Efficacy and safety of intravenous administration of high-dose selenium for preventing chemotherapy-induced peripheral neuropathy in platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer: study protocol for a phase III, double-blind, randomized study.

BACKGROUND: The second-line chemotherapy using paclitaxel, carboplatin, and bevacizumab for treating platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer frequently cause chemotherapy-induced peripheral neuropathy (CIPN), which is significantly associated with deterioration of quality of life. Despite the potential of some agents to prevent and treat CIPN, and there is still a lack of evidence of the effect. Although selenium has been suggested as an antioxidant candidate to prevent CIPN, there are insufficient data regarding its effect due to its low dose by oral administration. Thus, we hypothesized intravenous administration of high-dose selenium (2,000 µg/day) at each cycle of the second-line chemotherapy would prevent and reduce CIPN in patients with platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer. METHOD: This trial is an investigator-initiated, phase III, double-blinded, randomized controlled trial to evaluate the efficacy and safety of intravenous administration of high-dose selenium (2,000 µg/day) for preventing CIPN in patients with platinum-sensitive recurrent ovarian, fallopian or primary peritoneal cancer who receive paclitaxel, carboplatin, and bevacizumab. A total of 68 patients will be randomly assigned to the experimental and control groups at a 1:1 ratio. As the primary endpoint, the incidence rate of CIPN three months after six cycles of chemotherapy will be compared between the two groups according to the combined criteria of neuropathy using the World Health Organization-CIPN criteria and Common Terminology Criteria for Adverse Events version 5.0. As secondary endpoints, we will compare adverse events, patient-reported quality of life, and requirement of concomitant drugs for reducing CIPN between the two groups. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04201561.

A Prospective Randomized Study: The Usefulness and Efficacy of Negative Pressure Wound Therapy with Lipidocolloid Polyester Mesh Compared to Traditional Negative Pressure Wound Therapy for Treatment of Pressure Ulcers.

To improve healing of pressure ulcer wounds, it is important to optimize the conditions of the area surrounding the wound. Negative pressure wound therapy (NPWT) promotes wound healing, however, the removal of NPWT can cause pain or focal bleeding, delaying wound healing or causing infection. In this study, we reviewed the efficacy of the lipidocolloid non-adherent dressing (Urgotul®) as a wound contact layer. A total of 38 patients from the same facility who applied NPWT from April 2016 to October 2019 were included and divided into two groups; NPWT with the lipidocolloid non-adherent dressing (group 1, experimental group, 19 patients) and NPWT only (group 2, control group, 19 patients). The condition of the wound was examined prior to NPWT application, at one week, and again at three weeks after application. No significant differences were found between groups for general characteristics, bacterial culture or photo analysis. However, when comparing groups based on the time of examination, there was a significant reduction of the wound size in group 1 (p = 0.001) but not in group 2 (p = 0.082). Therefore, the current study finds that using the lipidocolloid non-adherent dressing as a wound contact layer in NPWT stimulates healing by shrinking the size of the pressure ulcer wound.

Selection of patients with ovarian cancer who may show survival benefit from hyperthermic intraperitoneal chemotherapy: A systematic review and meta-analysis.

