10.8, control: 100.0±5.6, p<0.05). The migration rates of THP-1 cells showed increased patterns after rBCG-dltA treatment in BCOC. The concentration of tumor necrosis factor-α and interleukin-6 after rBCG-dltA 30 MOI treatment was higher than control in T24 and 253J cell line. CONCLUSIONS: In conclusion, rBCG-dltA has the potential to have better anti-tumor activity and immunomodulatory effects than BCG. Furthermore, high-throughput BCOCs have potential to reflect the bladder cancer microenvironment.

Synergistic Encapsulation of Paclitaxel and Sorafenib by Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles for Ovarian Cancer Therapy.

Ovarian cancer has a high mortality rate due to difficult detection at an early stage. It is necessary to develop a novel anticancer treatment that demonstrates improved efficacy while reducing toxicity. Here, using the freeze-drying method, micelles encapsulating paclitaxel (PTX) and sorafenib (SRF) with various polymers were prepared, and the optimal polymer (mPEG-b-PCL) was selected by measuring drug loading (%), encapsulation efficiency (%), particle size, polydispersity index, and zeta potential. The final formulation was selected based on a molar ratio (PTX:SRF = 1:2.3) with synergistic effects on two ovarian cancer cell lines (SKOV3-red-fluc, HeyA8). In the in vitro release assay, PTX/SRF micelles showed a slower release than PTX and SRF single micelles. In pharmacokinetic evaluation, PTX/SRF micelles showed improved bioavailability compared to PTX/SRF solution. In in vivo toxicity assays, no significant differences were observed in body weight between the micellar formulation and the control group. The anticancer effect of PTX/SRF combination therapy was improved compared to the use of a single drug. In the xenografted BALB/c mouse model, the tumor growth inhibition rate of PTX/SRF micelles was 90.44%. Accordingly, PTX/SRF micelles showed improved anticancer effects compared to single-drug therapy in ovarian cancer (SKOV3-red-fluc).

Effects of Iloprost on Arterial Oxygenation and Lung Mechanics during One-Lung Ventilation in Supine-Positioned Patients: A Randomized Controlled Study.

Patients undergoing one-lung ventilation (OLV) in the supine position face an increased risk of intraoperative hypoxia compared with those in the lateral decubitus position. We hypothesized that iloprost (ILO) inhalation improves arterial oxygenation and lung mechanics. Sixty-four patients were enrolled and allocated to either the ILO or control group (n = 32 each), to whom ILO or normal saline was administered. The partial pressure of the arterial oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio, dynamic compliance, alveolar dead space, and hemodynamic variables were assessed 20 min after anesthesia induction with both lungs ventilated (T1) and 20 min after drug nebulization in OLV (T2). A linear mixed model adjusted for group and time was used to analyze repeated variables. While the alveolar dead space remained unchanged in the ILO group, it increased at T2 in the control group (n = 30 each) (p = 0.002). No significant differences were observed in the heart rate, mean blood pressure, PaO2/FiO2 ratio, or dynamic compliance in either group. Selective ILO nebulization was inadequate to enhance oxygenation parameters during OLV in the supine position. However, it favorably affected alveolar ventilation during OLV in supine-positioned patients without adverse hemodynamic effects.

A risk scoring system integrating postoperative factors for predicting early mortality after major non-cardiac surgery.

We aimed to develop a risk scoring system for 1-week and 1-month mortality after major non-cardiac surgery, and assess the impact of postoperative factors on 1-week and 1-month mortality using machine learning algorithms. We retrospectively reviewed the medical records of 21,510 patients who were transfused with red blood cells during non-cardiac surgery and collected pre-, intra-, and postoperative features. We derived two patient cohorts to predict 1-week and 1-month mortality and randomly split each of them into training and test cohorts at a ratio of 8:2. All the modeling steps were carried out solely based on the training cohorts, whereas the test cohorts were reserved for the evaluation of predictive performance. Incorporation of postoperative information demonstrated no significant benefit in predicting 1-week mortality but led to substantial improvement in predicting 1-month mortality. Risk scores predicting 1-week and 1-month mortality were associated with area under receiver operating characteristic curves of 84.58% and 90.66%, respectively. Brain surgery, amount of intraoperative red blood cell transfusion, preoperative platelet count, preoperative serum albumin, and American Society of Anesthesiologists physical status were included in the risk score predicting 1-week mortality. Postoperative day (POD) 5 (neutrophil count × mean platelet volume) to (lymphocyte count × platelet count) ratio, preoperative and POD 5 serum albumin, and occurrence of acute kidney injury were included in the risk score predicting 1-month mortality. Our scoring system advocates the importance of postoperative complete blood count differential and serum albumin to better predict mortality beyond the first week post-surgery.

Immunotherapeutic effects of recombinant Bacillus Calmette-Guérin containing sic gene in ex vivo and in vivo bladder cancer models.

PURPOSE: The recombinant Bacillus Calmette-Guérin (BCG) containing the streptococcal inhibitor of the complement gene (rBCG-sic) may be more resistant to antimicrobial peptides and improve internalization; therefore, it can enhance the immunotherapeutic effect of the BCG. Here we determined the optimal dose of rBCG-sic and compared its effectiveness with that of BCG. MATERIALS AND METHODS: We fabricated a high-throughput 3D-bioprinted bladder cancer-on-a-chip (BCOC) and used it to evaluate the effectiveness of the rBCG-sic in terms of cell viability, cell migration, and cytokine concentrations. Using an orthotopic mouse model, we evaluated its anticancer effect and toxicity via bioluminescence imaging. RESULTS: T24 cell viability was decreased after treatment with rBCG-sic 30 multiplicities of infection (MOI) versus the same dosage of mock BCG (42.8%±6.4% vs. 75.7%±6.6%, p<0.05). THP-1 cell migration was positively correlated with rBCG-sic concentration (2.42-fold at 30MOI, p<0.01). The interleukin-6 concentration of rBCG-sic 30MOI was significantly higher than that of mock BCG 30MOI (11.2±1.3 pg/mL vs. 6.7±0.6 pg/mL, p<0.05). In the orthotopic bladder cancer mouse model, lower tumor volume was observed in the rBCG-sic 30MOI group than in the BCG 30MOI group after 10 days of treatment (p<0.05). CONCLUSIONS: We concluded that rBCG-sic is a useful tool for overcoming BCG unresponsiveness in non-muscle invasive bladder cancer. Additionally, high-throughput BCOC with a microfluidic system can successfully reflect the bladder cancer microenvironment.

The Role of Postoperative Radiotherapy in Intracranial Solitary Fibrous Tumor/Hemangiopericytoma: A Multi-institutional Retrospective Study (KROG 18-11).

PURPOSE: This study aimed to evaluate the role of postoperative radiotherapy (PORT) in intracranial solitary fibrous tumor/hemangiopericytoma (SFT/HPC). MATERIALS AND METHODS: A total of 133 patients with histologically confirmed HPC were included from eight institutions. Gross total resection (GTR) and subtotal resection (STR) were performed in 86 and 47 patients, respectively. PORT was performed in 85 patients (64%). The prognostic effects of sex, age, performance, World Health Organization (WHO) grade, location, size, Ki-67, surgical extent, and PORT on local control (LC), distant metastasis-free survival (DMFS), progression-free survival (PFS), and overall survival (OS) were estimated by univariate and multivariate analyses. RESULTS: The 10-year PFS, and OS rates were 45%, and 71%, respectively. The multivariate analysis suggested that PORT significantly improved LC (p < 0.001) and PFS (p < 0.001). The PFS benefit of PORT was maintained in the subgroup of GTR (p=0.001), WHO grade II (p=0.001), or STR (p < 0.001). In the favorable subgroup of GTR and WHO grade II, PORT was also significantly related to better PFS (p=0.028). WHO grade III was significantly associated with poor DMFS (p=0.029). In the PORT subgroup, the 0-0.5 cm margin of the target volume showed an inferior LC to a large margin with 1.0-2.0 cm (p=0.021). Time-dependent Cox proportion analysis showed that distant failures were significantly associated with poor OS (p=0.003). CONCLUSION: This multicenter study supports the role of PORT in disease control of intracranial SFT/HPC, irrespective of the surgical extent and grade. For LC, PORT should enclose the tumor bed with sufficient margin.