BACKGROUND: The use of hyperthermic intraperitoneal chemotherapy (HIPEC) after cytoreductive surgery has been extensively studied in patients with peritoneal carcinomatosis from various malignancies. However, the effectiveness of HIPEC for ovarian cancer is still controversial. Therefore, we performed this meta-analysis to identify patients with ovarian cancer who can obtain survival benefit from HIPEC. METHODS: Articles regarding HIPEC in the MEDLINE, EMBASE, and Cochrane Library were searched till December 2018. In total, 13 case-control studies and two randomized controlled trials were included in this meta-analysis. We investigated the effect of HIPEC on disease-free survival (DFS) and overall survival (OS), and performed subgroup analyses based on the study design, adjustment of confounding variables, and quality of the study. RESULTS: HIPEC improved both DFS (hazard ratio [HR], 0.603; 95% confidence interval [CI], 0.513-0.709) and OS (HR, 0.640; 95% CI, 0.519-0.789). In cases of primary disease, HIPEC improved DFS (HR, 0.580; 95% CI, 0.476-0.706) and OS (HR, 0.611; 95% CI, 0.376-0.992). Subgroup analyses revealed that HIPEC did not improve OS but improved DFS of patients with residual tumors ≤1 cm or no visible tumors. In cases of recurrent disease, HIPEC was associated with better OS (HR, 0.566; 95% CI, 0.379-0.844) but not with DFS. Subgroup analyses also revealed similar tendencies. However, HIPEC improved DFS of patients with residual tumors ≤1 cm or no visible tumors, while it improved OS of only those with residual tumors ≤1 cm. CONCLUSIONS: HIPEC may improve DFS of patients with ovarian cancer when residual tumors were ≤1 cm or not visible. It may also improve OS of only patients with recurrent disease whose residual tumors were ≤1 cm.

Off-Target Effect of Sildenafil on Postsurgical Erectile Dysfunction: Alternate Pathways and Localized Delivery System.

INTRODUCTION: There is no consensus on the best oral phosphodiesterase type 5 inhibitor (PDE5I) for patients undergoing penile rehabilitation after surgical nerve injury. AIM: To determine the mechanism of PDE5I on cultured neuronal cells and the effectiveness of local drug delivery using nanospheres (NSPs) to sites of nerve injury in a rat model of bilateral cavernous nerve injury (BCNI). METHODS: The effects of sildenafil, tadalafil, and vardenafil on cyclic adenosine monophosphate, cyclic guanosine monophosphate, and cell survival after exposure to hypoxia and H2O2 were measured in PC12, SH-SY5Y, and NTERA-2 (NT2) cell cultures. The effects of phosphodiesterase type 4 inhibitor (PDE4I) and PDE5I on neuronal cell survival were evaluated. Male rats underwent BCNI and were untreated (BCNI), immediately treated with application of empty NSPs (BCNI + NSP), NSPs containing sildenafil (Sild + NSP), or NSPs containing rolipram (Rol + NSP). MAIN OUTCOME MEASURES: Viability of neuronal cells was measured. Intracavernous pressure changes after cavernous nerve electrostimulation and expression of neurofilament, nitric oxide synthase, and actin in mid-shaft of penis were analyzed 14 days after injury. RESULTS: Sildenafil and rolipram significantly decreased cell death after exposure to H2O2 and hypoxia in PC12, SH-SY5Y, and NT2 cells. PC12 cells did not express PDE5 and knockdown of PDE4 significantly increased cell viability in PC12, SH-SY5Y, and NT2 cells exposed to hypoxia. The ratio of intracavernous pressure to mean arterial pressure and expression of penile neurofilament, nitric oxide synthase, and actin were significantly higher in the Sild + NSP and Rol + NSP groups than in the BCNI and BCNI + NSP groups. Limitations included analysis in only two PDE families using only a single dose. CONCLUSION: Sildenafil showed the most profound neuroprotective effect compared with tadalafil and vardenafil. Sildenafil- or rolipram-loaded NSP delivery to the site of nerve injury prevented erectile dysfunction and led to increased neurofilament, nitric oxide synthase, smooth muscle content in rat penile tissue after BCNI.

A traditional herbal medication, Maekmoondong-tang, for cough: A systematic review and meta-analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Maekmoondong-tang (MMDT) is a traditional herbal medication widely used to improve cough in Korea, Japan, and China. It is composed of six herbs (Ophiopogonis Tuber, Pinelliae Tuber, Glycyrrhizae Radix, Zizyphi Fructus, Ginseng Radix, and Oryzae Semen). AIM OF THE STUDY: This study is aimed to systematically review the relevant randomised controlled trials (RCTs) to determine the effectiveness and safety of MMDT for cough. MATERIALS AND METHODS: Electronic and hand-searching of 7 databases (Cochrane Library, MEDLINE, EMBASE, OASIS, RISS, CNKI and CiNii) was systematically conducted up to February 2015 for RCTs testing MMDT in patients with cough. The primary outcome was cough symptom improvement using cough diary, visual analog scale, or response rate. Risk of bias of the included trials was evaluated with the Cochrane risk of bias assessment tool. The dichotomous data were pooled to obtain a risk ratio (RR) of cough persisting after treatment, with 95% confidence intervals (CI). RESULTS: Nine RCTs involving 2453 participants were included. The methodological quality was largely poor for a majority of the studies. MMDT reduced the severity of cough by 74% compared with the conventional antitussive medications in various conditions (n=1145; RR of cough persisting after treatment=0.26; 95% CI, 0.19-0.34, I(2)=0%). The addition of MMDT to conventional medication in patients with postinfectious cough significantly alleviated symptoms up to day 5 but the effect was not maintained one week afterwards. For other diseases/conditions including chronic obstructive pulmonary disease, lung cancer surgery, and asthma, the evidence is inconsistent for MMDT/mMMDT for cough. Adverse events appear to be rare but the reporting was poor. CONCLUSIONS: The current evidence from our systematic review and meta-analysis on MMDT for cough is inconclusive and we propose that rigorously designed, placebo-controlled trials of MMDT should be conducted to establish its place in management of cough.

Proteasome inhibitors with pyrazole scaffolds from structure-based virtual screening.

We performed a virtual screen of ∼340 000 small molecules against the active site of proteasomes followed by in vitro assays and subsequent optimization, yielding a proteasome inhibitor with pyrazole scaffold. The pyrazole-scaffold compound displayed excellent metabolic stability and was highly effective in suppressing solid tumor growth in vivo. Furthermore, the effectiveness of this compound was not negatively impacted by resistance to bortezomib or carfilzomib.

Electromagnetic acupuncture to enhance the effects of manual acupuncture on recovery from muscle fatigue of the quadriceps.

The aim of this study was to investigate a new method of manual acupuncture that used a magnetic field to stimulate only one acupoint vertically. We developed an eight-channel electromagnetic acupuncture (EMA) system that uses a solenoid-type electrode to insert the manual acupuncture needle into a hole in an electrode. We used a manual acupuncture needle for magnetic induction in order to penetrate vertically and deeply into tissues. In order to confirm the usefulness of EMA, we investigated the effects of treatment on muscle fatigue after strenuous knee extension/flexion exercises that had been performed by three groups: the nonstimulation, the manual acupuncture, and the EMA groups. Electromyograms showed that the median frequency (MF) in the EMA group had rapidly recovered after 4 minutes (p = 0.608), but that the peak torque had not recovered to the normal state (p < 0.05). Thus, we confirmed that compared with manual acupuncture, EMA resulted in better recovery from muscle fatigue.

Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening.

As a major component of the crucial nonlysosomal protein degradation pathway in the cells, the proteasome has been implicated in many diseases such as Alzheimer's disease, Huntington's disease, inflammatory bowel diseases, autoimmune diseases, multiple myeloma (MM) and other cancers. There are two main proteasome subtypes: the constitutive proteasome which is expressed in all eukaryotic cells and the immunoproteasome which is expressed in immune cells and can be induced in other cell types. Majority of currently available proteasome inhibitors are peptide backbone-based, having short half-lives in the body. It is highly desirable to identify novel, immunoproteasome-selective inhibitors with non-peptide scaffolds for development of novel therapeutics. Through combined virtual screening and experimental studies targeting the immunoproteasome, we have identified a set of novel immunoproteasome inhibitors with diverse non-peptide scaffolds. Some of the identified inhibitors have significant selectivity for the immunoproteasome over the constitutive proteasome. Unlike most of the currently available proteasome inhibitors, these new inhibitors lacking electrophilic pharmacophores are not expected to form a covalent bond with proteasome after the binding. These non-peptide scaffolds may provide a new platform for future rational drug design and discovery targeting the immunoproteasome.