Establishment of Three-Dimensional Bioprinted Bladder Cancer-on-a-Chip with a Microfluidic System Using Bacillus Calmette-Guérin.

Immunotherapy of bladder cancer is known to have favorable effects, although it is difficult to determine which patients will show a good response because of the different tumor microenvironments (TME). Here, we developed a bladder cancer-on-a-chip (BCOC) to mimic the TME using three-dimensional (3D) bioprinting and microfluidic technology. We fabricated a T24 and a 5637-cell line-based BCOC that also incorporated MRC-5, HUVEC, and THP-1 cells. We evaluated the effects of TME and assessed the immunologic reactions in response to different concentrations of Bacillus Calmette-Guérin (BCG) via live/dead assay and THP-1 monocytic migration, and concentrations of growth factors and cytokines. The results show that cell viability was maintained at 15% filling density in circle-shaped cell constructs at 20 µL/min microfluidic flow rate. A 3D co-culture increased the proliferation of BCOCs. We found that the appropriate time to evaluate the viability of BCOC, concentration of cytokines, and migration of monocytes was 6 h, 24 h, and three days after BGC treatment. Lastly, the immunotherapeutic effects of BCOC increased according to BCG dosage. To predict effects of immunotherapeutic agent in bladder cancer, we constructed a 3D bioprinted BCOC model. The BCOC was validated with BCG, which has been proven to be effective in the immunotherapy of bladder cancer.

Characterization and functional roles of KCNQ-encoded voltage-gated potassium (Kv7) channels in human corpus cavernosum smooth muscle.

The group of KCNQ-encoded voltage-gated potassium (Kv7) channels includes five family members (Kv7.1-7.5). We examined the molecular expression and functional roles of Kv7 channels in corporal smooth muscle (CSM). Isolated rabbit CSM strips were mounted in an organ bath system to characterize Kv7 channels during CSM relaxation. Intracellular Ca2+ levels were measured in the CSM using the Ca2+ dye Fluo-4 AM. The expression of the KCNQ1-5 (the encoding genes for Kv7.1-7.5) and KCNE1-5 subtypes was determined by quantitative real-time PCR. Electrophysiological recordings and an in situ proximity ligation assay (PLA) were also performed. ML213 (a Kv7.2/7.4/7.5 activator) exhibited the most potent relaxation effect. XE911 (a Kv7.1-7.5 blocker) significantly inhibited the relaxation caused by ML213. Removal of the endothelium from the CSM did not affect the relaxation effect of ML213. H-89 (a protein kinase A inhibitor) and ESI-09 (an exchange protein directly activated by cAMP inhibitor) significantly inhibited ML213-induced relaxation (H-89: 31.3%; ESI-09: 52.7%). XE991 significantly increased basal [Ca2+]i in hCSM cells. KCNQ4 (the Kv7.4-encoding gene) and KCNE4 in CSM were the most abundantly expressed subtypes in humans and rats, respectively. KCNQ4 and KCNE4 expression was significantly decreased in diabetes mellitus rats. ML213 significantly increased the outward current amplitude. XE991 inhibited the ML213-induced outward currents. ML213 hyperpolarized the hCSM cell membrane potential. Subsequent addition of XE991 completely reversed the ML213-induced hyperpolarizing effects. A combination of Kv7.4 and Kv7.5 antibodies generated a strong PLA signal. We found that the Kv7.4 channel is a potential target for ED treatment.

Persistent Erectile Dysfunction after Discontinuation of 5-Alpha Reductase Inhibitor Therapy in Rats Depending on the Duration of Treatment.

PURPOSE: The current study is aimed to assess whether a longer duration of 5α-reductase inhibitor (5α-RI) exposure was associated with higher rate of permanent erectile dysfunction (ED) in a rat model. MATERIALS AND METHODS: Male Sprague-Dawley rats (n=76) were assigned to five groups: (i) normal control group; (ii) dutasteride (0.5 mg/rat/d) for 4-weeks group; (iii) dutasteride for 4-weeks plus 2-weeks of resting group; (iv) dutasteride for 8-weeks group; and (v) dutasteride for 8-weeks plus 2-weeks of resting group. In vivo erectile responses to electrical stimulation, and changes of fibrotic factors and smooth muscle/collagen contents in the corpus cavernosum were evaluated in each group. RESULTS: Dutasteride administration for 4 and 8 weeks significantly decreased erectile parameters compared with the control group. Reduced erectile responses were recovered during 2 weeks of drug-free time in the 4-week treatment group, but were not in the 8-week group. Protein levels of fibrosis-related factors transforming growth factor (TGF)-ß1, TGF-ß2, and p-Smad/Smad (Smad 2/3) in the corpus cavernosum showed no significant change after 4 weeks of dutasteride oral administration, but were enhanced after 8 weeks. Dutasteride markedly decreased smooth muscle content and increased collagen after 4 and 8 weeks of use, but no nuclear size changes; however, neither group showed significant improvement in the smooth muscle to collagen ratio after the rest period. CONCLUSIONS: Our study showed that recovery from ED depended on the duration of medication, and administration of dutasteride for more than 8-weeks in rats could result in irreversible ED even after discontinuation of medication.

Effect of BKCa Channel Opener LDD175 on Erectile Function in an In Vivo Diabetic Rat Model.

INTRODUCTION: The development of novel therapeutic options is imperative in patients with erectile dysfunction, especially those non-responsive to phosphodiesterase type 5 inhibitors. LDD175, a potent BKCa channel opener, has a relaxation effect on the in vitro cavernosal smooth muscle strip. AIM: To investigate the effect of LDD175 on erectile function using in vivo animal disease model. METHODS: Male Sprague-Dawley rats were assigned to a normal control group and seven diabetic groups: diabetic control, sildenafil (1 and 5 mg/kg), LDD175 (5 and 10 mg/kg), LDD175 5 mg/kg plus sildenafil 1 mg/kg, and LDD175 10 mg/kg plus tetraethylammonium. MAIN OUTCOME MEASURES: Intracavernosal pressure (ICP), ratio of ICP to mean arterial pressure (MAP), and the area under curve of ICP/MAP of eight groups were compared using in vivo pelvic nerve stimulation. RESULTS: The ICP, ICP/MAP ratio, and area under curve of the ICP/MAP ratio of the normal control rats increased with an increase in electrical field stimulation voltage. All parameters in the diabetic control group were significantly lower than those in the normal control rats, with an electrical field stimulation ranging from 1 to 5 V (P < .05). LDD175 improved the erectile response in diabetic rats in a dose-dependent manner. The combination of sildenafil (1 mg/kg) and LDD175 (5 mg/kg) showed a significant additive effect (P < .05) on the improvement of erectile function compared with sildenafil (1 mg/kg) alone. The enhancement of erectile function by LDD175 was completely blocked by tetraethylammonium. CONCLUSION: The results showed that the BKCa channel opener LDD175 improved erectile function in an in vivo diabetic rat model. Furthermore, combination therapy of LDD175 and sildenafil had an additive effect on the improvement of erectile function in diabetic rats. LDD175 could be a new candidate for the treatment of erectile dysfunction.

New Methodology for Investigating Ejaculation Dysfunction: Measuring Intraluminal Seminal Vesicle Pressure in Rats with a Telemetric Device.