Use of pupil size to determine the effect of electromagnetic acupuncture on activation level of the autonomic nervous system.

Magnetic fields are widely considered as a method of treatment to increase the therapeutic effect when applied to acupoints. Hence, this study proposes a new method which creates significant stimulation of acupoints by using weak magnetic fields. We conducted this experiment in order to confirm the effect on the activation level of the autonomic nervous system by measuring pupil sizes in cases of stimulation by using manual acupuncture and electromagnetic acupuncture (EMA) at BL15. We selected 30 Hz of biphasic wave form with 570.1 Gauss. To confirm the biopotential by the magnetic flux density occurring in EMA that affected the activation of the autonomic nervous system, we observed the biopotential induced at the upper and the mid left and right trapezius. We observed a significant decrease in pupil size only in the EMA group (p < 0.05), thus confirming that EMA decreased the pupil size through activation of the parasympathetic nerve in the autonomic nervous system. Moreover, we confirmed that the amplitude of the biopotential which was caused by 570.1 Gauss was higher than ±20 µA. Thus, we can conclude that EMA treatment successfully activates the parasympathetic nerve in the autonomic nervous system by inducing a biotransformation by the induced biopotential.

Development and evaluation of a multi-frequency bioelectrical impedance analysis analyzer for estimating acupoint composition.

The purpose of this study was to suggest a new method of estimating acupoint compositions by using a multi-frequency bioelectrical impedance analysis (MF-BIA) method at 5 kHz, 50 kHz and 200 kHz within 2 cm of acupoints divided into local segments. To verify the system developed, we confirmed the stable occurrence of a constant current at every frequency, regardless of the impedance connected to the electrodes. Moreover, we found left and right distal bicep brachii aponeurosis to be identical by using ultrasound imaging, and we analyzed the repeatability of the findings by making 10 consecutive sets of measurements (p > 0.05). To evaluate the practical use of the acupoint composition, we used the MF-BIA analyzer to measure the left and right LU3, LU4, and LU9 at the lung meridian. We confirmed that the potentials generated were equal to the changes in the cell membrane function, which were caused by the applied frequency (p < 0.01). We also verified that the MF-BIA analyzer measurements corresponded to the acupoint components by comparing the left and right potentials generated (p > 0.05). Hence, we conclude that the MF-BIA analyzer can be used to estimate the acupoint composition based on the acupoint state.

Comparison of 2 methods of non-invasive treatment between transcutaneous electrical stimulation and pulsed electromagnetic field stimulation as replacement of invasive manual acupuncture.

The aim of this study was to find the non-invasive optimal alternative method for Manual Acupuncture. Existing researches had reported that Transcutaneous Electrical Acupoint Stimulation (TEAS) was an effective treatment method instead of manual acupuncture. In place of the TEAS, we suggested the Pulsed Electromagnetic Fields (PEMFs). Thus, we designed the PEMFs system which can stimulate only an acupoint. There have been no researches which reported therapeutic effect when stimulating at an identical acupoint by TEAS and PEMFs. Hence, this study investigated the therapeutic effect on the muscle fatigue after the strenuous knee extension/flexion exercise by two stimulations. We selected the stimulation method of both TEAS and PEMFs by using 2Hz biphasic rectangular wave pulse and pulse width 0.2ms. The magnetic flux was the 30.92mT (309.2gauss) at 2 Hz. The electromyogram (EMG) and the maximal voluntary contraction (MVC) at rectus femoris were measured. The Median Frequency (MF) at TEAS group was significantly effective at 6 minutes (p=0.499). The PEMFs group was recovered to the MF rapidly after 4 minutes (p=0.166). The results of the peak torque indicated that both non-stimulation group and TEAS group did not recover to the peak torque at pre-exercise during the recovery period (p<0.05). In contrast, the significant treatment effect of PEMFs group was found after 14 minutes (p=0.135). The results of this study demonstrated that PEMFs were better than TEAS as a non-invasive method to replace the manual acupuncture.