INTRODUCTION: Ejaculation dysfunction is one of the most common male sexual disorders. Despite its prevalence and adverse impact on patients, little attention has been given to investigating ejaculation dysfunction. AIM: We introduce a new method for evaluating ejaculation dysfunction in rats with a telemetric device. METHODS: A pressure transducer was surgically implanted in the seminal vesicles of 7-week-old male Sprague-Dawley rats. One week later, the rats were subcutaneously administered tamsulosin 3 µg/kg, and intra-seminal vesicle pressure (ISVP) was recorded in freely moving rats after an injection of apomorphine (80 µg/kg). Same rats repeated experiment with tamsulosin 10 µg/kg, silodosin 1 mg/kg, and normal saline with 3-day intervals. MAIN OUTCOME MEASURE: Sexual events were visually identified and recorded. Ejaculation was confirmed by visualization of a copulatory plug in the tip of the penis. We compared the maximal ISVP and area under the curve (AUC) of the ISVP. RESULTS: Adequate ISVP data were easily recorded and available in 66.6% rats (10/15) over a 6-week telemetric recording period (12 recordings). The mean number of ejaculations during an inspection time of 30 minutes was 1.5 ± 0.1. The maximal ISVP values in rats receiving 3 µg/kg (30.0 ± 5.2 mm Hg) and 10 µg/kg tamsulosin (15.1 ± 1.6 mm Hg) and 1 mg/kg silodosin (12.9 ± 2.2 mm Hg) were significantly lower than that in control rats (61.4 ± 13.4 mm Hg, P < 0.05). The AUC values in rats receiving 3 µg/kg (72.7 ± 18.9 mm Hg × s) and 10 µg/kg tamsulosin (23.5 ± 6.1 mm Hg) and 1 mg/kg silodosin (23.9 ± 8.0 mm Hg) were also lower than that of control rats (162.6 ± 34.3 mm Hg, P < 0.05). CONCLUSIONS: Telemetric ISVP assessment is reliable and feasible for investigating apomorphine-induced ejaculation in rats. Tamsulosin (3 µg/kg and 10 µg/kg) and silodosin 1 mg/kg decreased the ISVP during ejaculation.

Effect of the novel BKCa channel opener LDD175 on the modulation of corporal smooth muscle tone.

INTRODUCTION: The BKCa channel has been reported to play an important role in erectile function. Recently, novel BKCa channel activator, LDD175, was introduced. AIM: This study aims to investigate whether LDD175 relaxes corporal smooth muscle (CSM) via BKCa channel activation. METHODS: After isolation of CSM strip from a male rabbit model, contraction studies using organ bath was performed. Isolating human tissue and cell cultures, electrophysiological studies were done via whole-cell patch-clamp recording. MAIN OUTCOME MEASURES: Vasodilatory effects of LDD175 were evaluated by cumulative addition ranging from 10(-7) to 10(-4) M in corpus cavernosal strips after precontraction with 10(-5) M phenylephrine via organ bath system. Using cultured human CSM cells, patch-clamp recording was performed. Erectile function was measured by in vivo rat cavernous nerve stimulation. RESULTS: LDD175 caused an endothelium-independent relaxation of corporal tissues, and this effect was abolished by pretreatment with iberiotoxin. The relaxation effect of 10(-4) M LDD175 was greater than that of 10(-6) M udenafil (54.0 ± 3.1% vs. 34.5 ± 3.9%, P < 0.05); 10(-5) M LDD175 with 10(-6) M udenafil caused a greater relaxation effect on strips than 10(-5) M LDD175 or 10(-6) M udenafil alone (50.7%, 34.1%, vs. 20.7%, respectively, P < 0.001). In patch-clamp recordings, LDD175 increased K(+) currents in a dose-dependent manner, and washout of LDD175 or the addition of iberiotoxin fully reversed the increase. Intravenous LDD175 improved erectile function measured by area under the curve (AUC) of the intracavernosal pressure (ICP)/arterial blood pressure (ABP) ratio (1,612.1 ± 135.6 vs. 1,093.7 ± 123.1, P < 0.05). There was no difference between 10 mg/kg LDD175 and 1 mg/kg udenafil regarding maximal ICP, maximal ICP/ABP ratio, and the AUC of the ICP/ABP ratio (P > 0.05). CONCLUSIONS: LDD175 leads to an endothelium-independent relaxation of erectile tissue, primarily through the opening of BKCa channels. The results suggest that LDD175 might be a new candidate treatment for erectile dysfunction.

Effects of Schisandra chinensis extract on the relaxation of isolated human prostate tissue and smooth muscle cell.

ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis has been commonly used as a traditional herbal medicine to treat various diseases including body weakness, dysentery, impotence, enuresis and frequent urination in many countries including Korea, China and Russia. Benign prostate hyperplasia is a common disease for the elderly men and it induces lower urinary tract symptoms which hinder general activity and quality of life. We evaluated the therapeutic potential of Schisandra chinensis extract (SCE) in benign prostate hyperplasia using human prostate tissue. MATERIALS AND METHODS: Schisandra chinensis fruit was collected and extracted with ethanol. Human prostate tissues were obtained from 14 prostate cancer patients. Macroscopically normal tissue was excised from the transition zone and the periurethral regions. Isolated prostate tissue strips were mounted in an organ-bath system, and the relaxation effect of SCE was evaluated by cumulative addition to prostate strips pre-contracted with 10(-5)M norepinephrine. The effect of tamsulosin was compared, and the additive effect was evaluated. Electrophysiological studies using cultured human prostate smooth muscle cells (HPrSMC) were conducted. RESULTS: Cumulative dosing of SCE induced concentration-dependent relaxation in contracted prostate tissue (n=18, P<0.05). Simultaneous dosing of SCE and tamsulosin showed an additive relaxation effect. The relaxation effect of SCE was abolished by inhibition of K+ channels by pre-treatment with tetraethylammonium. In HPrSMC, extracellular application of 100 µg/mL SCE significantly increased outward currents, and this effect was significantly attenuated by treatment with 100 nM Iberiotoxin. CONCLUSIONS: SCE showed a dose dependent relaxation effect on human prostate tissue as well as an additive effect with tamsulosin. The relaxation effects of SCE on HPrSMC were, in part, due to the activation of K+ channels.

Endothelium-independent relaxant effect of Rubus coreanus extracts in corpus cavernosum smooth muscle.

INTRODUCTION: Rubus coreanus is a perennial shrub native to the southern part of the Korean peninsula. Although it is known that R. coreanus has a dose-dependent relaxation effect on rabbit corpus cavernosum (CC), the exact mechanism of action by which R. coreanus work is not fully known. AIMS: To elucidate the direct effects of unripe R. coreanus extract (RCE) on CC smooth muscle cells. METHODS: Dried unripe R. coreanus fruits were pulverized and extracted with 95% ethanol. Isolated rabbit CC strips were mounted in an organ-bath system, and the effects of RCE were evaluated. To estimate [Ca(2+)]i , we used a Fura-2 fluorescent technique. MAIN OUTCOME MEASURES: The effects of unripe RCE on ion channels and the intracellular Ca(2+) concentration ([Ca(2+)]i ) of CC. RESULTS: RCE effectively relaxed phenylephrine (PE)-induced tone in rabbit CC, and removal of the endothelium did not completely abolish the relaxation effect of RCE. Tetraethylammonium (1 mM) did not inhibit RCE-induced relaxation in strips precontracted by PE in the organ bath. However, CaCl2 -induced constriction of CC strips, bathed in Ca(2+)-free buffer and primed with PE, was abolished by RCE. In addition, RCE decreased basal [Ca(2+)]i in corporal smooth muscle cells. The increases of [Ca(2+)]i evoked by 60 mM K(+)-containing solution in A7r5 cells were suppressed by RCE, and RCE relaxed KCl-induced tone in endothelium-free CC, which indicated that RCE blocked the voltage-dependent Ca(2+) channels (VDCCs). RCE decreased basal [Ca(2+)]i and the [Arg8]-vasopressin-induced [Ca(2+)]i increases in A7r5 cells, and RCE inhibited the contraction of endothelium-free CC induced by PE in Ca(2+)-free solution, which suggested that RCE might act as a modulator of corporal smooth muscle cell tone by inhibiting Ca(2+) release from sarcoplasmic reticulum. CONCLUSION: RCE acts through endothelium-independent and endothelium-dependent pathways to relax CC. RCE may inhibit VDCCs and Ca(2+) release from sarcoplasmic reticulum.